Pharmaceutics

17 pages, 2401 KiB

Open AccessEditor’s ChoiceArticle

Sample Size Requirements of a Pharmaceutical Material Library: A Case in Predicting Direct Compression Tablet Tensile Strength by Latent Variable Modeling

by Junjie Cao, Haoran Shen, Shuying Zhao, Xiao Ma, Liping Chen, Shengyun Dai, Bing Xu and Yanjiang Qiao

Pharmaceutics 2024, 16(2), 242; https://doi.org/10.3390/pharmaceutics16020242 - 7 Feb 2024

Viewed by 1542

Abstract

The material library is an emerging, new data-driven approach for developing pharmaceutical process models. How many materials or samples should be involved in a particular application scenario is unclear, and the impact of sample size on process modeling is worth discussing. In this [...] Read more.

The material library is an emerging, new data-driven approach for developing pharmaceutical process models. How many materials or samples should be involved in a particular application scenario is unclear, and the impact of sample size on process modeling is worth discussing. In this work, the direct compression process was taken as the research object, and the effects of different sample sizes of material libraries on partial least squares (PLS) modeling in the prediction of tablet tensile strength were investigated. A primary material library comprising 45 materials was built. Then, material subsets containing 5 × i (i = 1, 2, 3, …, 8) materials were sampled from the primary material library. Each subset underwent sampling 1000 times to analyze variations in model fitting performance. Both hierarchical sampling and random sampling were employed and compared, with hierarchical sampling implemented with the help of the tabletability classification index d. For each subset, modeling data were organized, incorporating 18 physical properties and tableting pressure as the independent variables and tablet tensile strength as the dependent variable. A series of chemometric indicators was used to assess model performance and find important materials for model training. It was found that the minimum R² and RMSE values reached their maximum, and the corresponding values were kept almost unchanged when the sample sizes varied from 20 to 45. When the sample size was smaller than 15, the hierarchical sampling method was more reliable in avoiding low-quality few-shot PLS models than the random sampling method. Two important materials were identified as useful for building an initial material library. Overall, this work demonstrated that as the number of materials increased, the model’s reliability improved. It also highlighted the potential for effective few-shot modeling on a small material library by controlling its information richness. Full article

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16 pages, 13973 KiB

Open AccessEditor’s ChoiceArticle

3D Printing of Biodegradable Polymeric Microneedles for Transdermal Drug Delivery Applications

by Faisal Khaled Aldawood, Santosh Kumar Parupelli, Abhay Andar and Salil Desai

Pharmaceutics 2024, 16(2), 237; https://doi.org/10.3390/pharmaceutics16020237 - 6 Feb 2024

Cited by 6 | Viewed by 2645

Abstract

Microneedle (MN) technology is an optimal choice for the delivery of drugs via the transdermal route, with a minimally invasive procedure. MN applications are varied from drug delivery, cosmetics, tissue engineering, vaccine delivery, and disease diagnostics. The MN is a biomedical device that [...] Read more.

Microneedle (MN) technology is an optimal choice for the delivery of drugs via the transdermal route, with a minimally invasive procedure. MN applications are varied from drug delivery, cosmetics, tissue engineering, vaccine delivery, and disease diagnostics. The MN is a biomedical device that offers many advantages including but not limited to a painless experience, being time-effective, and real-time sensing. This research implements additive manufacturing (AM) technology to fabricate MN arrays for advanced therapeutic applications. Stereolithography (SLA) was used to fabricate six MN designs with three aspect ratios. The MN array included conical-shaped 100 needles (10 × 10 needle) in each array. The microneedles were characterized using optical and scanning electron microscopy to evaluate the dimensional accuracy. Further, mechanical and insertion tests were performed to analyze the mechanical strength and skin penetration capabilities of the polymeric MN. MNs with higher aspect ratios had higher deformation characteristics suitable for penetration to deeper levels beyond the stratum corneum. MNs with both 0.3 mm and 0.4 mm base diameters displayed consistent force–displacement behavior during a skin-equivalent penetration test. This research establishes guidelines for fabricating polymeric MN for high-accuracy and low-cost 3D printing. Full article

(This article belongs to the Special Issue 3D Printing Technology for Pharmaceutical and Biomedical Application)

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36 pages, 1088 KiB

Open AccessEditor’s ChoiceReview

New and Emerging Oral/Topical Small-Molecule Treatments for Psoriasis

by Elena Carmona-Rocha, Lluís Rusiñol and Lluís Puig

Pharmaceutics 2024, 16(2), 239; https://doi.org/10.3390/pharmaceutics16020239 - 6 Feb 2024

Cited by 6 | Viewed by 5858

Abstract

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research [...] Read more.

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on the development of oral therapies with improved efficacy and safety compared with available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate to severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways such as AhR, PDE-4, and Jak-STAT. Tapinarof (an AhR modulator) and roflumilast (a PDE-4 inhibitor) have exhibited favorable efficacy and safety outcomes and have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis, especially those that are currently under evaluation and development for the treatment of psoriasis. Full article

(This article belongs to the Special Issue Current and Emerging Biological and Oral/Topical Small-Molecule Treatments for Psoriasis)

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32 pages, 2501 KiB

Open AccessEditor’s ChoiceReview

Peptide-Mediated Nanocarriers for Targeted Drug Delivery: Developments and Strategies

by Yubo Wang, Lu Zhang, Chen Liu, Yiming Luo and Dengyue Chen

Pharmaceutics 2024, 16(2), 240; https://doi.org/10.3390/pharmaceutics16020240 - 6 Feb 2024

Viewed by 2930

Abstract

Effective drug delivery is essential for cancer treatment. Drug delivery systems, which can be tailored to targeted transport and integrated tumor therapy, are vital in improving the efficiency of cancer treatment. Peptides play a significant role in various biological and physiological functions and [...] Read more.

Effective drug delivery is essential for cancer treatment. Drug delivery systems, which can be tailored to targeted transport and integrated tumor therapy, are vital in improving the efficiency of cancer treatment. Peptides play a significant role in various biological and physiological functions and offer high design flexibility, excellent biocompatibility, adjustable morphology, and biodegradability, making them promising candidates for drug delivery. This paper reviews peptide-mediated drug delivery systems, focusing on self-assembled peptides and peptide–drug conjugates. It discusses the mechanisms and structural control of self-assembled peptides, the varieties and roles of peptide–drug conjugates, and strategies to augment peptide stability. The review concludes by addressing challenges and future directions. Full article

(This article belongs to the Special Issue Nanosystems for Drug Delivery)

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19 pages, 4570 KiB

Open AccessEditor’s ChoiceArticle

Rutin/Sulfobutylether-β-Cyclodextrin as a Promising Therapeutic Formulation for Ocular Infection

by Federica De Gaetano, Martina Pastorello, Venerando Pistarà, Antonio Rescifina, Fatima Margani, Vincenzina Barbera, Cinzia Anna Ventura and Andreana Marino

Pharmaceutics 2024, 16(2), 233; https://doi.org/10.3390/pharmaceutics16020233 - 5 Feb 2024

Cited by 1 | Viewed by 1532

Abstract

Ocular pathologies present significant challenges to achieving effective therapeutic results due to various anatomical and physiological barriers. Natural products such as flavonoids, alone or in association with allopathic drugs, present many therapeutic actions including anticancer, anti-inflammatory, and antibacterial action. However, their clinical employment [...] Read more.

Ocular pathologies present significant challenges to achieving effective therapeutic results due to various anatomical and physiological barriers. Natural products such as flavonoids, alone or in association with allopathic drugs, present many therapeutic actions including anticancer, anti-inflammatory, and antibacterial action. However, their clinical employment is challenging for scientists due to their low water solubility. In this study, we designed a liquid formulation based on rutin/sulfobutylether-β-cyclodextrin (RTN/SBE-β-CD) inclusion complex for treating ocular infections. The correct stoichiometry and the accurate binding constant were determined by employing SupraFit software (2.5.120) in the UV-vis titration experiment. A deep physical–chemical characterization of the RTN/SBE-β-CD inclusion complex was also performed; it confirmed the predominant formation of a stable complex (K_c, 9660 M⁻¹) in a 1:1 molar ratio, with high water solubility that was 20 times (2.5 mg/mL) higher than the free molecule (0.125 mg/mL), permitting the dissolution of the solid complex within 30 min. NMR studies revealed the involvement of the bicyclic flavonoid moiety in the complexation, which was also confirmed by molecular modeling studies. In vitro, the antibacterial and antibiofilm activity of the formulation was assayed against Staphylococcus aureus and Pseudomonas aeruginosa strains. The results demonstrated a significant activity of the formulation than that of the free molecules. Full article

(This article belongs to the Topic New Challenges in Ocular Drug Delivery)

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29 pages, 3835 KiB

Open AccessEditor’s ChoiceArticle

Simultaneously Predicting the Pharmacokinetics of CES1-Metabolized Drugs and Their Metabolites Using Physiologically Based Pharmacokinetic Model in Cirrhosis Subjects

by Xin Luo, Zexin Zhang, Ruijing Mu, Guangyu Hu, Li Liu and Xiaodong Liu

Pharmaceutics 2024, 16(2), 234; https://doi.org/10.3390/pharmaceutics16020234 - 5 Feb 2024

Viewed by 1763

Abstract

Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. [...] Read more.

Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. Six prodrugs (enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. Parameters such as organ blood flows, plasma-binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate (GFR) and gastrointestinal transit rate were integrated into the simulation. The pharmacokinetic profiles of these drugs and their active metabolites were simulated for 1000 virtual individuals. The developed semi-PBPK model, after validation in healthy individuals, was extrapolated to LC patients. Most of the observations fell within the 5th and 95th percentiles of simulations from 1000 virtual patients. The estimated AUC and C_max were within 0.5–2-fold of the observed values. The sensitivity analysis showed that the decreased plasma exposure of active metabolites due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model successfully predicted the pharmacokinetics of CES1 substrates and their metabolites in healthy individuals and LC patients, facilitating tailored dosing of CES1 substrates in LC patients. Full article

(This article belongs to the Special Issue Formulation Strategies to Optimize Drug Pharmacokinetics and Improve Therapeutic Outcomes)

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22 pages, 8785 KiB

Open AccessEditor’s ChoiceArticle

Development of Biotinylated Liposomes Encapsulating Metformin for Therapeutic Targeting of Inflammation-Based Diseases

by Giorgia Ailuno, Sara Baldassari, Alice Balboni, Sara Pastorino, Guendalina Zuccari, Katia Cortese, Federica Barbieri, Giuliana Drava, Tullio Florio and Gabriele Caviglioli

Pharmaceutics 2024, 16(2), 235; https://doi.org/10.3390/pharmaceutics16020235 - 5 Feb 2024

Cited by 2 | Viewed by 1639

Abstract

Inflammation is a physiological response to a damaging stimulus but sometimes can be the cause of the onset of neurodegenerative diseases, atherosclerosis, and cancer. These pathologies are characterized by the overexpression of inflammatory markers like endothelial adhesion molecules, such as Vascular Cell Adhesion [...] Read more.

Inflammation is a physiological response to a damaging stimulus but sometimes can be the cause of the onset of neurodegenerative diseases, atherosclerosis, and cancer. These pathologies are characterized by the overexpression of inflammatory markers like endothelial adhesion molecules, such as Vascular Cell Adhesion Molecule-1 (VCAM-1). In the present work, the development of liposomes for therapeutic targeted delivery to inflamed endothelia is described. The idea is to exploit a three-step pretargeting system based on the biotin–avidin high-affinity interaction: the first step involves a previously described biotin derivative bearing a VCAM-1 binding peptide; in the second step, the avidin derivative NeutrAvidin^TM, which strongly binds to the biotin moiety, is injected; the final step is the administration of biotinylated liposomes that would bind to Neutravidin^TM immobilized onto VCAM-1 overexpressing endothelium. Stealth biotinylated liposomes, prepared via the thin film hydration method followed by extrusion and purification via size exclusion chromatography, have been thoroughly characterized for their chemico-physical and morphological features and loaded with metformin hydrochloride, a potential anti-inflammatory agent. The three-step system, tested in vitro on different cell lines via confocal microscopy, FACS analysis and metformin uptake, has proved its suitability for therapeutic applications. Full article

(This article belongs to the Special Issue Novel Technological Approaches for Targeted Drug Delivery Systems)

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28 pages, 10382 KiB

Open AccessEditor’s ChoiceReview

Niosomes: Composition, Formulation Techniques, and Recent Progress as Delivery Systems in Cancer Therapy

by Sergio Liga, Cristina Paul, Elena-Alina Moacă and Francisc Péter

Pharmaceutics 2024, 16(2), 223; https://doi.org/10.3390/pharmaceutics16020223 - 4 Feb 2024

Cited by 14 | Viewed by 7257

Abstract

Niosomes are vesicular nanocarriers, biodegradable, relatively non-toxic, stable, and inexpensive, that provide an alternative for lipid-solid carriers (e.g., liposomes). Niosomes may resolve issues related to the instability, fast degradation, bioavailability, and insolubility of different drugs or natural compounds. Niosomes can be very efficient [...] Read more.

