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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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18 pages, 6864 KiB  
Review
Hypoxia-Activated Theragnostic Prodrugs (HATPs): Current State and Future Perspectives
by Sankarprasad Bhuniya and Eirinaios I. Vrettos
Pharmaceutics 2024, 16(4), 557; https://doi.org/10.3390/pharmaceutics16040557 - 19 Apr 2024
Cited by 1 | Viewed by 1355
Abstract
Hypoxia is a significant feature of solid tumors and frequently poses a challenge to the effectiveness of tumor-targeted chemotherapeutics, thereby limiting their anticancer activity. Hypoxia-activated prodrugs represent a class of bio-reductive agents that can be selectively activated in hypoxic compartments to unleash the [...] Read more.
Hypoxia is a significant feature of solid tumors and frequently poses a challenge to the effectiveness of tumor-targeted chemotherapeutics, thereby limiting their anticancer activity. Hypoxia-activated prodrugs represent a class of bio-reductive agents that can be selectively activated in hypoxic compartments to unleash the toxic warhead and thus, eliminate malignant tumor cells. However, their applicability can be further elevated by installing fluorescent modalities to yield hypoxia-activated theragnostic prodrugs (HATPs), which can be utilized for the simultaneous visualization and treatment of hypoxic tumor cells. The scope of this review is to summarize noteworthy advances in recent HATPs, highlight the challenges and opportunities for their further development, and discuss their potency to serve as personalized medicines in the future. Full article
(This article belongs to the Special Issue Research on Therapeutic Prodrugs for Targeted Cancer Therapy)
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20 pages, 7878 KiB  
Article
Host–Guest Complexation of Itraconazole with Cyclodextrins for Bioavailability Enhancement
by Lenuţa-Maria Şuta, Amalia Ridichie, Adriana Ledeţi, Claudia Temereancă, Ionuţ Ledeţi, Delia Muntean, Matilda Rădulescu, Renata-Maria Văruţ, Claudia Watz, Florentin Crăineanu, Denisa Ivan, Gabriela Vlase and Lavinia Stelea
Pharmaceutics 2024, 16(4), 560; https://doi.org/10.3390/pharmaceutics16040560 - 19 Apr 2024
Cited by 1 | Viewed by 1282
Abstract
Itraconazole is an antifungal agent included in the triazole pharmacological classification that belongs to the BCS class II, characterized by a low solubility in an aqueous medium (of 1 ng/mL, at neutral pH), which is frequently translated in a low oral bioavailability but [...] Read more.
Itraconazole is an antifungal agent included in the triazole pharmacological classification that belongs to the BCS class II, characterized by a low solubility in an aqueous medium (of 1 ng/mL, at neutral pH), which is frequently translated in a low oral bioavailability but with a high permeability. In this sense, it is necessary to find solutions to increase/improve the solubility of itraconazole in the aqueous environment. The main purpose of this study is the preparation and analysis of five different guest–host inclusion complexes containing intraconazole. Initially, a blind docking process was carried out to determine the interactions between itraconazole and the selected cyclodextrins. The second step of the study was to find out if the active pharmaceutical ingredient was entrapped in the cavity of the cyclodextrin, by using spectroscopic and thermal techniques. Also, the antifungal activity of the inclusion complexes was studied to examine if the entrapment of itraconazole influences the therapeutic effect. The results showed that the active substance was entrapped in the cavity of the cyclodextrins, with a molar ratio of 1:3 (itraconazole–cyclodextrin), and that the therapeutic effect was not influenced by the entrapment. Full article
(This article belongs to the Special Issue Cyclodextrins in Drug Delivery, 2nd Edition)
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18 pages, 4654 KiB  
Article
Polymeric Amorphous Solid Dispersions of Dasatinib: Formulation and Ecotoxicological Assessment
by Katarina Sokač, Martina Miloloža, Dajana Kučić Grgić and Krunoslav Žižek
Pharmaceutics 2024, 16(4), 551; https://doi.org/10.3390/pharmaceutics16040551 - 18 Apr 2024
Viewed by 1956
Abstract
Dasatinib (DAS), a potent anticancer drug, has been subjected to formulation enhancements due to challenges such as significant first-pass metabolism, poor absorption, and limited oral bioavailability. To improve its release profile, DAS was embedded in a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP). [...] Read more.
Dasatinib (DAS), a potent anticancer drug, has been subjected to formulation enhancements due to challenges such as significant first-pass metabolism, poor absorption, and limited oral bioavailability. To improve its release profile, DAS was embedded in a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP). Drug amorphization was induced in a planetary ball mill by solvent-free co-grinding, facilitating mechanochemical activation. This process resulted in the formation of amorphous solid dispersions (ASDs). The ASD capsules exhibited a notable enhancement in the release rate of DAS compared to capsules containing the initial drug. Given that anticancer drugs often undergo limited metabolism in the body with unchanged excretion, the ecotoxicological effect of the native form of DAS was investigated as well, considering its potential accumulation in the environment. The highest ecotoxicological effect was observed on the bacteria Vibrio fischeri, while other test organisms (bacteria Pseudomonas putida, microalgae Chlorella sp., and duckweed Lemna minor) exhibited negligible effects. The enhanced drug release not only contributes to improved oral absorption but also has the potential to reduce the proportion of DAS that enters the environment through human excretion. This comprehensive approach highlights the significance of integrating advances in drug development while considering its environmental implications. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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18 pages, 3752 KiB  
Article
Early Detection of Myeloid-Derived Suppressor Cells in the Lung Pre-Metastatic Niche by Shortwave Infrared Nanoprobes
by Jake N. Siebert, Jay V. Shah, Mei Chee Tan, Richard E. Riman, Mark C. Pierce, Edmund C. Lattime, Vidya Ganapathy and Prabhas V. Moghe
Pharmaceutics 2024, 16(4), 549; https://doi.org/10.3390/pharmaceutics16040549 - 17 Apr 2024
Viewed by 1864
Abstract
Metastatic breast cancer remains a significant source of mortality amongst breast cancer patients and is generally considered incurable in part due to the difficulty in detection of early micro-metastases. The pre-metastatic niche (PMN) is a tissue microenvironment that has undergone changes to support [...] Read more.