Niosomes are vesicular nanocarriers, biodegradable, relatively non-toxic, stable, and inexpensive, that provide an alternative for lipid-solid carriers (e.g., liposomes). Niosomes may resolve issues related to the instability, fast degradation, bioavailability, and insolubility of different drugs or natural compounds. Niosomes can be very efficient potential systems for the specific delivery of anticancer, antioxidant, anti-inflammatory, antimicrobial, and antibacterial molecules. This review aims to present an overview of their composition, the most common formulation techniques, as well as of recent utilizations as delivery systems in cancer therapy. Full article

(This article belongs to the Special Issue Recent Advances in Carriers for Drug Delivery: From Structures to Functionality)

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25 pages, 27127 KiB

Open AccessEditor’s ChoiceArticle

Nanogallium-poly(L-lactide) Composites with Contact Antibacterial Action

by Mario Kurtjak, Marjeta Maček Kržmanc, Matjaž Spreitzer and Marija Vukomanović

Pharmaceutics 2024, 16(2), 228; https://doi.org/10.3390/pharmaceutics16020228 - 4 Feb 2024

Viewed by 4033

Abstract

In diverse biomedical and other applications of polylactide (PLA), its bacterial contamination and colonization are unwanted. For this reason, this biodegradable polymer is often combined with antibacterial agents or fillers. Here, we present a new solution of this kind. Through the process of [...] Read more.

In diverse biomedical and other applications of polylactide (PLA), its bacterial contamination and colonization are unwanted. For this reason, this biodegradable polymer is often combined with antibacterial agents or fillers. Here, we present a new solution of this kind. Through the process of simple solvent casting, we developed homogeneous composite films from 28 ± 5 nm oleic-acid-capped gallium nanoparticles (Ga NPs) and poly(L-lactide) and characterized their detailed morphology, crystallinity, aqueous wettability, optical and thermal properties. The addition of Ga NPs decreased the ultraviolet transparency of the films, increased their hydrophobicity, and enhanced the PLA structural ordering during solvent casting. Albeit, above the glass transition, there is an interplay of heterogeneous nucleation and retarded chain mobility through interfacial interactions. The gallium content varied from 0.08 to 2.4 weight %, and films with at least 0.8% Ga inhibited the growth of Pseudomonas aeruginosa PAO1 in contact, while 2.4% Ga enhanced the effect of the films to be bactericidal. This contact action was a result of unwrapping the top film layer under biological conditions and the consequent bacterial contact with the exposed Ga NPs on the surface. All the tested films showed good cytocompatibility with human HaCaT keratinocytes and enabled the adhesion and growth of these skin cells on their surfaces when coated with poly(L-lysine). These properties make the nanogallium-polyl(L-lactide) composite a promising new polymer-based material worthy of further investigation and development for biomedical and pharmaceutical applications. Full article

(This article belongs to the Special Issue Biopolymers for Biomedical and Pharmaceutical Applications)

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26 pages, 2763 KiB

Open AccessEditor’s ChoiceReview

Recent Technological and Intellectual Property Trends in Antibody–Drug Conjugate Research

by Youngbo Choi, Youbeen Choi and Surin Hong

Pharmaceutics 2024, 16(2), 221; https://doi.org/10.3390/pharmaceutics16020221 - 3 Feb 2024

Cited by 2 | Viewed by 4746

Abstract

Antibody–drug conjugate (ADC) therapy, an advanced therapeutic technology comprising antibodies, chemical linkers, and cytotoxic payloads, addresses the limitations of traditional chemotherapy. This study explores key elements of ADC therapy, focusing on antibody development, linker design, and cytotoxic payload delivery. The global rise in [...] Read more.

Antibody–drug conjugate (ADC) therapy, an advanced therapeutic technology comprising antibodies, chemical linkers, and cytotoxic payloads, addresses the limitations of traditional chemotherapy. This study explores key elements of ADC therapy, focusing on antibody development, linker design, and cytotoxic payload delivery. The global rise in cancer incidence has driven increased investment in anticancer agents, resulting in significant growth in the ADC therapy market. Over the past two decades, notable progress has been made, with approvals for 14 ADC treatments targeting various cancers by 2022. Diverse ADC therapies for hematologic malignancies and solid tumors have emerged, with numerous candidates currently undergoing clinical trials. Recent years have seen a noteworthy increase in ADC therapy clinical trials, marked by the initiation of numerous new therapies in 2022. Research and development, coupled with patent applications, have intensified, notably from major companies like Pfizer Inc. (New York, NY, USA), AbbVie Pharmaceuticals Inc. (USA), Regeneron Pharmaceuticals Inc. (Tarrytown, NY, USA), and Seagen Inc. (Bothell, WA, USA). While ADC therapy holds great promise in anticancer treatment, challenges persist, including premature payload release and immune-related side effects. Ongoing research and innovation are crucial for advancing ADC therapy. Future developments may include novel conjugation methods, stable linker designs, efficient payload delivery technologies, and integration with nanotechnology, driving the evolution of ADC therapy in anticancer treatment. Full article

(This article belongs to the Special Issue Nano Drug Delivery System, 2nd Edition)

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16 pages, 3187 KiB

Open AccessEditor’s ChoiceArticle

Development of Ciprofloxacin-Loaded Electrospun Yarns of Application Interest as Antimicrobial Surgical Suture Materials

by Jorge Teno, Maria Pardo-Figuerez, Zoran Evtoski, Cristina Prieto, Luis Cabedo and Jose M. Lagaron

Pharmaceutics 2024, 16(2), 220; https://doi.org/10.3390/pharmaceutics16020220 - 3 Feb 2024

Cited by 2 | Viewed by 1813

Abstract

Surgical site infections (SSI) occur very frequently during post-operative procedures and are often treated with oral antibiotics, which may cause some side effects. This type of infection could be avoided by encapsulating antimicrobial/anti-inflammatory drugs within the surgical suture materials so that they can [...] Read more.

Surgical site infections (SSI) occur very frequently during post-operative procedures and are often treated with oral antibiotics, which may cause some side effects. This type of infection could be avoided by encapsulating antimicrobial/anti-inflammatory drugs within the surgical suture materials so that they can more efficiently act on the site of action during wound closure, avoiding post-operative bacterial infection and spreading. This work was aimed at developing novel electrospun bio-based anti-infective fibre-based yarns as novel suture materials for preventing surgical site infections. For this, yarns based on flying intertwined microfibres (1.95 ± 0.22 µm) were fabricated in situ during the electrospinning process using a specially designed yarn collector. The electrospun yarn sutures (diameter 300–500 µm) were made of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with different contents of 3HV units and contained ciprofloxacin hydrochloride (CPX) as the antimicrobial active pharmaceutical ingredient (API). The yarns were then analysed by scanning electron microscopy, Fourier transform infrared spectroscopy, wide-angle X-ray scattering, differential scanning calorimetry, and in vitro drug release. The yarns were also analysed in terms of antimicrobial and mechanical properties. The material characterization indicated that the varying polymer molecular architecture affected the attained polymer crystallinity, which was correlated with the different drug-eluting profiles. Moreover, the materials exhibited the inherent stiff behaviour of PHBV, which was further enhanced by the API. Lastly, all the yarn sutures presented antimicrobial properties for a time release of 5 days against both Gram-positive and Gram-negative pathogenic bacteria. The results highlight the potential of the developed antimicrobial electrospun yarns in this study as potential innovative suture materials to prevent surgical infections. Full article

(This article belongs to the Special Issue Novel Technologies for Buccal and Transdermal Drug Delivery)

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22 pages, 7119 KiB

Open AccessEditor’s ChoiceReview

Delivery Strategies for Colchicine as a Critical Dose Drug: Reducing Toxicity and Enhancing Efficacy

by Yaran Lei, Yulu Yang, Guobao Yang, Ao Li, Yang Yang, Yuli Wang and Chunsheng Gao

Pharmaceutics 2024, 16(2), 222; https://doi.org/10.3390/pharmaceutics16020222 - 3 Feb 2024

Cited by 3 | Viewed by 2519

Abstract

Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, [...] Read more.

Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, injection, and oral drug delivery are the three main delivery strategies for COL. This article elaborates on the research progress of different delivery strategies in terms of toxicity reduction and efficacy enhancement, depicting that the transdermal drug delivery route can avoid the first-pass effect and the traumatic pain associated with the oral and injection routes, respectively. Therefore, such a dosage form holds a significant promise that requires the development of further research to investigate effective COL delivery formulations. In addition, the permeation-promoting technologies utilized for transdermal drug delivery systems are briefly discussed. This article is expected to provide scientific ideas and theoretical guidance for future research and the exploration of COL delivery strategies. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems of Phytomedicines)

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17 pages, 2732 KiB

Open AccessEditor’s ChoiceReview

The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

by Miklós Bege and Anikó Borbás

Pharmaceutics 2024, 16(2), 217; https://doi.org/10.3390/pharmaceutics16020217 - 2 Feb 2024

Cited by 8 | Viewed by 4345

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms [...] Read more.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is Paxlovid^TM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (M^pro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed. Full article

(This article belongs to the Special Issue Recent Advances in Prevention and Treatment of Infectious Diseases)

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25 pages, 5714 KiB

Open AccessEditor’s ChoiceReview

Versatile Peptide-Based Nanosystems for Photodynamic Therapy

by Qiuyan Li, Ruiqi Ming, Lili Huang and Ruoyu Zhang

Pharmaceutics 2024, 16(2), 218; https://doi.org/10.3390/pharmaceutics16020218 - 2 Feb 2024

Cited by 18 | Viewed by 2199

Abstract

Photodynamic therapy (PDT) has become an important therapeutic strategy because it is highly controllable, effective, and does not cause drug resistance. Moreover, precise delivery of photosensitizers to tumor lesions can greatly reduce the amount of drug administered and optimize therapeutic outcomes. As alternatives [...] Read more.

Photodynamic therapy (PDT) has become an important therapeutic strategy because it is highly controllable, effective, and does not cause drug resistance. Moreover, precise delivery of photosensitizers to tumor lesions can greatly reduce the amount of drug administered and optimize therapeutic outcomes. As alternatives to protein antibodies, peptides have been applied as useful targeting ligands for targeted biomedical imaging, drug delivery and PDT. In addition, other functionalities of peptides such as stimuli responsiveness, self-assembly, and therapeutic activity can be integrated with photosensitizers to yield versatile peptide-based nanosystems for PDT. In this article, we start with a brief introduction to PDT and peptide-based nanosystems, followed by more detailed descriptions about the structure, property, and architecture of peptides as background information. Finally, the most recent advances in peptide-based nanosystems for PDT are emphasized and summarized according to the functionalities of peptide in the system to reveal the design and development principle in different therapeutic circumstances. We hope this review could provide useful insights and valuable reference for the development of peptide-based nanosystems for PDT. Full article

(This article belongs to the Special Issue Advances in Cancer Nanotechnology for Photodynamic and Photothermal Therapy)

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14 pages, 5326 KiB

Open AccessEditor’s ChoiceArticle

Piperacillin/Tazobactam Co-Delivery by Micellar Ionic Conjugate Systems Carrying Pharmaceutical Anions and Encapsulated Drug

by Katarzyna Niesyto, Aleksy Mazur and Dorota Neugebauer

Pharmaceutics 2024, 16(2), 198; https://doi.org/10.3390/pharmaceutics16020198 - 30 Jan 2024

Cited by 3 | Viewed by 1326

Abstract

Previously obtained amphiphilic graft copolymers based on [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA) ionic liquid were used as the matrices of three types of nanocarriers, i.e., conjugates with ionic piperacillin (PIP) and micelles with tazobactam (TAZ), which represented single systems, and dual systems bearing PIP anions [...] Read more.

Previously obtained amphiphilic graft copolymers based on [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA) ionic liquid were used as the matrices of three types of nanocarriers, i.e., conjugates with ionic piperacillin (PIP) and micelles with tazobactam (TAZ), which represented single systems, and dual systems bearing PIP anions and encapsulated TAZ for co-delivery. The exchange of Cl anions in TMAMA units with PIP ones resulted in a yield of 45.6–72.7 mol.%. The self-assembling properties were confirmed by the critical micelle concentration (CMC), which, after ion exchange, increased significantly (from 0.011–0.020 mg/mL to 0.041–0.073 mg/mL). The amphiphilic properties were beneficial for TAZ encapsulation to reach drug loading contents (DLCs) in the ranges of 37.2–69.5 mol.% and 50.4–80.4 mol.% and to form particles with sizes of 97–319 nm and 24–192 nm in the single and dual systems, respectively. In vitro studies indicated that the ionically conjugated drug (PIP) was released in quantities of 66–81% (7.8–15.0 μg/mL) from single-drug systems and 21–25% (2.6–3.9 μg/mL) from dual-drug systems. The release of encapsulated TAZ was more efficient, achieving 47–98% (7.5–9.0 μg/mL) release from the single systems and 47–69% (9.6–10.4 μg/mL) release from the dual ones. Basic cytotoxicity studies showed non-toxicity of the polymer matrices, while the introduction of the selected drugs induced cytotoxicity against normal human bronchial epithelial cells (BEAS-2B) with the increase in concentration. Full article

(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications, 2nd Edition)

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34 pages, 2610 KiB

Open AccessEditor’s ChoiceReview

Exploring Amino Acid Transporters as Therapeutic Targets for Cancer: An Examination of Inhibitor Structures, Selectivity Issues, and Discovery Approaches

by Sebastian Jakobsen and Carsten Uhd Nielsen

Pharmaceutics 2024, 16(2), 197; https://doi.org/10.3390/pharmaceutics16020197 - 30 Jan 2024

Cited by 3 | Viewed by 3085

Abstract

Amino acid transporters are abundant amongst the solute carrier family and have an important role in facilitating the transfer of amino acids across cell membranes. Because of their impact on cell nutrient distribution, they also appear to have an important role in the [...] Read more.

Amino acid transporters are abundant amongst the solute carrier family and have an important role in facilitating the transfer of amino acids across cell membranes. Because of their impact on cell nutrient distribution, they also appear to have an important role in the growth and development of cancer. Naturally, this has made amino acid transporters a novel target of interest for the development of new anticancer drugs. Many attempts have been made to develop inhibitors of amino acid transporters to slow down cancer cell growth, and some have even reached clinical trials. The purpose of this review is to help organize the available information on the efforts to discover amino acid transporter inhibitors by focusing on the amino acid transporters ASCT2 (SLC1A5), LAT1 (SLC7A5), xCT (SLC7A11), SNAT1 (SLC38A1), SNAT2 (SLC38A2), and PAT1 (SLC36A1). We discuss the function of the transporters, their implication in cancer, their known inhibitors, issues regarding selective inhibitors, and the efforts and strategies of discovering inhibitors. The goal is to encourage researchers to continue the search and development within the field of cancer treatment research targeting amino acid transporters. Full article

(This article belongs to the Special Issue Emerging Anti-cancer and Cellular Targets and Their Mechanism(s) of Action as New Tools for Therapeutics Approaches)

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13 pages, 2160 KiB

Open AccessEditor’s ChoiceArticle

Designing Advanced Drug Delivery Systems: Core-Shell Alginate Particles through Electro-Fluid Dynamic Atomization

by Iriczalli Cruz-Maya, Carmine Schiavone, Rosalia Ferraro, Nergis Zeynep Renkler, Sergio Caserta and Vincenzo Guarino

Pharmaceutics 2024, 16(2), 193; https://doi.org/10.3390/pharmaceutics16020193 - 29 Jan 2024

Cited by 1 | Viewed by 1702

Abstract

Innovations in drug delivery systems are crucial for enhancing therapeutic efficiency. Our research presents a novel approach based on using electro-fluid dynamic atomization (EFDA) to fabricate core-shell monophasic particles (CSMp) from sodium alginate blends of varying molecular weights. This study explores the morphological [...] Read more.

Innovations in drug delivery systems are crucial for enhancing therapeutic efficiency. Our research presents a novel approach based on using electro-fluid dynamic atomization (EFDA) to fabricate core-shell monophasic particles (CSMp) from sodium alginate blends of varying molecular weights. This study explores the morphological characteristics of these particles in relation to material properties and process conditions, highlighting their potential in drug delivery applications. A key aspect of our work is the development of a mathematical model that simulates the release kinetics of small molecules, specifically sodium diclofenac. By assessing the diffusion properties of different molecules and gel formulations through transport and rheological models, we have created a predictive tool for evaluating the efficiency of these particles in drug delivery. Our findings underscore two critical, independent parameters for optimizing drug release: the external shell thickness and the diffusivity ratios within the dual layers. This allows for precise control over the timing and intensity of the release profile. This study advances our understanding of EFDA in the fabrication of CSMp and offers promising avenues for enhancing drug delivery systems by tailoring release profiles through particle characteristic manipulation. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy, 2nd Edition)

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10 pages, 1221 KiB

Open AccessEditor’s ChoiceArticle

In Vivo Deposition of High-Flow Nasal Aerosols Using Breath-Enhanced Nebulization

by Jeyanthan Jayakumaran and Gerald C. Smaldone

Pharmaceutics 2024, 16(2), 182; https://doi.org/10.3390/pharmaceutics16020182 - 28 Jan 2024

Cited by 1 | Viewed by 1126

Abstract

Aerosol delivery using conventional nebulizers with fixed maximal output rates is limited and unpredictable under high-flow conditions. This study measured regulated aerosol delivery to the lungs of normal volunteers using a nebulizer designed to overcome the limitations of HFNC therapy (i-AIRE (InspiRx, [...] Read more.

Aerosol delivery using conventional nebulizers with fixed maximal output rates is limited and unpredictable under high-flow conditions. This study measured regulated aerosol delivery to the lungs of normal volunteers using a nebulizer designed to overcome the limitations of HFNC therapy (i-AIRE (InspiRx, Inc., Somerset, NJ, USA)). This breath-enhanced jet nebulizer, in series with the high-flow catheter, utilizes the high flow to increase aerosol output beyond those of conventional devices. Nine normal subjects breathing tidally via the nose received humidified air at 60 L/min. The nebulizer was connected to the HFNC system upstream to the humidifier and received radio-labeled saline as a marker for drug delivery (^99mTc DTPA) infused by a syringe pump (mCi/min). The dose to the subject was regulated at 12, 20 and 50 mL/h. Rates of aerosol deposition in the lungs (µCi/min) were measured via a gamma camera for each infusion rate and converted to µg NaCl/min. The deposition rate, as expressed as µg of NaCl/min, was closely related to the infusion rate: 7.84 ± 3.2 at 12 mL/h, 43.0 ± 12 at 20 mL/h and 136 ± 45 at 50 mL/h. The deposition efficiency ranged from 0.44 to 1.82% of infused saline, with 6% deposited in the nose. A regional analysis indicated peripheral deposition of aerosol (central/peripheral ratio 0.99 ± 0.27). The data were independent of breathing frequency. Breath-enhanced nebulization via HFNC reliably delivered aerosol to the lungs at the highest nasal airflows. The rate of delivery was controlled simply by regulating the infusion rate, indicating that lung deposition in the critically ill can be titrated clinically at the bedside. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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42 pages, 6282 KiB

Open AccessEditor’s ChoiceReview

Polymer Delivery Systems for Long-Acting Antiretroviral Drugs

by Mohammad Ullah Nayan, Sudipta Panja, Ashrafi Sultana, Lubaba A. Zaman, Lalitkumar K. Vora, Brady Sillman, Howard E. Gendelman and Benson Edagwa

Pharmaceutics 2024, 16(2), 183; https://doi.org/10.3390/pharmaceutics16020183 - 28 Jan 2024

Cited by 3 | Viewed by 2318

Abstract

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence [...] Read more.

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients’ needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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17 pages, 2840 KiB

Open AccessEditor’s ChoiceArticle

Potentiation of Antibiotic Activity of Aztreonam against Metallo-β-Lactamase-Producing Multidrug-Resistant Pseudomonas aeruginosa by 3-O-Substituted Difluoroquercetin Derivatives

by Seongyeon Lee, Taegum Lee, Mi Kyoung Kim, Joong Hoon Ahn, Seri Jeong, Ki-Ho Park and Youhoon Chong

Pharmaceutics 2024, 16(2), 185; https://doi.org/10.3390/pharmaceutics16020185 - 28 Jan 2024

Viewed by 1454

Abstract

The combination of aztreonam (ATM) and ceftazidime–avibactam (CAZ-AVI; CZA) has shown therapeutic potential against serine-β-lactamase (SBL)- and metallo-β-lactamase (MBL)-producing Enterobacterales. However, the ability of CZA to restore the antibiotic activity of ATM is severely limited in MBL-producing multidrug-resistant (MDR) Pseudomonas aeruginosa strains [...] Read more.

The combination of aztreonam (ATM) and ceftazidime–avibactam (CAZ-AVI; CZA) has shown therapeutic potential against serine-β-lactamase (SBL)- and metallo-β-lactamase (MBL)-producing Enterobacterales. However, the ability of CZA to restore the antibiotic activity of ATM is severely limited in MBL-producing multidrug-resistant (MDR) Pseudomonas aeruginosa strains because of the myriad of intrinsic and acquired resistance mechanisms associated with this pathogen. We reasoned that the simultaneous inhibition of multiple targets associated with multidrug resistance mechanisms may potentiate the antibiotic activity of ATM against MBL-producing P. aeruginosa. During a search for the multitarget inhibitors through a molecular docking study, we discovered that di-F-Q, the previously reported efflux pump inhibitor of MDR P. aeruginosa, binds to the active sites of the efflux pump (MexB), as well as various β-lactamases, and these sites are open to the 3-O-position of di-F-Q. The 3-O-substituted di-F-Q derivatives were thus synthesized and showed hereto unknown multitarget MDR inhibitory activity against various ATM-hydrolyzing β-lactamases (AmpC, KPC, and New Delhi metallo-β-lactamase (NDM)) and the efflux pump of P. aeruginosa, presumably by forming additional hydrophobic contacts with the targets. The multitarget MDR inhibitor 27 effectively potentiated the antimicrobial activity of ATM and reduced the MIC of ATM more than four-fold in 19 out of 21 MBL-producing P. aeruginosa clinical strains, including the NDM-producing strains which were highly resistant to various combinations of ATM with β-lactamase inhibitors and/or efflux pump inhibitors. Our findings suggest that the simultaneous inhibition of multiple MDR targets might provide new avenues for the discovery of safe and efficient MDR reversal agents which can be used in combination with ATM against MBL-producing MDR P. aeruginosa. Full article

(This article belongs to the Special Issue Recent Advances in Prevention and Treatment of Infectious Diseases)

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25 pages, 5051 KiB

Open AccessEditor’s ChoiceArticle

PEG–Lipid–PLGA Hybrid Particles for Targeted Delivery of Anti-Inflammatory Drugs

by Jana Ismail, Lea C. Klepsch, Philipp Dahlke, Ekaterina Tsarenko, Antje Vollrath, David Pretzel, Paul M. Jordan, Kourosh Rezaei, Justyna A. Czaplewska, Steffi Stumpf, Baerbel Beringer-Siemers, Ivo Nischang, Stephanie Hoeppener, Oliver Werz and Ulrich S. Schubert

Pharmaceutics 2024, 16(2), 187; https://doi.org/10.3390/pharmaceutics16020187 - 28 Jan 2024

Cited by 3 | Viewed by 2761

Abstract

Hybrid nanoparticles (HNPs) were designed by combining a PLGA core with a lipid shell that incorporated PEG–Lipid conjugates with various functionalities (-RGD, -cRGD, -NH₂, and -COOH) to create targeted drug delivery systems. Loaded with a neutral lipid orange dye, the HNPs [...] Read more.

Hybrid nanoparticles (HNPs) were designed by combining a PLGA core with a lipid shell that incorporated PEG–Lipid conjugates with various functionalities (-RGD, -cRGD, -NH₂, and -COOH) to create targeted drug delivery systems. Loaded with a neutral lipid orange dye, the HNPs were extensively characterized using various techniques and investigated for their uptake in human monocyte-derived macrophages (MDMs) using FC and CLSM. Moreover, the best-performing HNPs (i.e., HNP-COOH and HNP-RGD as well as HNP-RGD/COOH mixed) were loaded with the anti-inflammatory drug BRP-201 and prepared in two size ranges (d_H ~140 nm and d_H ~250 nm). The HNPs were examined further for their stability, degradation, MDM uptake, and drug delivery efficiency by studying the inhibition of 5-lipoxygenase (5-LOX) product formation, whereby HNP-COOH and HNP-RGD both exhibited superior uptake, and the HNP-COOH/RGD (2:1) displayed the highest inhibition. Full article

(This article belongs to the Special Issue Next Generation of PLGA-Based Nanoparticles as Drug Delivery Systems for Biomedical Applications)

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27 pages, 6292 KiB

Open AccessEditor’s ChoiceReview

Improving the Efficacy of Common Cancer Treatments via Targeted Therapeutics towards the Tumour and Its Microenvironment

by Daniel Cecchi, Nolan Jackson, Wayne Beckham and Devika B. Chithrani

Pharmaceutics 2024, 16(2), 175; https://doi.org/10.3390/pharmaceutics16020175 - 26 Jan 2024

Viewed by 2106

Abstract

Cancer is defined as the uncontrolled proliferation of heterogeneous cell cultures in the body that develop abnormalities and mutations, leading to their resistance to many forms of treatment. Left untreated, these abnormal cell growths can lead to detrimental and even fatal complications for [...] Read more.