Metastatic breast cancer remains a significant source of mortality amongst breast cancer patients and is generally considered incurable in part due to the difficulty in detection of early micro-metastases. The pre-metastatic niche (PMN) is a tissue microenvironment that has undergone changes to support the colonization and growth of circulating tumor cells, a key component of which is the myeloid-derived suppressor cell (MDSC). Therefore, the MDSC has been identified as a potential biomarker for PMN formation, the detection of which would enable clinicians to proactively treat metastases. However, there is currently no technology capable of the in situ detection of MDSCs available in the clinic. Here, we propose the use of shortwave infrared-emitting nanoprobes for the tracking of MDSCs and identification of the PMN. Our rare-earth albumin nanocomposites (ReANCs) are engineered to bind the Gr-1 surface marker of murine MDSCs. When delivered intravenously in murine models of breast cancer with high rates of metastasis, the targeted ReANCs demonstrated an increase in localization to the lungs in comparison to control ReANCs. However, no difference was seen in the model with slower rates of metastasis. This highlights the potential utility of MDSC-targeted nanoprobes to assess PMN development and prognosticate disease progression. Full article
(This article belongs to the Special Issue Cancer Nanomedicine—from the Bench to the Bedside, 2nd Edition)
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20 pages, 2311 KiB  
Article
LDLR-Mediated Targeting and Productive Uptake of siRNA-Peptide Ligand Conjugates In Vitro and In Vivo
by Baptiste Broc, Karine Varini, Rose Sonnette, Belinda Pecqueux, Florian Benoist, Maxime Masse, Yasmine Mechioukhi, Géraldine Ferracci, Jamal Temsamani, Michel Khrestchatisky, Guillaume Jacquot and Pascaline Lécorché
Pharmaceutics 2024, 16(4), 548; https://doi.org/10.3390/pharmaceutics16040548 - 17 Apr 2024
Cited by 1 | Viewed by 2066
Abstract
Small RNA molecules such as microRNA and small interfering RNA (siRNA) have become promising therapeutic agents because of their specificity and their potential to modulate gene expression. Any gene of interest can be potentially up- or down-regulated, making RNA-based technology the healthcare breakthrough [...] Read more.
Small RNA molecules such as microRNA and small interfering RNA (siRNA) have become promising therapeutic agents because of their specificity and their potential to modulate gene expression. Any gene of interest can be potentially up- or down-regulated, making RNA-based technology the healthcare breakthrough of our era. However, the functional and specific delivery of siRNAs into tissues of interest and into the cytosol of target cells remains highly challenging, mainly due to the lack of efficient and selective delivery systems. Among the variety of carriers for siRNA delivery, peptides have become essential candidates because of their high selectivity, stability, and conjugation versatility. Here, we describe the development of molecules encompassing siRNAs against SOD1, conjugated to peptides that target the low-density lipoprotein receptor (LDLR), and their biological evaluation both in vitro and in vivo. Full article
(This article belongs to the Special Issue Peptide-Based Carriers for Drug Delivery)
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23 pages, 5698 KiB  
Article
Preparation and Characterization of Polymeric Microparticles Based on Poly(ethylene brassylate-co-squaric Acid) Loaded with Norfloxacin
by Alexandru-Mihail Șerban, Isabella Nacu, Irina Rosca, Alina Ghilan, Alina Gabriela Rusu, Loredana Elena Niță, Raluca Nicoleta Darie-Niță and Aurica P. Chiriac
Pharmaceutics 2024, 16(4), 550; https://doi.org/10.3390/pharmaceutics16040550 - 17 Apr 2024
Cited by 1 | Viewed by 1209
Abstract
In recent years, increasing interest has been accorded to polyester-based polymer microstructures, driven by their promising potential as advanced drug delivery systems. This study presents the preparation and characterization of new polymeric microparticles based on poly(ethylene brassylate-co-squaric acid) loaded with norfloxacin, a broad-spectrum [...] Read more.
In recent years, increasing interest has been accorded to polyester-based polymer microstructures, driven by their promising potential as advanced drug delivery systems. This study presents the preparation and characterization of new polymeric microparticles based on poly(ethylene brassylate-co-squaric acid) loaded with norfloxacin, a broad-spectrum antibiotic. Polymacrolactone was synthesised in mild conditions through the emulsion polymerization of bio-based and renewable monomers, ethylene brassylate, and squaric acid. The microparticles were obtained using the precipitation technique and subsequently subjected to comprehensive characterization. The impact of the copolymer/drug ratio on various properties of the new system was systematically evaluated, confirming the structure of the copolymer and the encapsulation of norfloxacin. The microspheres are approximately spherical and predominantly homogeneously distributed. The average hydrodynamic diameter of the microparticles falls between 400 and 2000 nm, a decrease that is observed with the increase in norfloxacin content. All samples showed good encapsulation efficiency and drug loading capacity, with the highest values obtained for microparticles synthesised using an equal ratio of copolymer and drug. In vitro drug release results disclose that norfloxacin molecules are released in a sustained biphasic manner for up to 24 h. Antimicrobial activity was also studied, with samples showing very good activity against E. coli and moderate activity against S. aureus and E. faecalis. In addition, HDFA human fibroblast cell cultures demonstrated the cytocompatibility of the microparticles. Full article
(This article belongs to the Special Issue Recent Advances in Carriers for Drug Delivery: From Structures to Functionality)
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15 pages, 2928 KiB  
Article
Cryo-Milled β-Glucan Nanoparticles for Oral Drug Delivery
by Guanyu Chen, Yi Liu, Darren Svirskis, Hongyu Li, Man Ying, Weiyue Lu and Jingyuan Wen
Pharmaceutics 2024, 16(4), 546; https://doi.org/10.3390/pharmaceutics16040546 - 16 Apr 2024
Viewed by 1481
Abstract
Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a [...] Read more.
Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a novel nanoparticulate drug delivery system for the oral delivery of gemcitabine to improve its oral bioavailability. In this study, gemcitabine-loaded β-glucan NPs were fabricated using a film-casting method followed by a freezer-milling technique. As a result, the NPs showed a small particle size of 447.6 ± 14.2 nm, and a high drug entrapment efficiency of 64.3 ± 2.1%. By encapsulating gemcitabine into β-glucan NPs, a sustained drug release profile was obtained, and the anomalous diffusion release mechanism was analyzed, indicating that the drug release was governed by diffusion through the NP matrix as well as matrix erosion. The drug-loaded NPs had a greater ex vivo drug permeation through the porcine intestinal epithelial membrane compared to the plain drug solution. Cytotoxicity studies showed a safety profile of the β-glucan polymers, and the IC50s of drug solution and drug-loaded β-glucan NPs were calculated as 228.8 ± 31.2 ng·mL−1 and 306.1 ± 46.3 ng·mL−1, respectively. Additionally, the LD50 of BALB/c nude mice was determined as 204.17 mg/kg in the acute toxicity studies. Notably, pharmacokinetic studies showed that drug-loaded β-glucan NPs could achieve a 7.4-fold longer T1/2 and a 5.1-fold increase in oral bioavailability compared with plain drug solution. Finally, in vivo pharmacodynamic studies showed the promising capability of gemcitabine-loaded β-glucan NPs to inhibit the 4T1 breast tumor growth, with a 3.04- and 1.74-fold reduction compared to the untreated control and drug solution groups, respectively. In conclusion, the presented freezer-milled β-glucan NP system is a suitable drug delivery method for the oral delivery of gemcitabine and demonstrates a promising potential platform for oral chemotherapy. Full article
(This article belongs to the Special Issue Advances in Oral Administration)
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39 pages, 1216 KiB  
Review
Aptamers for the Delivery of Plant-Based Compounds: A Review
by Joana Gamboa, Pedro Lourenço, Carla Cruz and Eugenia Gallardo
Pharmaceutics 2024, 16(4), 541; https://doi.org/10.3390/pharmaceutics16040541 - 14 Apr 2024
Viewed by 2325
Abstract
Natural compounds have a high potential for the treatment of various conditions, including infections, inflammatory diseases, and cancer. However, they usually present poor pharmacokinetics, low specificity, and even toxicity, which limits their use. Therefore, targeted drug delivery systems, typically composed of a carrier [...] Read more.
Natural compounds have a high potential for the treatment of various conditions, including infections, inflammatory diseases, and cancer. However, they usually present poor pharmacokinetics, low specificity, and even toxicity, which limits their use. Therefore, targeted drug delivery systems, typically composed of a carrier and a targeting ligand, can enhance natural product selectivity and effectiveness. Notably, aptamers—short RNA or single-stranded DNA molecules—have gained attention as promising ligands in targeted drug delivery since they are simple to synthesize and modify, and they present high tissue permeability, stability, and a wide array of available targets. The combination of natural products, namely plant-based compounds, with a drug delivery system utilizing aptamers as targeting agents represents an emerging strategy that has the potential to broaden its applications. This review discusses the potential of aptamers as targeting agents in the delivery of natural compounds, as well as new trends and developments in their utilization in the field of medicine. Full article
(This article belongs to the Special Issue Novel Technological Approaches for Targeted Drug Delivery Systems)
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34 pages, 627 KiB  
Review
Comprehensive Therapeutic Approaches to Tuberculous Meningitis: Pharmacokinetics, Combined Dosing, and Advanced Intrathecal Therapies
by Ahmad Khalid Madadi and Moon-Jun Sohn
Pharmaceutics 2024, 16(4), 540; https://doi.org/10.3390/pharmaceutics16040540 - 14 Apr 2024
Cited by 1 | Viewed by 2638
Abstract
Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood–brain barrier (BBB), which significantly restricts the [...] Read more.
Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood–brain barrier (BBB), which significantly restricts the delivery of anti-tuberculous medications to the central nervous system (CNS), leading to subtherapeutic drug levels and poor treatment outcomes. The standard regimen for initial TBM treatment frequently falls short, followed by adverse side effects, vasculitis, and hydrocephalus, driving the condition toward a refractory state. To overcome this obstacle, intrathecal (IT) sustained release of anti-TB medication emerges as a promising approach. This method enables a steady, uninterrupted, and prolonged release of medication directly into the cerebrospinal fluid (CSF), thus preventing systemic side effects by limiting drug exposure to the rest of the body. Our review diligently investigates the existing literature and treatment methodologies, aiming to highlight their shortcomings. As part of our enhanced strategy for sustained IT anti-TB delivery, we particularly seek to explore the utilization of nanoparticle-infused hydrogels containing isoniazid (INH) and rifampicin (RIF), alongside osmotic pump usage, as innovative treatments for TBM. This comprehensive review delineates an optimized framework for the management of TBM, including an integrated approach that combines pharmacokinetic insights, concomitant drug administration strategies, and the latest advancements in IT and intraventricular (IVT) therapy for CNS infections. By proposing a multifaceted treatment strategy, this analysis aims to enhance the clinical outcomes for TBM patients, highlighting the critical role of targeted drug delivery in overcoming the formidable challenges presented by the blood–brain barrier and the complex pathophysiology of TBM. Full article
(This article belongs to the Topic Challenges and Future Prospects of Antibacterial Therapy)
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18 pages, 4092 KiB  
Article
First Generic Teriparatide: Structural and Biological Sameness to Its Reference Medicinal Product
by Jimena Fernández-Carneado, Mariona Vallès-Miret, Sílvia Arrastia-Casado, Ana Almazán-Moga, Maria J. Macias, Pau Martin-Malpartida, Marta Vilaseca, Mireia Díaz-Lobo, Mayte Vazquez, Rosa M. Sanahuja, Gemma Gambús and Berta Ponsati
Pharmaceutics 2024, 16(4), 537; https://doi.org/10.3390/pharmaceutics16040537 - 13 Apr 2024
Cited by 1 | Viewed by 1989
Abstract
Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential [...] Read more.
Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential similarity between synthetic teriparatide BGW and the reference medicinal product (RMP), and thus to ensure the development of the first generic teriparatide drug. Hence, an extensive side-by-side comparative exercise, focusing on structural and biological activity, was performed using a wide range of state-of-the-art orthogonal methods. Nuclear magnetic resonance (NMR), ion mobility–mass spectrometry (IM–MS), UV, circular dichroism (CD) and Fourier transform infrared (FTIR) demonstrated the structural similarity between teriparatide BGW and the RMP. Comparative cell-based bioassays showed that the synthetic and recombinant peptides have identical behaviors. Teriparatide BGW, as a generic drug, provides an available treatment option for patients with osteoporosis and offers clinical benefits identical to those provided by the RMP. Full article
(This article belongs to the Section Biologics and Biosimilars)
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20 pages, 2693 KiB  
Article
A Novel Class of Human ADAM8 Inhibitory Antibodies for Treatment of Triple-Negative Breast Cancer
by Nora D. Mineva, Stefania Pianetti, Sonia G. Das, Srimathi Srinivasan, Nicolas M. Billiald and Gail E. Sonenshein
Pharmaceutics 2024, 16(4), 536; https://doi.org/10.3390/pharmaceutics16040536 - 13 Apr 2024
Cited by 2 | Viewed by 1827
Abstract
New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and [...] Read more.
New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange–mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment. Full article
(This article belongs to the Special Issue Advances in Anticancer Agent, 2nd Edition)
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19 pages, 4137 KiB  
Article
Investigation of Photodynamic Therapy Promoted by Cherenkov Light Activated Photosensitizers—New Aspects and Revelations
by Lisa Hübinger, Kerstin Wetzig, Roswitha Runge, Holger Hartmann, Falk Tillner, Katja Tietze, Marc Pretze, David Kästner, Robert Freudenberg, Claudia Brogsitter and Jörg Kotzerke
Pharmaceutics 2024, 16(4), 534; https://doi.org/10.3390/pharmaceutics16040534 - 13 Apr 2024
Viewed by 1107
Abstract
This work investigates the proposed enhanced efficacy of photodynamic therapy (PDT) by activating photosensitizers (PSs) with Cherenkov light (CL). The approaches of Yoon et al. to test the effect of CL with external radiation were taken up and refined. The results were used [...] Read more.
This work investigates the proposed enhanced efficacy of photodynamic therapy (PDT) by activating photosensitizers (PSs) with Cherenkov light (CL). The approaches of Yoon et al. to test the effect of CL with external radiation were taken up and refined. The results were used to transfer the applied scheme from external radiation therapy to radionuclide therapy in nuclear medicine. Here, the CL for the activation of the PSs (psoralen and trioxsalen) is generated by the ionizing radiation from rhenium-188 (a high-energy beta-emitter, Re-188). In vitro cell survival studies were performed on FaDu, B16 and 4T1 cells. A characterization of the PSs (absorbance measurement and gel electrophoresis) and the CL produced by Re-188 (luminescence measurement) was performed as well as a comparison of clonogenic assays with and without PSs. The methods of Yoon et al. were reproduced with a beam line at our facility to validate their results. In our studies with different concentrations of PS and considering the negative controls without PS, the statements of Yoon et al. regarding the positive effect of CL could not be confirmed. There are slight differences in survival fractions, but they are not significant when considering the differences in the controls. Gel electrophoresis showed a dominance of trioxsalen over psoralen in conclusion of single and double strand breaks in plasmid DNA, suggesting a superiority of trioxsalen as a PS (when irradiated with UVA). In addition, absorption measurements showed that these PSs do not need to be shielded from ambient light during the experiment. An observational test setup for a PDT nuclear medicine approach was found. The CL spectrum of Re-188 was measured. Fluctuating inconclusive results from clonogenic assays were found. Full article
(This article belongs to the Special Issue Photodynamic Therapy in Cancer: Principles, State of the Art, and Future Directions)
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17 pages, 872 KiB  
Review
Delivery of DNA-Based Therapeutics for Treatment of Chronic Diseases
by Carleigh Sussman, Rachel A. Liberatore and Marek M. Drozdz
Pharmaceutics 2024, 16(4), 535; https://doi.org/10.3390/pharmaceutics16040535 - 13 Apr 2024
Cited by 1 | Viewed by 2028
Abstract
Gene therapy and its role in the medical field have evolved drastically in recent decades. Studies aim to define DNA-based medicine as well as encourage innovation and the further development of novel approaches. Gene therapy has been established as an alternative approach to [...] Read more.
Gene therapy and its role in the medical field have evolved drastically in recent decades. Studies aim to define DNA-based medicine as well as encourage innovation and the further development of novel approaches. Gene therapy has been established as an alternative approach to treat a variety of diseases. Its range of mechanistic applicability is wide; gene therapy has the capacity to address the symptoms of disease, the body’s ability to fight disease, and in some cases has the ability to cure disease, making it a more attractive intervention than some traditional approaches to treatment (i.e., medicine and surgery). Such versatility also suggests gene therapy has the potential to address a greater number of indications than conventional treatments. Many DNA-based therapies have shown promise in clinical trials, and several have been approved for use in humans. Whereas current treatment regimens for chronic disease often require frequent dosing, DNA-based therapies can produce robust and durable expression of therapeutic genes with fewer treatments. This benefit encourages the application of DNA-based gene therapy to manage chronic diseases, an area where improving efficiency of current treatments is urgent. Here, we provide an overview of two DNA-based gene therapies as well as their delivery methods: adeno associated virus (AAV)-based gene therapy and plasmid DNA (pDNA)-based gene therapy. We will focus on how these therapies have already been utilized to improve treatment of chronic disease, as well as how current literature supports the expansion of these therapies to treat additional chronic indications in the future. Full article
(This article belongs to the Special Issue Plasmid DNA for Gene Therapy and DNA Vaccine Applications, 2nd Edition)
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22 pages, 4338 KiB  
Article
Non-Invasive Delivery of Negatively Charged Nanobodies by Anodal Iontophoresis: When Electroosmosis Dominates Electromigration
by Phedra Firdaws Sahraoui, Oscar Vadas and Yogeshvar N. Kalia
Pharmaceutics 2024, 16(4), 539; https://doi.org/10.3390/pharmaceutics16040539 - 13 Apr 2024
Viewed by 1476
Abstract
Iontophoresis enables the non-invasive transdermal delivery of moderately-sized proteins and the needle-free cutaneous delivery of antibodies. However, simple descriptors of protein characteristics cannot accurately predict the feasibility of iontophoretic transport. This study investigated the cathodal and anodal iontophoretic transport of the negatively charged [...] Read more.
Iontophoresis enables the non-invasive transdermal delivery of moderately-sized proteins and the needle-free cutaneous delivery of antibodies. However, simple descriptors of protein characteristics cannot accurately predict the feasibility of iontophoretic transport. This study investigated the cathodal and anodal iontophoretic transport of the negatively charged M7D12H nanobody and a series of negatively charged variants with single amino acid substitutions. Surprisingly, M7D12H and its variants were only delivered transdermally by anodal iontophoresis. In contrast, transdermal permeation after cathodal iontophoresis and passive diffusion was <LOQ. The anodal iontophoretic delivery of these negatively charged proteins was achieved because electroosmosis was the dominant electrotransport mechanism. Cutaneous deposition after the anodal iontophoresis of M7D12HWT (wild type), and the R54E and K65E variants, was statistically superior to that after cathodal iontophoresis (6.07 ± 2.11, 9.22 ± 0.80, and 14.45 ± 3.45 μg/cm2, versus 1.12 ± 0.30, 0.72 ± 0.27, and 0.46 ± 0.07 µg/cm2, respectively). This was not the case for S102E, where cutaneous deposition after anodal and cathodal iontophoresis was 11.89 ± 0.87 and 8.33 ± 2.62 µg/cm2, respectively; thus, a single amino acid substitution appeared to be sufficient to impact the iontophoretic transport of a 17.5 kDa protein. Visualization studies using immunofluorescent labeling showed that skin transport of M7D12HWT was achieved via the intercellular and follicular routes. Full article
(This article belongs to the Special Issue Transdermal Delivery: Challenges and Opportunities)
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32 pages, 12016 KiB  
Review
Cell Membrane-Coated Biomimetic Nanoparticles in Cancer Treatment
by Shu Zhang, Xiaojuan Zhang, Huan Gao, Xiaoqin Zhang, Lidan Sun, Yueyan Huang, Jie Zhang and Baoyue Ding
Pharmaceutics 2024, 16(4), 531; https://doi.org/10.3390/pharmaceutics16040531 - 12 Apr 2024
Cited by 6 | Viewed by 2247
Abstract
Nanoparticle-based drug delivery systems hold promise for cancer treatment by enhancing the solubility and stability of anti-tumor drugs. Nonetheless, the challenges of inadequate targeting and limited biocompatibility persist. In recent years, cell membrane nano-biomimetic drug delivery systems have emerged as a focal point [...] Read more.