Cancer is defined as the uncontrolled proliferation of heterogeneous cell cultures in the body that develop abnormalities and mutations, leading to their resistance to many forms of treatment. Left untreated, these abnormal cell growths can lead to detrimental and even fatal complications for patients. Radiation therapy is involved in around 50% of cancer treatment workflows; however, it presents significant recurrence rates and normal tissue toxicity, given the inevitable deposition of the dose to the surrounding healthy tissue. Chemotherapy is another treatment modality with excessive normal tissue toxicity that significantly affects patients’ quality of life. To improve the therapeutic efficacy of radiotherapy and chemotherapy, multiple conjunctive modalities have been proposed, which include the targeting of components of the tumour microenvironment inhibiting tumour spread and anti-therapeutic pathways, increasing the oxygen content within the tumour to revert the hypoxic nature of the malignancy, improving the local dose deposition with metal nanoparticles, and the restriction of the cell cycle within radiosensitive phases. The tumour microenvironment is largely responsible for inhibiting nanoparticle capture within the tumour itself and improving resistance to various forms of cancer therapy. In this review, we discuss the current literature surrounding the administration of molecular and nanoparticle therapeutics, their pharmacokinetics, and contrasting mechanisms of action. The review aims to demonstrate the advancements in the field of conjugated nanomaterials and radiotherapeutics targeting, inhibiting, or bypassing the tumour microenvironment to promote further research that can improve treatment outcomes and toxicity rates. Full article

(This article belongs to the Special Issue Nano-Drug Delivery Systems for Targeting the Tumor Microenvironment and Simultaneously Overcoming Drug Resistance Properties)

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51 pages, 4394 KiB

Open AccessEditor’s ChoiceReview

Biomaterial-Based Responsive Nanomedicines for Targeting Solid Tumor Microenvironments

by Konstantinos Avgoustakis and Athina Angelopoulou

Pharmaceutics 2024, 16(2), 179; https://doi.org/10.3390/pharmaceutics16020179 - 26 Jan 2024

Cited by 4 | Viewed by 2020

Abstract

Solid tumors are composed of a highly complex and heterogenic microenvironment, with increasing metabolic status. This environment plays a crucial role in the clinical therapeutic outcome of conventional treatments and innovative antitumor nanomedicines. Scientists have devoted great efforts to conquering the challenges of [...] Read more.

Solid tumors are composed of a highly complex and heterogenic microenvironment, with increasing metabolic status. This environment plays a crucial role in the clinical therapeutic outcome of conventional treatments and innovative antitumor nanomedicines. Scientists have devoted great efforts to conquering the challenges of the tumor microenvironment (TME), in respect of effective drug accumulation and activity at the tumor site. The main focus is to overcome the obstacles of abnormal vasculature, dense stroma, extracellular matrix, hypoxia, and pH gradient acidosis. In this endeavor, nanomedicines that are targeting distinct features of TME have flourished; these aim to increase site specificity and achieve deep tumor penetration. Recently, research efforts have focused on the immune reprograming of TME in order to promote suppression of cancer stem cells and prevention of metastasis. Thereby, several nanomedicine therapeutics which have shown promise in preclinical studies have entered clinical trials or are already in clinical practice. Various novel strategies were employed in preclinical studies and clinical trials. Among them, nanomedicines based on biomaterials show great promise in improving the therapeutic efficacy, reducing side effects, and promoting synergistic activity for TME responsive targeting. In this review, we focused on the targeting mechanisms of nanomedicines in response to the microenvironment of solid tumors. We describe responsive nanomedicines which take advantage of biomaterials’ properties to exploit the features of TME or overcome the obstacles posed by TME. The development of such systems has significantly advanced the application of biomaterials in combinational therapies and in immunotherapies for improved anticancer effectiveness. Full article

(This article belongs to the Special Issue Responsive Polymer Nanostructured Assemblies: Activity in Cancer Therapy)

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18 pages, 2330 KiB

Open AccessEditor’s ChoiceArticle

A Tunable Glycosaminoglycan–Peptide Nanoparticle Platform for the Protection of Therapeutic Peptides

by Harkanwalpreet Sodhi and Alyssa Panitch

Pharmaceutics 2024, 16(2), 173; https://doi.org/10.3390/pharmaceutics16020173 - 25 Jan 2024

Cited by 1 | Viewed by 1267

Abstract

The popularity of Glycosaminoglycans (GAGs) in drug delivery systems has grown as their innate ability to sequester and release charged molecules makes them adept in the controlled release of therapeutics. However, peptide therapeutics have been relegated to synthetic, polymeric systems, despite their high [...] Read more.

The popularity of Glycosaminoglycans (GAGs) in drug delivery systems has grown as their innate ability to sequester and release charged molecules makes them adept in the controlled release of therapeutics. However, peptide therapeutics have been relegated to synthetic, polymeric systems, despite their high specificity and efficacy as therapeutics because they are rapidly degraded in vivo when not encapsulated. We present a GAG-based nanoparticle system for the easy encapsulation of cationic peptides, which offers control over particle diameter, peptide release behavior, and swelling behavior, as well as protection from proteolytic degradation, using a singular, organic polymer and no covalent linkages. These nanoparticles can encapsulate cargo with a particle diameter range spanning 130–220 nm and can be tuned to release cargo over a pH range of 4.5 to neutral through the modulation of the degree of sulfation and the molecular weight of the GAG. This particle system also confers better in vitro performance than the unencapsulated peptide via protection from enzymatic degradation. This method provides a facile way to protect therapeutic peptides via the inclusion of the presented binding sequence and can likely be expanded to larger, more diverse cargo as well, abrogating the complexity of previously demonstrated systems while offering broader tunability. Full article

(This article belongs to the Special Issue Natural and/or Synthetic-Based Nanostructured Systems as Drug Delivery Platforms)

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16 pages, 3612 KiB

Open AccessEditor’s ChoiceArticle

Innovative Multilayer Electrospun Patches for the Slow Release of Natural Oily Extracts as Dressings to Boost Wound Healing

by Noemi Fiaschini, Fiorella Carnevali, Stephen Andrew Van der Esch, Roberta Vitali, Mariateresa Mancuso, Maria Sulli, Gianfranco Diretto, Anna Negroni and Antonio Rinaldi

Pharmaceutics 2024, 16(2), 159; https://doi.org/10.3390/pharmaceutics16020159 - 24 Jan 2024

Cited by 3 | Viewed by 1837

Abstract

Electrospinning is an advanced manufacturing strategy used to create innovative medical devices from continuous nanoscale fibers that is endowed with tunable biological, chemical, and physical properties. Innovative medical patches manufactured entirely by electrospinning are discussed in this paper, using a specific plant-derived formulation [...] Read more.

Electrospinning is an advanced manufacturing strategy used to create innovative medical devices from continuous nanoscale fibers that is endowed with tunable biological, chemical, and physical properties. Innovative medical patches manufactured entirely by electrospinning are discussed in this paper, using a specific plant-derived formulation “1 Primary Wound Dressing©” (1-PWD) as an active pharmaceutical ingredient (API). 1-PWD is composed of neem oil (Azadirachta indica A. Juss.) and the oily extracts of Hypericum perforatum (L.) flowers, according to the formulation patented by the ENEA of proven therapeutic efficacy as wound dressings. The goal of this work is to encapsulate this API and demonstrate that its slow release from an engineered electrospun patch can increase the therapeutic efficacy for wound healing. The prototyped patch is a three-layer core–shell membrane, with a core made of fibers from a 1-PWD-PEO blend, enveloped within two external layers made of medical-grade polycaprolactone (PCL), ensuring mechanical strength and integrity during manipulation. The system was characterized via electron microscopy (SEM) and chemical and contact angle tests. The encapsulation, release, and efficacy of the API were confirmed by FTIR and LC-HRMS and were validated via in vitro toxicology and scratch assays. Full article

(This article belongs to the Special Issue Nanofibrous Scaffolds Application in Biomedicine)

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22 pages, 2187 KiB

Open AccessEditor’s ChoiceReview

Nano-Formulations for Pulmonary Delivery: Past, Present, and Future Perspectives

by Siyuan Peng, Wenhao Wang, Rui Zhang, Chuanbin Wu, Xin Pan and Zhengwei Huang

Pharmaceutics 2024, 16(2), 161; https://doi.org/10.3390/pharmaceutics16020161 - 24 Jan 2024

Cited by 9 | Viewed by 3591

Abstract

With the development of nanotechnology and confronting the problems of traditional pharmaceutical formulations in treating lung diseases, inhalable nano-formulations have attracted interest. Inhalable nano-formulations for treating lung diseases allow for precise pulmonary drug delivery, overcoming physiological barriers, improving aerosol lung deposition rates, and [...] Read more.

With the development of nanotechnology and confronting the problems of traditional pharmaceutical formulations in treating lung diseases, inhalable nano-formulations have attracted interest. Inhalable nano-formulations for treating lung diseases allow for precise pulmonary drug delivery, overcoming physiological barriers, improving aerosol lung deposition rates, and increasing drug bioavailability. They are expected to solve the difficulties faced in treating lung diseases. However, limited success has been recorded in the industrialization translation of inhalable nano-formulations. Only one relevant product has been approved by the FDA to date, suggesting that there are still many issues to be resolved in the clinical application of inhalable nano-formulations. These systems are characterized by a dependence on inhalation devices, while the adaptability of device formulation is still inconclusive, which is the most important issue impeding translational research. In this review, we categorized various inhalable nano-formulations, summarized the advantages of inhalable nano-formulations over conventional inhalation formulations, and listed the inhalable nano-formulations undergoing clinical studies. We focused on the influence of inhalation devices on nano-formulations and analyzed their adaptability. After extensive analysis of the drug delivery mechanisms, technical processes, and limitations of different inhalation devices, we concluded that vibrating mesh nebulizers might be most suitable for delivering inhalable nano-formulations, and related examples were introduced to validate our view. Finally, we presented the challenges and outlook for future development. We anticipate providing an informative reference for the field. Full article

(This article belongs to the Special Issue Recent Advances in Pulmonary Inhalation of Nanoformulations)

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27 pages, 2488 KiB

Open AccessEditor’s ChoiceReview

An Overview of Biofilm-Associated Infections and the Role of Phytochemicals and Nanomaterials in Their Control and Prevention

by Tsvetozara Damyanova, Petya D. Dimitrova, Dayana Borisova, Tanya Topouzova-Hristova, Emi Haladjova and Tsvetelina Paunova-Krasteva

Pharmaceutics 2024, 16(2), 162; https://doi.org/10.3390/pharmaceutics16020162 - 24 Jan 2024

Cited by 7 | Viewed by 2562

Abstract

Biofilm formation is considered one of the primary virulence mechanisms in Gram-positive and Gram-negative pathogenic species, particularly those responsible for chronic infections and promoting bacterial survival within the host. In recent years, there has been a growing interest in discovering new compounds capable [...] Read more.

Biofilm formation is considered one of the primary virulence mechanisms in Gram-positive and Gram-negative pathogenic species, particularly those responsible for chronic infections and promoting bacterial survival within the host. In recent years, there has been a growing interest in discovering new compounds capable of inhibiting biofilm formation. This is considered a promising antivirulence strategy that could potentially overcome antibiotic resistance issues. Effective antibiofilm agents should possess distinctive properties. They should be structurally unique, enable easy entry into cells, influence quorum sensing signaling, and synergize with other antibacterial agents. Many of these properties are found in both natural systems that are isolated from plants and in synthetic systems like nanoparticles and nanocomposites. In this review, we discuss the clinical nature of biofilm-associated infections and some of the mechanisms associated with their antibiotic tolerance. We focus on the advantages and efficacy of various natural and synthetic compounds as a new therapeutic approach to control bacterial biofilms and address multidrug resistance in bacteria. Full article

(This article belongs to the Special Issue Recent Advances in the Prevention and Eradication Strategies for Combating Biofilm-Related Infections)

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15 pages, 6963 KiB

Open AccessEditor’s ChoiceArticle

Chitosan-Functionalized Poly(β-Amino Ester) Hybrid System for Gene Delivery in Vaginal Mucosal Epithelial Cells

by Xueqin Gao, Dirong Dong, Chong Zhang, Yuxing Deng, Jiahui Ding, Shiqi Niu, Songwei Tan and Lili Sun

Pharmaceutics 2024, 16(1), 154; https://doi.org/10.3390/pharmaceutics16010154 - 22 Jan 2024

Cited by 3 | Viewed by 1987

Abstract

Gene therapy displays great promise in the treatment of cervical cancer. The occurrence of cervical cancer is highly related to persistent human papilloma virus (HPV) infection. The HPV oncogene can be cleaved via gene editing technology to eliminate carcinogenic elements. However, the successful [...] Read more.