Nanoparticle-based drug delivery systems hold promise for cancer treatment by enhancing the solubility and stability of anti-tumor drugs. Nonetheless, the challenges of inadequate targeting and limited biocompatibility persist. In recent years, cell membrane nano-biomimetic drug delivery systems have emerged as a focal point of research and development, due to their exceptional traits, including precise targeting, low toxicity, and good biocompatibility. This review outlines the categorization and advantages of cell membrane bionic nano-delivery systems, provides an introduction to preparation methods, and assesses their applications in cancer treatment, including chemotherapy, gene therapy, immunotherapy, photodynamic therapy, photothermal therapy, and combination therapy. Notably, the review delves into the challenges in the application of various cell membrane bionic nano-delivery systems and identifies opportunities for future advancement. Embracing cell membrane-coated biomimetic nanoparticles presents a novel and unparalleled avenue for personalized tumor therapy. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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24 pages, 3499 KiB  
Review
Mirk/Dyrk1B Kinase Inhibitors in Targeted Cancer Therapy
by Nikolaos Kokkorakis, Marios Zouridakis and Maria Gaitanou
Pharmaceutics 2024, 16(4), 528; https://doi.org/10.3390/pharmaceutics16040528 - 11 Apr 2024
Cited by 1 | Viewed by 1843
Abstract
During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising [...] Read more.
During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising pharmacological target in cancer since it is overexpressed in many tumors, and its overexpression is correlated with patients’ poor prognosis. Mirk/Dyrk1B acts as a negative cell cycle regulator, maintaining the survival of quiescent cancer cells and conferring their resistance to chemotherapies. Many studies have demonstrated the valuable therapeutic effect of Mirk/Dyrk1B inhibitors in cancer cell lines, mouse xenografts, and patient-derived 3D-organoids, providing a perspective for entering clinical trials. Since the majority of Mirk/Dyrk1B inhibitors target the highly conserved ATP-binding site, they exhibit off-target effects with other kinases, especially with the highly similar Dyrk1A. In this review, apart from summarizing the data establishing Dyrk1B as a therapeutic target in cancer, we highlight the most potent Mirk/Dyrk1B inhibitors recently reported. We also discuss the limitations and perspectives for the structure-based design of Mirk/Dyrk1B potent and highly selective inhibitors based on the accumulated structural data of Dyrk1A and the recent crystal structure of Dyrk1B with AZ191 inhibitor. Full article
(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy, 2nd Edition)
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27 pages, 547 KiB  
Review
Progress in the Use of Hydrogels for Antioxidant Delivery in Skin Wounds
by Lidia Maeso, Pablo Edmundo Antezana, Ailen Gala Hvozda Arana, Pablo Andrés Evelson, Gorka Orive and Martín Federico Desimone
Pharmaceutics 2024, 16(4), 524; https://doi.org/10.3390/pharmaceutics16040524 - 10 Apr 2024
Cited by 2 | Viewed by 1495
Abstract
The skin is the largest organ of the body, and it acts as a protective barrier against external factors. Chronic wounds affect millions of people worldwide and are associated with significant morbidity and reduced quality of life. One of the main factors involved [...] Read more.
The skin is the largest organ of the body, and it acts as a protective barrier against external factors. Chronic wounds affect millions of people worldwide and are associated with significant morbidity and reduced quality of life. One of the main factors involved in delayed wound healing is oxidative injury, which is triggered by the overproduction of reactive oxygen species. Oxidative stress has been implicated in the pathogenesis of chronic wounds, where it is known to impair wound healing by causing damage to cellular components, delaying the inflammatory phase of healing, and inhibiting the formation of new blood vessels. Thereby, the treatment of chronic wounds requires a multidisciplinary approach that addresses the underlying causes of the wound, provides optimal wound care, and promotes wound healing. Among the promising approaches to taking care of chronic wounds, antioxidants are gaining interest since they offer multiple benefits related to skin health. Therefore, in this review, we will highlight the latest advances in the use of natural polymers with antioxidants to generate tissue regeneration microenvironments for skin wound healing. Full article
(This article belongs to the Special Issue Biopolymer Materials for Wound Healing, 2nd Edition)
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14 pages, 2287 KiB  
Article
Interaction of γ-Polyglutamic Acid/Polyethyleneimine/Plasmid DNA Ternary Complexes with Serum Components Plays a Crucial Role in Transfection in Mice
by Tomotaka Ko, Shintaro Fumoto, Tomoaki Kurosaki, Moe Nakashima, Hirotaka Miyamoto, Hitoshi Sasaki and Koyo Nishida
Pharmaceutics 2024, 16(4), 522; https://doi.org/10.3390/pharmaceutics16040522 - 9 Apr 2024
Cited by 1 | Viewed by 1032
Abstract
Typical examples of non-viral vectors are binary complexes of plasmid DNA with cationic polymers such as polyethyleneimine (PEI). However, problems such as cytotoxicity and hemagglutination, owing to their positively charged surfaces, hinder their in vivo use. Coating binary complexes with anionic polymers, such [...] Read more.