Gene therapy displays great promise in the treatment of cervical cancer. The occurrence of cervical cancer is highly related to persistent human papilloma virus (HPV) infection. The HPV oncogene can be cleaved via gene editing technology to eliminate carcinogenic elements. However, the successful application of the gene therapy method depends on effective gene delivery into the vagina. To improve mucosal penetration and adhesion ability, quaternized chitosan was introduced into the poly(β-amino ester) (PBAE) gene-delivery system in the form of quaternized chitosan-g-PBAE (QCP). At a mass ratio of PBAE:QCP of 2:1, the polymers exhibited the highest green fluorescent protein (GFP) transfection efficiency in HEK293T and ME180 cells, which was 1.1 and 5.4 times higher than that of PEI 25 kD. At this mass ratio, PBAE–QCP effectively compressed the GFP into spherical polyplex nanoparticles (PQ–GFP NPs) with a diameter of 255.5 nm. In vivo results indicated that owing to the mucopenetration and adhesion capability of quaternized CS, the GFP transfection efficiency of the PBAE–QCP hybrid system was considerably higher than those of PBAE and PEI 25 kD in the vaginal epithelial cells of Sprague–Dawley rats. Furthermore, the new system demonstrated low toxicity and good safety, laying an effective foundation for its further application in gene therapy. Full article

(This article belongs to the Special Issue Delivery System for Biomacromolecule Drugs: Design and Application)

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20 pages, 2604 KiB

Open AccessEditor’s ChoiceArticle

Is Gender an Important Factor in the Precision Medicine Approach to Levocetirizine?

by Seung-Hyun Jeong, Ji-Hun Jang and Yong-Bok Lee

Pharmaceutics 2024, 16(1), 146; https://doi.org/10.3390/pharmaceutics16010146 - 21 Jan 2024

Viewed by 1351

Abstract

Currently, there is insufficient information on the variability in levocetirizine pharmacometrics among individuals, a crucial aspect for establishing its clinical use. The gender differences in pharmacokinetics and the extent of variation in pharmacodynamics have not been definitively identified. The primary goal of this [...] Read more.

Currently, there is insufficient information on the variability in levocetirizine pharmacometrics among individuals, a crucial aspect for establishing its clinical use. The gender differences in pharmacokinetics and the extent of variation in pharmacodynamics have not been definitively identified. The primary goal of this study was to investigate gender differences in levocetirizine pharmacokinetics and quantitatively predict and compare how these gender-related pharmacokinetic differences impact pharmacodynamics, using population pharmacokinetic–pharmacodynamic modeling. Bioequivalence results for levocetirizine (only from the control formulation) were obtained from both healthy Korean men and women. Physiological and biochemical parameters for each individual were utilized as pharmacokinetic comparison and modeling data between genders. Pharmacodynamic modeling was performed using reported data on antihistamine responses following levocetirizine exposure. Gender, weight, body surface area, peripheral distribution volume, albumin, central–peripheral inter-compartmental clearance, and the fifth sequential absorption rate constant were explored as effective covariates. A comparison of the model simulation results showed a higher maximum concentration and faster plasma loss in females than in males, resulting in a faster recovery to baseline of the antihistamine effect; however, the absolute differences between genders in the mean values were not large within 10 ng/mL (for plasma concentrations) or % (wheal and flare size changes). Regarding the pharmacokinetics and pharmacodynamics of levocetirizine, the gender effect may not be significant when applying the usual dosage (5 mg/day). This study will be useful for bridging the knowledge gap in scientific precision medicine by introducing previously unconfirmed information regarding gender differences in levocetirizine pharmacometrics. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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15 pages, 4260 KiB

Open AccessEditor’s ChoiceArticle

Neuroprotective Effect of Polyvalent Immunoglobulins on Mouse Models of Chemotherapy-Induced Peripheral Neuropathy

by Mohamad Mroué, Flavien Bessaguet, Angélique Nizou, Laurence Richard, Franck Sturtz, Laurent Magy, Sylvie Bourthoumieu, Aurore Danigo and Claire Demiot

Pharmaceutics 2024, 16(1), 139; https://doi.org/10.3390/pharmaceutics16010139 - 20 Jan 2024

Cited by 2 | Viewed by 1612

Abstract

The occurrence of neuropathic pain in chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting effect of many commonly-used anticancer agents. Polyvalent human immunoglobulins (hIg), used in the treatment of several peripheral neuropathies, may alleviate neuropathic pain. The aim of this project was to [...] Read more.

The occurrence of neuropathic pain in chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting effect of many commonly-used anticancer agents. Polyvalent human immunoglobulins (hIg), used in the treatment of several peripheral neuropathies, may alleviate neuropathic pain. The aim of this project was to investigate the preventive effect of hIg in two mouse models of CIPN, induced by vincristine (VCR, 100 µg/kg/d) and oxaliplatin (OXP, 6 mg/kg/3d). Human Ig were administered one day before the first injection of chemotherapy. The onset of CIPN and effects of hIg were assessed via functional tests and morphological analyses of sensory nerves. To evaluate the effect of hIg on chemotherapy cytotoxicity, viability assays were performed using hIg (0 to 12 mg/mL) combined with anticancer agents on human cancer cell lines. The preventive treatment with hIg alleviated tactile hypersensitivity and nerve injuries induced by VCR. It also alleviated tactile/cold hypersensitivities and nerve injuries induced by OXP. Treatment with hIg did not affect the cytotoxicity of either chemotherapy. Furthermore, in combination with VCR, hIg potentiated chemo-induced cell death. In conclusion, hIg is a promising therapy to prevent the onset of CIPN and potentiate chemotherapy effect on cancer, reinforcing the interest in hIg in the management of CIPN. Full article

(This article belongs to the Section Gene and Cell Therapy)

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23 pages, 4095 KiB

Open AccessEditor’s ChoiceArticle

A Bilayer Microarray Patch (MAP) for HIV Pre-Exposure Prophylaxis: The Role of MAP Designs and Formulation Composition in Enhancing Long-Acting Drug Delivery

by Lalitkumar K. Vora, Ismaiel A. Tekko, Fabiana Volpe Zanutto, Akmal Sabri, Robert K. M. Choy, Jessica Mistilis, Priscilla Kwarteng, Courtney Jarrahian, Helen O. McCarthy and Ryan F. Donnelly

Pharmaceutics 2024, 16(1), 142; https://doi.org/10.3390/pharmaceutics16010142 - 20 Jan 2024

Cited by 9 | Viewed by 1923

Abstract

Microarray patches (MAPs) have shown great potential for efficient and patient-friendly drug delivery through the skin; however, improving their delivery efficiency for long-acting drug release remains a significant challenge. This research provides an overview of novel strategies aimed at enhancing the efficiency of [...] Read more.

Microarray patches (MAPs) have shown great potential for efficient and patient-friendly drug delivery through the skin; however, improving their delivery efficiency for long-acting drug release remains a significant challenge. This research provides an overview of novel strategies aimed at enhancing the efficiency of MAP delivery of micronized cabotegravir sodium (CAB Na) for HIV pre-exposure prophylaxis (PrEP). The refinement of microneedle design parameters, including needle length, shape, density, and arrangement, and the formulation properties, such as solubility, viscosity, polymer molecular weight, and stability, are crucial for improving penetration and release profiles. Additionally, a bilayer MAP optimization step was conducted by diluting the CAB Na polymeric mixture to localize the drug into the tips of the needles to enable rapid drug deposition into the skin following MAP application. Six MAP designs were analyzed and investigated with regard to delivery efficiency into the skin in ex vivo and in vivo studies. The improved MAP design and formulations were found to be robust and had more than 30% in vivo delivery efficiency, with plasma levels several-fold above the therapeutic concentration over a month. Repeated weekly dosing demonstrated the robustness of MAPs in delivering a consistent and sustained dose of CAB. In summary, CAB Na MAPs were able to deliver therapeutically relevant levels of drug. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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35 pages, 10219 KiB

Open AccessEditor’s ChoiceReview

Chemistry and Art of Developing Lipid Nanoparticles for Biologics Delivery: Focus on Development and Scale-Up

by Rijo John, Jasmin Monpara, Shankar Swaminathan and Rahul Kalhapure

Pharmaceutics 2024, 16(1), 131; https://doi.org/10.3390/pharmaceutics16010131 - 19 Jan 2024

Cited by 12 | Viewed by 5993

Abstract

Lipid nanoparticles (LNPs) have gained prominence as primary carriers for delivering a diverse array of therapeutic agents. Biological products have achieved a solid presence in clinical settings, and the anticipation of creating novel variants is increasing. These products predominantly encompass therapeutic proteins, nucleic [...] Read more.

Lipid nanoparticles (LNPs) have gained prominence as primary carriers for delivering a diverse array of therapeutic agents. Biological products have achieved a solid presence in clinical settings, and the anticipation of creating novel variants is increasing. These products predominantly encompass therapeutic proteins, nucleic acids and messenger RNA. The advancement of efficient LNP-based delivery systems for biologics that can overcome their limitations remains a highly favorable formulation strategy. Moreover, given their small size, biocompatibility, and biodegradation, LNPs can proficiently transport therapeutic moiety into the cells without significant toxicity and adverse reactions. This is especially crucial for the existing and upcoming biopharmaceuticals since large molecules as a group present several challenges that can be overcome by LNPs. This review describes the LNP technology for the delivery of biologics and summarizes the developments in the chemistry, manufacturing, and characterization of lipids used in the development of LNPs for biologics. Finally, we present a perspective on the potential opportunities and the current challenges pertaining to LNP technology. Full article

(This article belongs to the Special Issue Innovative Drug Release and Vaccine Delivery Systems)

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33 pages, 3676 KiB

Open AccessEditor’s ChoiceReview

Micro- and Nanostructured Fibrous Composites via Electro-Fluid Dynamics: Design and Applications for Brain

by Nergis Zeynep Renkler, Stefania Scialla, Teresa Russo, Ugo D’Amora, Iriczalli Cruz-Maya, Roberto De Santis and Vincenzo Guarino

Pharmaceutics 2024, 16(1), 134; https://doi.org/10.3390/pharmaceutics16010134 - 19 Jan 2024

Viewed by 1843

Abstract

The brain consists of an interconnected network of neurons tightly packed in the extracellular matrix (ECM) to form complex and heterogeneous composite tissue. According to recent biomimicry approaches that consider biological features as active components of biomaterials, designing a highly reproducible microenvironment for [...] Read more.

The brain consists of an interconnected network of neurons tightly packed in the extracellular matrix (ECM) to form complex and heterogeneous composite tissue. According to recent biomimicry approaches that consider biological features as active components of biomaterials, designing a highly reproducible microenvironment for brain cells can represent a key tool for tissue repair and regeneration. Indeed, this is crucial to support cell growth, mitigate inflammation phenomena and provide adequate structural properties needed to support the damaged tissue, corroborating the activity of the vascular network and ultimately the functionality of neurons. In this context, electro-fluid dynamic techniques (EFDTs), i.e., electrospinning, electrospraying and related techniques, offer the opportunity to engineer a wide variety of composite substrates by integrating fibers, particles, and hydrogels at different scales—from several hundred microns down to tens of nanometers—for the generation of countless patterns of physical and biochemical cues suitable for influencing the in vitro response of coexistent brain cell populations mediated by the surrounding microenvironment. In this review, an overview of the different technological approaches—based on EFDTs—for engineering fibrous and/or particle-loaded composite substrates will be proposed. The second section of this review will primarily focus on describing current and future approaches to the use of composites for brain applications, ranging from therapeutic to diagnostic/theranostic use and from repair to regeneration, with the ultimate goal of providing insightful information to guide future research efforts toward the development of more efficient and reliable solutions. Full article

(This article belongs to the Special Issue Nanofibrous Scaffolds Application in Biomedicine)

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21 pages, 10997 KiB

Open AccessEditor’s ChoiceArticle

Mesoporous Silica-Layered Gold Nanorod Core@Silver Shell Nanostructures for Intracellular SERS Imaging and Phototherapy

by Sun-Hwa Seo, Ara Joe, Hyo-Won Han, Panchanathan Manivasagan and Eue-Soon Jang

Pharmaceutics 2024, 16(1), 137; https://doi.org/10.3390/pharmaceutics16010137 - 19 Jan 2024

Cited by 1 | Viewed by 1831

Abstract

Precision diagnosis-guided efficient treatment is crucial to extending the lives of cancer patients. The integration of surface-enhanced Raman scattering (SERS) imaging and phototherapy into a single nanoplatform has been considered a more accurate diagnosis and treatment strategy for cancer nanotheranostics. Herein, we constructed [...] Read more.

Precision diagnosis-guided efficient treatment is crucial to extending the lives of cancer patients. The integration of surface-enhanced Raman scattering (SERS) imaging and phototherapy into a single nanoplatform has been considered a more accurate diagnosis and treatment strategy for cancer nanotheranostics. Herein, we constructed a new type of mesoporous silica-layered gold nanorod core@silver shell nanostructures loaded with methylene blue (GNR@Ag@mSiO₂-MB) as a multifunctional nanotheranostic agent for intracellular SERS imaging and phototherapy. The synthesized GNR@Ag@mSiO₂-MB nanostructures possessed a uniform core–shell structure, strong near-infrared (NIR) absorbance, photothermal conversion efficiency (65%), dye loading ability, SERS signal, and Raman stability under phototherapy conditions. Under single 785 nm NIR laser irradiation, the intracellular GNR@Ag@mSiO₂-MB nanostructures were dramatically decreased to <9%, which showed excellent photothermal and photodynamic effects toward cancer cell killing, indicating that the combination of photothermal therapy (PTT) and photodynamic therapy (PDT) of the GNR@Ag@mSiO₂-MB nanostructures could greatly enhance the therapeutic efficacy of cancer cell death. GNR@Ag@mSiO₂-MB nanostructures demonstrated a strong Raman signal at 450 and 502 cm⁻¹, corresponding to the δ(C–N–C) mode, suggesting that the Raman bands of GNR@Ag@mSiO₂-MB nanostructures were more efficient to detect CT-26 cell SERS imaging with high specificity. Our results indicate that GNR@Ag@mSiO₂-MB nanostructures offer an excellent multifunctional nanotheranostic platform for SERS imaging and synergistic anticancer phototherapy in the future. Full article

(This article belongs to the Special Issue Nanodynamic Therapies against Cancer and Microbial Infections)

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22 pages, 4600 KiB

Open AccessEditor’s ChoiceArticle

The Impact of Various Poly(vinylpyrrolidone) Polymers on the Crystallization Process of Metronidazole

by Luiza Orszulak, Taoufik Lamrani, Magdalena Tarnacka, Barbara Hachuła, Karolina Jurkiewicz, Patryk Zioła, Anna Mrozek-Wilczkiewicz, Ewa Kamińska and Kamil Kamiński

Pharmaceutics 2024, 16(1), 136; https://doi.org/10.3390/pharmaceutics16010136 - 19 Jan 2024

Cited by 2 | Viewed by 1797

Abstract

In this paper, we propose one-step synthetic strategies for obtaining well-defined linear and star-shaped polyvinylpyrrolidone (linPVP and starPVP). The produced macromolecules and a commercial PVP K30 with linear topology were investigated as potential matrices for suppressing metronidazole (MTZ) crystallization. Interestingly, [...] Read more.

In this paper, we propose one-step synthetic strategies for obtaining well-defined linear and star-shaped polyvinylpyrrolidone (linPVP and starPVP). The produced macromolecules and a commercial PVP K30 with linear topology were investigated as potential matrices for suppressing metronidazole (MTZ) crystallization. Interestingly, during the formation of binary mixtures (BMs) containing different polymers and MTZ, we found that linear PVPs exhibit maximum miscibility with the drug at a 50:50 weight ratio (w/w), while the star-shaped polymer mixes with MTZ even at a 30:70 w/w. To explain these observations, comprehensive studies of MTZ-PVP formulations with various contents of both components were performed using Fourier-transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The obtained results clearly showed that the polymer’s topology plays a significant role in the type of interactions occurring between the matrix and MTZ. Additionally, we established that for MTZ-PVP 50:50 and 75:25 w/w BMs, linear polymers have the most substantial impact on inhibiting the crystallization of API. The star-shaped macromolecule turned out to be the least effective in stabilizing amorphous MTZ at these polymer concentrations. Nevertheless, long-term structural investigations of the MTZ-starPVP 30:70 w/w system (which is not achievable for linear PVPs) demonstrated its complete amorphousness for over one month. Full article

(This article belongs to the Special Issue Novel Applications of Modern Excipients in Advanced Pharmaceutical Products)

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16 pages, 2533 KiB

Open AccessEditor’s ChoiceArticle

Biomolecules to Biomarkers? U87MG Marker Evaluation on the Path towards Glioblastoma Multiforme Pathogenesis

by Markéta Pokorná, Viera Kútna, Saak V. Ovsepian, Radoslav Matěj, Marie Černá and Valerie Bríd O’Leary

Pharmaceutics 2024, 16(1), 123; https://doi.org/10.3390/pharmaceutics16010123 - 18 Jan 2024

Cited by 3 | Viewed by 1814

Abstract

The heterogeneity of the glioma subtype glioblastoma multiforme (GBM) challenges effective neuropathological treatment. The reliance on in vitro studies and xenografted animal models to simulate human GBM has proven ineffective. Currently, a dearth of knowledge exists regarding the applicability of cell line biomolecules [...] Read more.

The heterogeneity of the glioma subtype glioblastoma multiforme (GBM) challenges effective neuropathological treatment. The reliance on in vitro studies and xenografted animal models to simulate human GBM has proven ineffective. Currently, a dearth of knowledge exists regarding the applicability of cell line biomolecules to the realm of GBM pathogenesis. Our study’s objectives were to address this preclinical issue and assess prominin-1, ICAM-1, PARTICLE and GAS5 as potential GBM diagnostic targets. The methodologies included haemoxylin and eosin staining, immunofluorescence, in situ hybridization and quantitative PCR. The findings identified that morphology correlates with malignancy in GBM patient pathology. Immunofluorescence confocal microscopy revealed prominin-1 in pseudo-palisades adjacent to necrotic foci in both animal and human GBM. Evidence is presented for an ICAM-1 association with degenerating vasculature. Significantly elevated nuclear PARTICLE expression from in situ hybridization and quantitative PCR reflected its role as a tumor activator. GAS5 identified within necrotic GBM validated this potential prognostic biomolecule with extended survival. Here we present evidence for the stem cell marker prominin-1 and the chemotherapeutic target ICAM-1 in a glioma animal model and GBM pathology sections from patients that elicited alternative responses to adjuvant chemotherapy. This foremost study introduces the long non-coding RNA PARTICLE into the context of human GBM pathogenesis while substantiating the role of GAS5 as a tumor suppressor. The validation of GBM biomarkers from cellular models contributes to the advancement towards superior detection, therapeutic responders and the ultimate attainment of promising prognoses for this currently incurable brain cancer. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Glioblastoma)

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18 pages, 7208 KiB

Open AccessEditor’s ChoiceArticle

Antibiotics against Pseudomonas aeruginosa on Human Skin Cell Lines: Determination of the Highest Non-Cytotoxic Concentrations with Antibiofilm Capacity for Wound Healing Strategies

by María I. Quiñones-Vico, Ana Fernández-González, Ana Ubago-Rodríguez, Kirsten Moll, Anna Norrby-Teglund, Mattias Svensson, José Gutiérrez-Fernández, Jesús M. Torres and Salvador Arias-Santiago

Pharmaceutics 2024, 16(1), 117; https://doi.org/10.3390/pharmaceutics16010117 - 17 Jan 2024

Cited by 3 | Viewed by 1719

Abstract

Pseudomonas aeruginosa is one of the most common microorganisms causing infections of severe skin wounds. Antibiotic or antiseptic treatments are crucial to prevent and curb these infections. Antiseptics have been reported to be cytotoxic to skin cells and few studies evaluate the impact [...] Read more.

Pseudomonas aeruginosa is one of the most common microorganisms causing infections of severe skin wounds. Antibiotic or antiseptic treatments are crucial to prevent and curb these infections. Antiseptics have been reported to be cytotoxic to skin cells and few studies evaluate the impact of commonly used antibiotics. This study evaluates how clinical antibiotics affect skin cells’ viability, proliferation, migration, and cytokine secretion and defines the highest non-cytotoxic concentrations that maintain antibacterial activity. Cell proliferation, viability, and migration were evaluated on cell monolayers. Cytokines related to the wound healing process were determined. The minimum inhibitory concentrations and the impact on bacterial biofilm were assessed. Results showed that 0.02 mg/mL ciprofloxacin and 1 mg/mL meropenem are the highest non-cytotoxic concentrations for fibroblasts and keratinocytes while 1.25 mg/mL amikacin and 0.034 mg/mL colistin do not affect fibroblasts’ viability and cytokine secretion but have an impact on keratinocytes. These concentrations are above the minimum inhibitory concentration but only amikacin could eradicate the biofilm. For the other antibiotics, cytotoxic concentrations are needed to eradicate the biofilm. Combinations with colistin at non-cytotoxic concentrations effectively eliminate the biofilm. These results provide information about the concentrations required when administering topical antibiotic treatments on skin lesions, and how these antibiotics affect wound management therapies. This study set the basis for the development of novel antibacterial wound healing strategies such as antibiotic artificial skin substitutes. Full article

(This article belongs to the Special Issue Studies on the Cytotoxicity and Antimicrobial Effects of Synthetic and Natural Compounds)

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20 pages, 8957 KiB

Open AccessEditor’s ChoiceArticle

Exploring the Ocular Absorption Pathway of Fasudil Hydrochloride towards Developing a Nanoparticulate Formulation with Improved Performance

by Barzan Osi, Ali A. Al-Kinani, Zinah K. Al-Qaysi, Mouhamad Khoder and Raid G. Alany

Pharmaceutics 2024, 16(1), 112; https://doi.org/10.3390/pharmaceutics16010112 - 15 Jan 2024

Cited by 2 | Viewed by 1556

Abstract

Rho-kinase (ROCK) inhibitors represent a new category of anti-glaucoma medications. Among them, Fasudil hydrochloride, a selective ROCK inhibitor, has demonstrated promising outcomes in glaucoma treatment. It works by inhibiting the ROCK pathway, which plays a crucial role in regulating the trabecular meshwork and [...] Read more.

Rho-kinase (ROCK) inhibitors represent a new category of anti-glaucoma medications. Among them, Fasudil hydrochloride, a selective ROCK inhibitor, has demonstrated promising outcomes in glaucoma treatment. It works by inhibiting the ROCK pathway, which plays a crucial role in regulating the trabecular meshwork and canal of Schlemm’s aqueous humor outflow. This study aims to investigate the ocular absorption pathway of Fasudil hydrochloride and, subsequently, develop a nanoparticle-based delivery system for enhanced corneal absorption. Employing the ionic gelation method and statistical experimental design, the factors influencing chitosan nanoparticle (Cs NP) characteristics and performance were explored. Fasudil in vitro release and ex vivo permeation studies were performed, and Cs NP ocular tolerability and cytotoxicity on human lens epithelial cells were evaluated. Permeation studies on excised bovine eyes revealed significantly higher Fasudil permeation through the sclera compared to the cornea (370.0 μg/cm² vs. 96.8 μg/cm², respectively). The nanoparticle size (144.0 ± 15.6 nm to 835.9 ± 23.4 nm) and entrapment efficiency range achieved (17.2% to 41.4%) were predominantly influenced by chitosan quantity. Cs NPs showed a substantial improvement in the permeation of Fasudil via the cornea, along with slower release compared to the Fasudil aqueous solution. The results from the Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) and Bovine Corneal Opacity and Permeability (BCOP) tests indicated good conjunctival and corneal biocompatibility of the formulated chitosan nanoparticles, respectively. Lens epithelial cells displayed excellent tolerance to low concentrations of these nanoparticles (>94% cell viability). To the best of our knowledge, this is the first report on the ocular absorption pathway of topically applied Fasudil hydrochloride where the cornea has been identified as a potential barrier that could be overcome using Cs NPs. Full article

(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)

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17 pages, 3748 KiB

Open AccessEditor’s ChoiceArticle

Enhancing Liver Delivery of Gold Nanoclusters via Human Serum Albumin Encapsulation for Autoimmune Hepatitis Alleviation

by Cong Meng, Yu Liu, Yuping Ming, Cao Lu, Yanggege Li, Yulu Zhang, Dongdong Su, Xueyun Gao and Qing Yuan

Pharmaceutics 2024, 16(1), 110; https://doi.org/10.3390/pharmaceutics16010110 - 14 Jan 2024

Cited by 2 | Viewed by 1749

Abstract

Peptide-protected gold nanoclusters (AuNCs), possessing exceptional biocompatibility and remarkable physicochemical properties, have demonstrated intrinsic pharmaceutical activity in immunomodulation, making them a highly attractive frontier in the field of nanomedicine exploration. Autoimmune hepatitis (AIH) is a serious autoimmune liver disease caused by the disruption [...] Read more.