Typical examples of non-viral vectors are binary complexes of plasmid DNA with cationic polymers such as polyethyleneimine (PEI). However, problems such as cytotoxicity and hemagglutination, owing to their positively charged surfaces, hinder their in vivo use. Coating binary complexes with anionic polymers, such as γ-polyglutamic acid (γ-PGA), can prevent cytotoxicity and hemagglutination. However, the role of interactions between these complexes and serum components in in vivo gene transfer remains unclear. In this study, we analyzed the contribution of serum components to in vivo gene transfer using PEI/plasmid DNA binary complexes and γ-PGA/PEI/plasmid DNA ternary complexes. In binary complexes, heat-labile components in the serum greatly contribute to the hepatic and splenic gene expression of the luciferase gene. In contrast, serum albumin and salts affected the hepatic and splenic gene expression in the ternary complexes. Changes in physicochemical characteristics, such as increased particle size and decreased absolute values of ζ-potential, might be involved in the enhanced gene expression. These findings would contribute to a better understanding of in vivo non-viral gene transfer using polymers, such as PEI and γ-PGA. Full article
(This article belongs to the Section Gene and Cell Therapy)
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10 pages, 706 KiB  
Communication
Therapeutic Aqueous Humor Concentrations of Latanoprost Attained in Rats by Administration in a Very-High-Molecular-Weight Hyaluronic Acid Eye Drop
by Kazunari Higa, Reona Kimoto, Takashi Kojima, Murat Dogru, Wolfgang G. K. Müller-Lierheim and Jun Shimazaki
Pharmaceutics 2024, 16(4), 523; https://doi.org/10.3390/pharmaceutics16040523 - 9 Apr 2024
Cited by 1 | Viewed by 1053
Abstract
The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA [...] Read more.
The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA (LPvHiHA), commercial LP (cLP), and diluted LP (dLP)) and after instilling the eye drops, the aqueous humor (AH) was collected at 0.5, 1, 2, 4, and 6 h to measure the LP concentration using an enzyme-linked immunosorbent assay (ELISA). Although the LP concentration in the LPvHiHA eye drop formulation was 3.57 times lower than in the commercial eye drops used (cLP), the LP concentration in the AH following LPvHiHA administration reached a value close to that of cLP. The cLP was diluted to the same concentration of LP as in the LPvHiHA eye drops for the dLP group, but the LP concentration in the AH of these animals was lower than that of the LPvHiHA rats at all time points. The higher LP concentration in the AH of the LPvHiHA rats suggests that vHiHA may aid the transport of LP across the ocular surface epithelium. Full article
(This article belongs to the Special Issue Advances in Ocular Drug Delivery)
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14 pages, 7480 KiB  
Article
Size Tuning of Mesoporous Silica Adjuvant for One-Shot Vaccination with Long-Term Anti-Tumor Effect
by Xiupeng Wang, Yu Sogo and Xia Li
Pharmaceutics 2024, 16(4), 516; https://doi.org/10.3390/pharmaceutics16040516 - 8 Apr 2024
Viewed by 1462
Abstract
Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect [...] Read more.
Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect by one-shot vaccination. This strategy is based on the size-dependent immunostimulation mechanism of mesoporous silica particles. Hollow mesoporous silica (HMS) nanoparticles enhance the antigen uptake with dendritic cells around the immunization site in vivo. In contrast, hierarchically porous silica (HPS) microparticles prolong cancer antigen retention and release in vivo. The size tuning of the mesoporous silica adjuvant prepared by combining both nanoparticles and microparticles demonstrates the immunological properties of both components and has a long-term anti-tumor effect after one-shot vaccination. One-shot vaccination with HMS-HPS-ovalbumin (OVA)-Poly IC (PIC, a TLR3 agonist) increases CD4+ T cell, CD8+ T cell, and CD86+ cell populations in draining lymph nodes even 4 months after vaccination, as well as effector memory CD8+ T cell and tumor-specific tetramer+CD8+ T cell populations in splenocytes. The increases in the numbers of effector memory CD8+ T cells and tumor-specific tetramer+CD8+ T cells indicate that the one-shot vaccination with HMS-HPS-OVA-PIC achieved the longest survival time after a challenge with E.G7-OVA cells among all groups. The size tuning of the mesoporous silica adjuvant shows promise for one-shot vaccination that mimics multiple clinical vaccinations in future cancer immunoadjuvant development. This study may have important implications in the long-term vaccine design of one-shot vaccinations. Full article
(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)
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21 pages, 3557 KiB  
Article
Effect of Micromixer Design on Lipid Nanocarriers Manufacturing for the Delivery of Proteins and Nucleic Acids
by Enrica Chiesa, Alessandro Caimi, Marco Bellotti, Alessia Giglio, Bice Conti, Rossella Dorati, Ferdinando Auricchio and Ida Genta
Pharmaceutics 2024, 16(4), 507; https://doi.org/10.3390/pharmaceutics16040507 - 7 Apr 2024
Cited by 2 | Viewed by 1569
Abstract
Lipid-based nanocarriers have emerged as helpful tools to deliver sensible biomolecules such as proteins and oligonucleotides. To have a fast and robust microfluidic-based nanoparticle synthesis method, the setup of versatile equipment should allow for the rapid transfer to scale cost-effectively while ensuring tunable, [...] Read more.
Lipid-based nanocarriers have emerged as helpful tools to deliver sensible biomolecules such as proteins and oligonucleotides. To have a fast and robust microfluidic-based nanoparticle synthesis method, the setup of versatile equipment should allow for the rapid transfer to scale cost-effectively while ensuring tunable, precise and reproducible nanoparticle attributes. The present work aims to assess the effect of different micromixer geometries on the manufacturing of lipid nanocarriers taking into account the influence on the mixing efficiency by changing the fluid–fluid interface and indeed the mass transfer. Since the geometry of the adopted micromixer varies from those already published, a Design of Experiment (DoE) was necessary to identify the operating (total flow, flow rate ratio) and formulation (lipid concentration, lipid molar ratios) parameters affecting the nanocarrier quality. The suitable application of the platform was investigated by producing neutral, stealth and cationic liposomes, using DaunoXome®, Myocet®, Onivyde® and Onpattro® as the benchmark. The effect of condensing lipid (DOTAP, 3–10–20 mol%), coating lipids (DSPE-PEG550 and DSPE-PEG2000), as well as structural lipids (DSPC, eggPC) was pointed out. A very satisfactory encapsulation efficiency, always higher than 70%, was successfully obtained for model biomolecules (myoglobin, short and long nucleic acids). Full article
(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)
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14 pages, 14092 KiB  
Article
Polydopamine-Modified Copper Coordination Mesoporous Silica Nanoparticles Loaded with Disulfiram for Synergistic Chemo-Photothermal Therapy
by Junhong Ling, Yingying Cai, Haozhan Feng, Zhen Liu and Xiao-kun Ouyang
Pharmaceutics 2024, 16(4), 512; https://doi.org/10.3390/pharmaceutics16040512 - 7 Apr 2024
Cited by 2 | Viewed by 1664
Abstract
Disulfiram (DSF) degrades to diethyldithiocarbamate (DTC) in vivo and coordinates with copper ions to form CuET, which has higher antitumor activity. In this study, DSF@CuMSN-PDA nanoparticles were prepared using mesoporous silica with copper ions, DSF as a carrier, and polydopamine (PDA) as a [...] Read more.