Peptide-protected gold nanoclusters (AuNCs), possessing exceptional biocompatibility and remarkable physicochemical properties, have demonstrated intrinsic pharmaceutical activity in immunomodulation, making them a highly attractive frontier in the field of nanomedicine exploration. Autoimmune hepatitis (AIH) is a serious autoimmune liver disease caused by the disruption of immune balance, for which effective treatment options are still lacking. In this study, we initially identified glutathione (GSH)-protected AuNCs as a promising nanodrug candidate for AIH alleviating in a Concanavalin A (Con A)-induced mice model. However, to enhance treatment efficiency, liver-targeted delivery needs to be improved. Therefore, human serum albumin (HSA)-encapsulated AuNCs were constructed to achieve enhanced liver targeting and more potent mitigation of Con A-induced elevations in plasma aspartate transaminase (AST), alanine transaminase (ALT), and liver injury in mice. In vivo and in vitro mechanism studies indicated that AuNCs could suppress the secretion of IFN-γ by Con A-stimulated T cells and subsequently inhibit the activation of the JAK2/STAT1 pathway and eventual hepatocyte apoptosis induced by IFN-γ. These actions ultimately protect the liver from immune cell infiltration and damage caused by Con A. These findings suggest that bio-protected AuNCs hold promise as nanodrugs for AIH therapy, with their liver targeting capabilities and therapeutic efficiency being further improved via rational surface ligand engineering. Full article

(This article belongs to the Special Issue Nanosystems for Drug Delivery)

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17 pages, 3307 KiB

Open AccessEditor’s ChoiceArticle

The Development of an Oral Solution Containing Nirmatrelvir and Ritonavir and Assessment of Its Pharmacokinetics and Stability

by Lili Wang, Zhuang Ding, Zhengping Wang, Yanna Zhao, Hengqian Wu, Qipeng Wei, Lingfeng Gao and Jun Han

Pharmaceutics 2024, 16(1), 109; https://doi.org/10.3390/pharmaceutics16010109 - 14 Jan 2024

Viewed by 1820

Abstract

Paxlovid^®, a co-packaged medication comprised of separate tablets containing two active ingredients, nirmatrelvir (NRV) and ritonavir (RTV), exhibits good effectiveness against coronavirus disease 2019 (COVID-19). However, the size of the NRV/RTV tablets makes them difficult for some patients to swallow, especially [...] Read more.

Paxlovid^®, a co-packaged medication comprised of separate tablets containing two active ingredients, nirmatrelvir (NRV) and ritonavir (RTV), exhibits good effectiveness against coronavirus disease 2019 (COVID-19). However, the size of the NRV/RTV tablets makes them difficult for some patients to swallow, especially the elderly and those with dysphagia. Therefore, an oral liquid formulation that can overcome this shortcoming and improve patient compliance is required. In this study, we developed a liquid formulation containing NRV and RTV by adopting strategies that used co-solvents and surfactants to enhance the solubility and inhibit possible recrystallization. The in vitro release results showed that NRV and RTV could be maintained at high concentrations in solution for a certain period in the investigated media. In vivo studies in rats showed that the oral bioavailability of NRV/RTV solution was significantly enhanced. Compared to Paxlovid^® tablets, the AUC_(0–t) of NRV and RTV increased by 6.1 and 3.8 times, respectively, while the C_max increased by 5.5 times for both. Furthermore, the promoting effect of the absorption of RTV on the bioavailability of NRV was confirmed. Experiments with a beagle showed a similar trend. Stability studies were also conducted at 4 °C, 25 °C, and 40 °C for 90 days, indicating that the oral liquid formulation was physically and chemically stable. This study can be used as a valuable resource for developing and applying oral liquid NRV/RTV formulations in a clinical context. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)

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12 pages, 3542 KiB

Open AccessEditor’s ChoiceArticle

The Effect of Systemic Parameters and Baseline Characteristics in Short-Term Response Analysis with Intravitreal Ranibizumab in Treatment-Naive Patients with Neovascular Age-Related Macular Degeneration

by Laura García-Quintanilla, Pablo Almuiña-Varela, María José Rodríguez-Cid, María Gil-Martínez, Maximino J. Abraldes, Francisco Gómez-Ulla, Miguel González-Barcia, Cristina Mondelo-García, Ana Estany-Gestal, Francisco J. Otero-Espinar, Maribel Fernández-Rodríguez and Anxo Fernández-Ferreiro

Pharmaceutics 2024, 16(1), 105; https://doi.org/10.3390/pharmaceutics16010105 - 13 Jan 2024

Viewed by 1400

Abstract

Anti-vascular endothelial growth factor drugs keep being the main therapy for neovascular age-related macular degeneration (AMD). Possible predictive parameters (demographic, biochemical and/or inflammatory) could anticipate short-term treatment response with ranibizumab. 46 treatment-naive patients were included in a prospective observational study. They underwent three [...] Read more.

Anti-vascular endothelial growth factor drugs keep being the main therapy for neovascular age-related macular degeneration (AMD). Possible predictive parameters (demographic, biochemical and/or inflammatory) could anticipate short-term treatment response with ranibizumab. 46 treatment-naive patients were included in a prospective observational study. They underwent three monthly injections of intravitreal ranibizumab for neovascular AMD and the clinical examination was made at baseline and one month after the third injection. Demographic characteristics, co-morbidities and concomitant treatments were recorded at the baseline visit. Biochemical parameters, complete blood count and inflammation biomarkers were also measured at these times. Uric Acid was found to be statistically significant with a one-point difference between good and poor responders in both basal and treated patients, but only in basal parameters was statistical significance reached (p = 0.007 vs. p = 0.071 in treated patients). Cholesterol and inflammatory parameters such as white blood cell count and neutrophils were significantly reduced over time when treated with intravitreal ranibizumab. On the other hand, women seemed to have a worse prognosis for short-term response to intravitreal ranibizumab treatment. Uric acid may help identify possible non-responders before initial treatment with ranibizumab, and cholesterol and white blood cells could be good candidates to monitor short-term response to ranibizumab treatment. Full article

(This article belongs to the Special Issue Unveiling New Insights and Treatment Options for Ocular Surface Diseases)

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20 pages, 3698 KiB

Open AccessEditor’s ChoiceArticle

Co-Delivery of a Novel Lipidated TLR7/8 Agonist and Hemagglutinin-Based Influenza Antigen Using Silica Nanoparticles Promotes Enhanced Immune Responses

by Walid M. Abdelwahab, Sarah Auclair, Timothy Borgogna, Karthik Siram, Alexander Riffey, Hélène G. Bazin, Howard B. Cottam, Tomoko Hayashi, Jay T. Evans and David J. Burkhart

Pharmaceutics 2024, 16(1), 107; https://doi.org/10.3390/pharmaceutics16010107 - 13 Jan 2024

Cited by 1 | Viewed by 2568

Abstract

Co-delivery of antigens and adjuvants to the same antigen-presenting cells (APCs) can significantly improve the efficacy and safety profiles of vaccines. Here, we report amine-grafted silica nanoparticles (A-SNP) as a tunable vaccine co-delivery platform for TLR7/8 agonists along with the recombinant influenza antigen [...] Read more.

Co-delivery of antigens and adjuvants to the same antigen-presenting cells (APCs) can significantly improve the efficacy and safety profiles of vaccines. Here, we report amine-grafted silica nanoparticles (A-SNP) as a tunable vaccine co-delivery platform for TLR7/8 agonists along with the recombinant influenza antigen hemagglutinin H7 (H7) to APCs. A-SNP of two different sizes (50 and 200 nm) were prepared and coated with INI-4001 at different coating densities, followed by co-adsorption of H7. Both INI-4001 and H7 showed >90% adsorption to the tested A-SNP formulations. TNF-α and IFN-α cytokine release by human peripheral blood mononuclear cells as well as TNF-α, IL-6, and IL-12 release by mouse bone marrow-derived dendritic cells revealed that the potency of the INI-4001-adsorbed A-SNP (INI-4001/A-SNP) formulations was improved relative to aqueous formulation control. This improved potency was dependent on particle size and ligand coating density. In addition, slow-release profiles of INI-4001 were measured from INI-4001/A-SNP formulations in plasma with 30–50% INI-4001 released after 7 days. In vivo murine immunization studies demonstrated significantly improved H7-specific humoral and Th1/Th17-polarized T cell immune responses with no observed adverse reactions. Low-density 50 nm INI-4001/A-SNP elicited significantly higher IFN-γ and IL-17 induction over that of the H7 antigen-only group and INI-4001 aqueous formulation controls. In summary, this work introduces an effective and biocompatible SNP-based co-delivery platform that enhances the immunogenicity of TLR7/8 agonist-adjuvanted subunit influenza vaccines. Full article

(This article belongs to the Special Issue Innovative Drug Release and Vaccine Delivery Systems)

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15 pages, 4672 KiB

Open AccessEditor’s ChoiceArticle

Engineering Neurotoxin-Functionalized Exosomes for Targeted Delivery to the Peripheral Nervous System

by Mena Asha Krishnan, Olawale A. Alimi, Tianshu Pan, Mitchell Kuss, Zeljka Korade, Guoku Hu, Bo Liu and Bin Duan

Pharmaceutics 2024, 16(1), 102; https://doi.org/10.3390/pharmaceutics16010102 - 12 Jan 2024

Cited by 1 | Viewed by 2376

Abstract

The administration of therapeutics to peripheral nerve tissue is challenging due to the complexities of peripheral neuroanatomy and the limitations imposed by the blood–nerve barrier (BNB). Therefore, there is a pressing need to enhance delivery effectiveness and implement targeted delivery methods. Recently, erythrocyte-derived [...] Read more.

The administration of therapeutics to peripheral nerve tissue is challenging due to the complexities of peripheral neuroanatomy and the limitations imposed by the blood–nerve barrier (BNB). Therefore, there is a pressing need to enhance delivery effectiveness and implement targeted delivery methods. Recently, erythrocyte-derived exosomes (Exos) have gained widespread attention as biocompatible vehicles for therapeutics in clinical applications. However, engineering targeted Exos for the peripheral nervous system (PNS) is still challenging. This study aims to develop a targeted Exo delivery system specifically designed for presynaptic terminals of peripheral nerve tissue. The clostridium neurotoxin, tetanus toxin-C fragment (TTC), was tethered to the surface of red blood cell (RBC)-derived Exos via a facile and efficient bio-orthogonal click chemistry method without a catalyst. Additionally, Cyanine5 (Cy5), a reactive fluorescent tag, was also conjugated to track Exo movement in both in vitro and in vivo models. Subsequently, Neuro-2a, a mouse neuronal cell line, was treated with dye-labeled Exos with/without TTC in vitro, and the results indicated that TTC-Exos exhibited more efficient accumulation along the soma and axonal circumference, compared to their unmodified counterparts. Further investigation, using a mouse model, revealed that within 72 h of intramuscular administration, engineered TTC-Exos were successfully transported into the neuromuscular junction and sciatic nerve tissues. These results indicated that TTC played a crucial role in the Exo delivery system, improving the affinity to peripheral nerves. These promising results underscore the potential of using targeted Exo carriers to deliver therapeutics for treating peripheral neuropathies. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems, 2nd Edition)

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32 pages, 2419 KiB

Open AccessEditor’s ChoiceReview

Assessment of In Vitro Release Testing Methods for Colloidal Drug Carriers: The Lack of Standardized Protocols

by Laura Gómez-Lázaro, Cristina Martín-Sabroso, Juan Aparicio-Blanco and Ana Isabel Torres-Suárez

Pharmaceutics 2024, 16(1), 103; https://doi.org/10.3390/pharmaceutics16010103 - 12 Jan 2024

Cited by 3 | Viewed by 3218

Abstract

Although colloidal carriers have been in the pipeline for nearly four decades, standardized methods for testing their drug-release properties remain to be established in pharmacopeias. The in vitro assessment of drug release from these colloidal carriers is one of the most important parameters [...] Read more.

Although colloidal carriers have been in the pipeline for nearly four decades, standardized methods for testing their drug-release properties remain to be established in pharmacopeias. The in vitro assessment of drug release from these colloidal carriers is one of the most important parameters in the development and quality control of drug-loaded nano- and microcarriers. This lack of standardized protocols occurs due to the difficulties encountered in separating the released drug from the encapsulated one. This review aims to compare the most frequent types of release testing methods (i.e., membrane diffusion techniques, sample and separate methods and in situ detection techniques) in terms of the advantages and disadvantages of each one and of the key parameters that influence drug release in each case. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application, 2nd Edition)

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26 pages, 9454 KiB

Open AccessEditor’s ChoiceArticle

3D-Printed Alginate/Pectin-Based Patches Loaded with Olive Leaf Extracts for Wound Healing Applications: Development, Characterization and In Vitro Evaluation of Biological Properties

by Francesco Patitucci, Marisa Francesca Motta, Marco Dattilo, Rocco Malivindi, Adele Elisabetta Leonetti, Giuseppe Pezzi, Sabrina Prete, Olga Mileti, Domenico Gabriele, Ortensia Ilaria Parisi and Francesco Puoci

Pharmaceutics 2024, 16(1), 99; https://doi.org/10.3390/pharmaceutics16010099 - 11 Jan 2024

Cited by 3 | Viewed by 2053

Abstract

Traditional wound dressings may lack suitability for diverse wound types and individual patient requirements. In this context, this study aimed to innovate wound care by developing a 3D-printed patch using alginate and pectin and incorporating Olive Leaf Extract (OLE) as an active ingredient. [...] Read more.

Traditional wound dressings may lack suitability for diverse wound types and individual patient requirements. In this context, this study aimed to innovate wound care by developing a 3D-printed patch using alginate and pectin and incorporating Olive Leaf Extract (OLE) as an active ingredient. Different polymer-to-plasticizer ratios were systematically examined to formulate a printable ink with optimal viscosity. The resultant film, enriched with OLE, exhibited a substantial polyphenolic content of 13.15 ± 0.41 mg CAE/g, showcasing significant antioxidant and anti-inflammatory properties. Notably, the film demonstrated potent scavenging abilities against DPPH, ABTS, and NO radicals, with IC₅₀ values of 0.66 ± 0.07, 0.47 ± 0.04, and 2.02 ± 0.14 mg/mL, respectively. In vitro release and diffusion studies were carried out and the release profiles revealed an almost complete release of polyphenols from the patch within 48 h. Additionally, the fabricated film exhibited the capacity to enhance cell motility and accelerate wound healing, evidenced by increased collagen I expression in BJ fibroblast cells. Structural assessments affirmed the ability of the patch to absorb exudates and maintain the optimal moisture balance, while biocompatibility studies underscored its suitability for biomedical applications. These compelling findings endorse the potential application of the developed film in advanced wound care, with the prospect of tailoring patches to individual patient needs. Full article

(This article belongs to the Special Issue Polymer-Based Wound Dressings)

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27 pages, 8711 KiB

Open AccessEditor’s ChoiceReview

Electrospun Antimicrobial Drug Delivery Systems and Hydrogels Used for Wound Dressings

by Zahra Moazzami Goudarzi, Angelika Zaszczyńska, Tomasz Kowalczyk and Paweł Sajkiewicz

Pharmaceutics 2024, 16(1), 93; https://doi.org/10.3390/pharmaceutics16010093 - 10 Jan 2024

Cited by 8 | Viewed by 2566

Abstract

Wounds and chronic wounds can be caused by bacterial infections and lead to discomfort in patients. To solve this problem, scientists are working to create modern wound dressings with antibacterial additives, mainly because traditional materials cannot meet the general requirements for complex wounds [...] Read more.

Wounds and chronic wounds can be caused by bacterial infections and lead to discomfort in patients. To solve this problem, scientists are working to create modern wound dressings with antibacterial additives, mainly because traditional materials cannot meet the general requirements for complex wounds and cannot promote wound healing. This demand is met by material engineering, through which we can create electrospun wound dressings. Electrospun wound dressings, as well as those based on hydrogels with incorporated antibacterial compounds, can meet these requirements. This manuscript reviews recent materials used as wound dressings, discussing their formation, application, and functionalization. The focus is on presenting dressings based on electrospun materials and hydrogels. In contrast, recent advancements in wound care have highlighted the potential of thermoresponsive hydrogels as dynamic and antibacterial wound dressings. These hydrogels contain adaptable polymers that offer targeted drug delivery and show promise in managing various wound types while addressing bacterial infections. In this way, the article is intended to serve as a compendium of knowledge for researchers, medical practitioners, and biomaterials engineers, providing up-to-date information on the state of the art, possibilities of innovative solutions, and potential challenges in the area of materials used in dressings. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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15 pages, 766 KiB

Open AccessEditor’s ChoiceArticle

Pharmacokinetic Interpretation of Applying Local Drug Delivery System for the Treatment of Deep Surgical Site Infection in the Spine

by Ahmad Khalid Madadi and Moon-Jun Sohn

Pharmaceutics 2024, 16(1), 94; https://doi.org/10.3390/pharmaceutics16010094 - 10 Jan 2024

Viewed by 1771

Abstract

Surgical site infections (SSIs) after spinal surgery present significant challenges, including poor antibiotic penetration and biofilm formation on implants, leading to frequent treatment failures. Polymethylmethacrylate (PMMA) is widely used for localized drug delivery in bone infections, yet quantifying individual drug release kinetics is [...] Read more.

Surgical site infections (SSIs) after spinal surgery present significant challenges, including poor antibiotic penetration and biofilm formation on implants, leading to frequent treatment failures. Polymethylmethacrylate (PMMA) is widely used for localized drug delivery in bone infections, yet quantifying individual drug release kinetics is often impractical. This retrospective study analyzed 23 cases of deep SSIs (DSSIs) following spinal surgery treated with antibiotic-loaded PMMA. A mathematical model estimated personalized drug release kinetics from PMMA, considering disease types, pathogens, and various antibiotics. The study found that vancomycin (VAN), ceftriaxone (CRO), and ceftazidime (CAZ) reached peak concentrations of 15.43%, 15.42%, and 15.41%, respectively, within the first two days, which was followed by a lag phase (4.91–4.92%) on days 2–3. On days 5–7, concentrations stabilized, with CRO at 3.22% and CAZ/VAN between 3.63% and 3.65%, averaging 75.4 µg/cm². Key factors influencing release kinetics include solubility, diffusivity, porosity, tortuosity, and bead diameter. Notably, a patient with a low glomerular filtration rate (ASA IV) was successfully treated with a shortened 9-day intravenous VAN regimen, avoiding systemic complications. This study affirms the effectiveness of local drug delivery systems (DDS) in treating DSSIs and underscores the value of mathematical modeling in determining drug release kinetics. Further research is essential to optimize release rates and durations and to mitigate risks of burst release and tissue toxicity. Full article

(This article belongs to the Special Issue Drug Delivery Systems for Bone Targeted Therapeutics: Current Approach and Future Perspectives)

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21 pages, 2576 KiB

Open AccessEditor’s ChoiceReview

Towards More Precise Targeting of Inhaled Aerosols to Different Areas of the Respiratory System

by Tomasz R. Sosnowski

Pharmaceutics 2024, 16(1), 97; https://doi.org/10.3390/pharmaceutics16010097 - 10 Jan 2024

Cited by 2 | Viewed by 2221

Abstract

Pharmaceutical aerosols play a key role in the treatment of lung disorders, but also systemic diseases, due to their ability to target specific areas of the respiratory system (RS). This article focuses on identifying and clarifying the influence of various factors involved in [...] Read more.

Pharmaceutical aerosols play a key role in the treatment of lung disorders, but also systemic diseases, due to their ability to target specific areas of the respiratory system (RS). This article focuses on identifying and clarifying the influence of various factors involved in the generation of aerosol micro- and nanoparticles on their regional distribution and deposition in the RS. Attention is given to the importance of process parameters during the aerosolization of liquids or powders and the role of aerosol flow dynamics in the RS. The interaction of deposited particles with the fluid environment of the lung is also pointed out as an important step in the mass transfer of the drug to the RS surface. The analysis presented highlights the technical aspects of preparing the precursors to ensure that the properties of the aerosol are suitable for a given therapeutic target. Through an analysis of existing technical limitations, selected strategies aimed at enhancing the effectiveness of targeted aerosol delivery to the RS have been identified and presented. These strategies also include the use of smart inhaling devices and systems with built-in AI algorithms. Full article

(This article belongs to the Special Issue Drug Delivery Systems for Respiratory Diseases)

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24 pages, 5202 KiB

Open AccessEditor’s ChoiceArticle

Combined Role of Interleukin-15 Stimulated Natural Killer Cell-Derived Extracellular Vesicles and Carboplatin in Osimertinib-Resistant H1975 Lung Cancer Cells with EGFR Mutations

by Aakash Nathani, Li Sun, Islauddin Khan, Mounika Aare, Arvind Bagde, Yan Li and Mandip Singh

Pharmaceutics 2024, 16(1), 83; https://doi.org/10.3390/pharmaceutics16010083 - 8 Jan 2024

Cited by 4 | Viewed by 2709

Abstract

In this study, we evaluated IL-15 stimulated natural killer cell-derived EVs (NK-EVs) as therapeutic agents in vitro and in vivo in Osimertinib-resistant lung cancer (H1975R) with EGFR mutations (L858R) in combination with carboplatin (CBP). NK-EVs were isolated by ultracentrifugation and characterized by nanoparticle [...] Read more.

In this study, we evaluated IL-15 stimulated natural killer cell-derived EVs (NK-EVs) as therapeutic agents in vitro and in vivo in Osimertinib-resistant lung cancer (H1975R) with EGFR mutations (L858R) in combination with carboplatin (CBP). NK-EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, and atomic force microscopy imaging revealed vesicles with a spherical form and sizes meeting the criteria of exosomal EVs. Further, Western blot studies demonstrated the presence of regular EV markers along with specific NK markers (perforin and granzyme). EVs were also characterized by proteomic analysis, which demonstrated that EVs had proteins for natural killer cell-mediated cytotoxicity (Granzyme B) and T cell activation (perforin and plastin-2). Gene oncology analysis showed that these differentially expressed proteins are involved in programmed cell death and positive regulation of cell death. Further, isolated NK-EVs were cytotoxic to H1975R cells in vitro in 2D and 3D cell cultures. CBP’s IC₅₀ was reduced by approximately in 2D and 3D cell cultures when combined with NK-EVs. The EVs were then combined with CBP and administered by i.p. route to H1975R tumor xenografts, and a significant reduction in tumor volume in vivo was observed. Our findings show for the first time that NK-EVs target the PD-L1/PD-1 immunological checkpoint to induce apoptosis and anti-inflammatory response by downregulation of SOD2, PARP, BCL2, SET, NF-κB, and TGF-ß. The ability to isolate functional NK-EVs on a large scale and use them with platinum-based drugs may lead to new clinical applications. The results of the present study suggest the possibility of the combination of NK-cell-derived EVs and CBP as a viable immunochemotherapeutic strategy for resistant cancers. Full article

(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)

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17 pages, 674 KiB

Open AccessEditor’s ChoiceReview

Vaccines to Treat Substance Use Disorders: Current Status and Future Directions

by Tangsheng Lu, Xue Li, Wei Zheng, Chenyan Kuang, Bingyi Wu, Xiaoxing Liu, Yanxue Xue, Jie Shi, Lin Lu and Ying Han

Pharmaceutics 2024, 16(1), 84; https://doi.org/10.3390/pharmaceutics16010084 - 8 Jan 2024

Cited by 1 | Viewed by 2832

Abstract

Addiction, particularly in relation to psychostimulants and opioids, persists as a global health crisis with profound social and economic ramifications. Traditional interventions, including medications and behavioral therapies, often encounter limited success due to the chronic and relapsing nature of addictive disorders. Consequently, there [...] Read more.

Addiction, particularly in relation to psychostimulants and opioids, persists as a global health crisis with profound social and economic ramifications. Traditional interventions, including medications and behavioral therapies, often encounter limited success due to the chronic and relapsing nature of addictive disorders. Consequently, there is significant interest in the development of innovative therapeutics to counteract the effects of abused substances. In recent years, vaccines have emerged as a novel and promising strategy to tackle addiction. Anti-drug vaccines are designed to stimulate the immune system to produce antibodies that bind to addictive compounds, such as nicotine, cocaine, morphine, methamphetamine, and heroin. These antibodies effectively neutralize the target molecules, preventing them from reaching the brain and eliciting their rewarding effects. By obstructing the rewarding sensations associated with substance use, vaccines aim to reduce cravings and the motivation to engage in drug use. Although anti-drug vaccines hold significant potential, challenges remain in their development and implementation. The reversibility of vaccination and the potential for combining vaccines with other addiction treatments offer promise for improving addiction outcomes. This review provides an overview of anti-drug vaccines, their mechanisms of action, and their potential impact on treatment for substance use disorders. Furthermore, this review summarizes recent advancements in vaccine development for each specific drug, offering insights for the development of more effective and personalized treatments capable of addressing the distinct challenges posed by various abused substances. Full article

(This article belongs to the Special Issue Advances in Vaccines for Substance Use Disorders)

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