Disulfiram (DSF) degrades to diethyldithiocarbamate (DTC) in vivo and coordinates with copper ions to form CuET, which has higher antitumor activity. In this study, DSF@CuMSN-PDA nanoparticles were prepared using mesoporous silica with copper ions, DSF as a carrier, and polydopamine (PDA) as a gate system. The nanoparticles selectively released CuET into tumor tissue by taking advantage of the tumor microenvironment, where PDA could be degraded. The release ratio reached 79.17% at pH 5.0, indicating pH-responsive drug release from the nanoparticles. The PDA-gated system provided the nanoparticles with unique photothermal conversion performance and significantly improved antitumor efficiency. In vivo, antitumor experiments showed that the designed DSF@CuMSN-PDA nanoparticles combined with near-infrared light (808 nm, 1 W/cm2) irradiation effectively inhibited tumor growth in HCT116 cells by harnessing the combined potential of chemotherapy and photothermal therapy; a synergistic effect was achieved. Taken together, these results suggest that the designed DSF@CuMSN-PDA construct can be employed as a promising candidate for combined chemo-photothermal therapy. Full article
(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)
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16 pages, 3464 KiB  
Article
Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation
by Yong-Kyun Kim, Kyeong-Min Jo, Jae-Ha Lee, Ji-Hoon Jang, Eun-Jun Choe, Gaeun Kang, Dae-Young Zang and Dong-Hwan Lee
Pharmaceutics 2024, 16(4), 499; https://doi.org/10.3390/pharmaceutics16040499 - 5 Apr 2024
Viewed by 1391
Abstract
In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK [...] Read more.
In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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29 pages, 1791 KiB  
Article
Comparative Fitting of Mathematical Models to Carvedilol Release Profiles Obtained from Hypromellose Matrix Tablets
by Tadej Ojsteršek, Franc Vrečer and Grega Hudovornik
Pharmaceutics 2024, 16(4), 498; https://doi.org/10.3390/pharmaceutics16040498 - 4 Apr 2024
Cited by 2 | Viewed by 1061
Abstract
The mathematical models available in DDSolver were applied to experimental dissolution data obtained by analysing carvedilol release from hypromellose (HPMC)-based matrix tablets. Different carvedilol release profiles were generated by varying a comprehensive selection of fillers and carvedilol release modifiers in the formulation. Model [...] Read more.
The mathematical models available in DDSolver were applied to experimental dissolution data obtained by analysing carvedilol release from hypromellose (HPMC)-based matrix tablets. Different carvedilol release profiles were generated by varying a comprehensive selection of fillers and carvedilol release modifiers in the formulation. Model fitting was conducted for the entire relevant dissolution data, as determined by using a paired t-test, and independently for dissolution data up to approximately 60% of carvedilol released. The best models were selected based on the residual sum of squares (RSS) results used as a general measure of goodness of fit, along with the utilization of various criteria for visual assessment of model fit and determination of the acceptability of estimated model parameters indicating burst release or lag time concerning experimental dissolution results and previous research. In addition, a model-dependent analysis of carvedilol release mechanisms was carried out. Full article
(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)
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20 pages, 5222 KiB  
Article
Unraveling Drug Delivery from Cyclodextrin Polymer-Coated Breast Implants: Integrating a Unidirectional Diffusion Mathematical Model with COMSOL Simulations
by Jacobo Hernandez-Montelongo, Javiera Salazar-Araya, Elizabeth Mas-Hernández, Douglas Soares Oliveira and Juan Paulo Garcia-Sandoval
Pharmaceutics 2024, 16(4), 486; https://doi.org/10.3390/pharmaceutics16040486 - 2 Apr 2024
Viewed by 1559
Abstract
Breast cancer ranks among the most commonly diagnosed cancers worldwide and bears the highest mortality rate. As an integral component of cancer treatment, mastectomy entails the complete removal of the affected breast. Typically, breast reconstruction, involving the use of silicone implants (augmentation mammaplasty), [...] Read more.
Breast cancer ranks among the most commonly diagnosed cancers worldwide and bears the highest mortality rate. As an integral component of cancer treatment, mastectomy entails the complete removal of the affected breast. Typically, breast reconstruction, involving the use of silicone implants (augmentation mammaplasty), is employed to address the aftermath of mastectomy. To mitigate postoperative risks associated with mammaplasty, such as capsular contracture or bacterial infections, the functionalization of breast implants with coatings of cyclodextrin polymers as drug delivery systems represents an excellent alternative. In this context, our work focuses on the application of a mathematical model for simulating drug release from breast implants coated with cyclodextrin polymers. The proposed model considers a unidirectional diffusion process following Fick’s second law, which was solved using the orthogonal collocation method, a numerical technique employed to approximate solutions for ordinary and partial differential equations. We conducted simulations to obtain release profiles for three therapeutic molecules: pirfenidone, used for preventing capsular contracture; rose Bengal, an anticancer agent; and the antimicrobial peptide KR-12. Furthermore, we calculated the diffusion profiles of these drugs through the cyclodextrin polymers, determining parameters related to diffusivity, solute solid–liquid partition coefficients, and the Sherwood number. Finally, integrating these parameters in COMSOL multiphysics simulations, the unidirectional diffusion mathematical model was validated. Full article
(This article belongs to the Special Issue Mathematical Modeling in Drug Delivery)
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30 pages, 6228 KiB  
Article
The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine
by Khairulanwar Burhanuddin, Afzal Mohammed and Raj K. S. Badhan
Pharmaceutics 2024, 16(4), 489; https://doi.org/10.3390/pharmaceutics16040489 - 2 Apr 2024
Viewed by 1610
Abstract
The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity [...] Read more.
The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity on amlodipine pharmacokinetics and the need for dose adjustment has not been studied previously. This study applied the physiologically based pharmacokinetic modelling and established a paediatric obesity population to assess the impact of obesity on amlodipine pharmacokinetics in children and explore the possible dose adjustments required to reach the same plasma concentration as non-obese paediatrics. The difference in predicted maximum concentration (Cmax) and area under the curve (AUC) were significant between children with and without obesity across the age group 2 to 18 years old when a fixed-dose regimen was used. On the contrary, a weight-based dose regimen showed no difference in Cmax between obese and non-obese from 2 to 9 years old. Thus, when a fixed-dose regimen is to be administered, a 1.25- to 1.5-fold increase in dose is required in obese children to achieve the same Cmax concentration as non-obese children, specifically for children aged 5 years and above. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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19 pages, 3966 KiB  
Article
Membrane-Fusing Vehicles for Re-Sensitizing Transporter-Mediated Multiple-Drug Resistance in Cancer
by Sahel Vahdati and Alf Lamprecht
Pharmaceutics 2024, 16(4), 493; https://doi.org/10.3390/pharmaceutics16040493 - 2 Apr 2024
Cited by 1 | Viewed by 1155
Abstract
Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three [...] Read more.
Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC50 value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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20 pages, 5181 KiB  
Article
Ionic Liquid Transdermal Patches of Two Active Ingredients Based on Semi-Ionic Hydrogen Bonding for Rheumatoid Arthritis Treatment
by Faxing Zhang, Lu Li, Xinyuan Zhang, Hongyu Yang, Yingzhen Fan, Jian Zhang, Ting Fang, Yaming Liu, Zhihao Nie and Dongkai Wang
Pharmaceutics 2024, 16(4), 480; https://doi.org/10.3390/pharmaceutics16040480 - 1 Apr 2024
Cited by 3 | Viewed by 1618
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to deformities and disabilities in patients. Conventional treatment focuses on delaying progression; therefore, new treatments are necessary. The present study reported a novel ionic liquid transdermal platform for efficient RA treatment, and the [...] Read more.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to deformities and disabilities in patients. Conventional treatment focuses on delaying progression; therefore, new treatments are necessary. The present study reported a novel ionic liquid transdermal platform for efficient RA treatment, and the underlying mechanism was elucidated using FTIR, 1H-NMR, Raman, XPS, and molecular simulations. The results showed that the reversibility of the semi-ionic hydrogen bonding facilitated high drug loading and enhanced drug permeability. Actarit’s drug loading had an approximately 11.34-times increase. The in vitro permeability of actarit and ketoprofen was improved by 5.46 and 2.39 times, respectively. And they had the same significant effect in vivo. Furthermore, through the integration of network pharmacology, Western blotting (WB), and radiology analyses, the significant osteoprotective effects of SIHDD-PSA (semi-ionic H-bond double-drug pressure-sensitive adhesive transdermal patch) were revealed through the modulation of the JAK-STAT pathway. The SIHDD-PSA significantly reduced paw swelling and inflammation in the rat model, and stimulatory properties evaluation confirmed the safety of SIHDD-PSA. In conclusion, these findings provide a novel approach for the effective treatment of RA, and the semi-ionic hydrogen bonding strategy contributes a new theoretical basis for developing TDDS. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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16 pages, 5552 KiB  
Review
Engineering Nanomedicine for Non-Viral RNA-Based Gene Therapy of Glioblastoma
by Wenya He, Ningyang Wang, Yaping Wang, Mengyao Liu, Qian Qing, Qihang Su, Yan Zou and Yang Liu
Pharmaceutics 2024, 16(4), 482; https://doi.org/10.3390/pharmaceutics16040482 - 1 Apr 2024
Viewed by 2102
Abstract
Glioblastoma multiforme (GBM) is the most common type of malignant tumor of the central nervous system, characterized by aggressiveness, genetic instability, heterogenesis, and unpredictable clinical behavior. Disappointing results from the current clinical therapeutic methods have fueled a search for new therapeutic targets and [...] Read more.
Glioblastoma multiforme (GBM) is the most common type of malignant tumor of the central nervous system, characterized by aggressiveness, genetic instability, heterogenesis, and unpredictable clinical behavior. Disappointing results from the current clinical therapeutic methods have fueled a search for new therapeutic targets and treatment modalities. GBM is characterized by various genetic alterations, and RNA-based gene therapy has raised particular attention in GBM therapy. Here, we review the recent advances in engineered non-viral nanocarriers for RNA drug delivery to treat GBM. Therapeutic strategies concerning the brain-targeted delivery of various RNA drugs involving siRNA, microRNA, mRNA, ASO, and short-length RNA and the therapeutical mechanisms of these drugs to tackle the challenges of chemo-/radiotherapy resistance, recurrence, and incurable stem cell-like tumor cells of GBM are herein outlined. We also highlight the progress, prospects, and remaining challenges of non-viral nanocarriers-mediated RNA-based gene therapy. Full article
(This article belongs to the Special Issue Nanocarriers: A Novel Strategy for Cell and Gene Delivery)
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28 pages, 5511 KiB  
Review
Evaluation of Advanced Nanomaterials for Cancer Diagnosis and Treatment
by Nkanyiso L. Ndlovu, Wendy B. Mdlalose, Bulelwa Ntsendwana and Thomas Moyo
Pharmaceutics 2024, 16(4), 473; https://doi.org/10.3390/pharmaceutics16040473 - 28 Mar 2024
Cited by 5 | Viewed by 3493
Abstract
Cancer is a persistent global disease and a threat to the human species, with numerous cases reported every year. Over recent decades, a steady but slowly increasing mortality rate has been observed. While many attempts have been made using conventional methods alone as [...] Read more.
Cancer is a persistent global disease and a threat to the human species, with numerous cases reported every year. Over recent decades, a steady but slowly increasing mortality rate has been observed. While many attempts have been made using conventional methods alone as a theragnostic strategy, they have yielded very little success. Most of the shortcomings of such conventional methods can be attributed to the high demands of industrial growth and ever-increasing environmental pollution. This requires some high-tech biomedical interventions and other solutions. Thus, researchers have been compelled to explore alternative methods. This has brought much attention to nanotechnology applications, specifically magnetic nanomaterials, as the sole or conjugated theragnostic methods. The exponential growth of nanomaterials with overlapping applications in various fields is due to their potential properties, which depend on the type of synthesis route used. Either top-down or bottom-up strategies synthesize various types of NPs. The top-down only branches out to one method, i.e., physical, and the bottom-up has two methods, chemical and biological syntheses. This review highlights some synthesis techniques, the types of nanoparticle properties each technique produces, and their potential use in the biomedical field, more specifically for cancer. Despite the evident drawbacks, the success achieved in furthering nanoparticle applications to more complex cancer stages and locations is unmatched. Full article
(This article belongs to the Special Issue Research on New Strategies for Tumor Therapy Based on Nanostructured Materials)
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14 pages, 3576 KiB  
Article
Influenza Virus Inactivated by Heavy Ion Beam Irradiation Stimulates Antigen-Specific Immune Responses
by Kai Schulze, Ulrich Weber, Christoph Schuy, Marco Durante and Carlos Alberto Guzmán
Pharmaceutics 2024, 16(4), 465; https://doi.org/10.3390/pharmaceutics16040465 - 27 Mar 2024
Cited by 1 | Viewed by 2213
Abstract
The COVID-19 pandemic has made clear the need for effective and rapid vaccine development methods. Conventional inactivated virus vaccines, together with new technologies like vector and mRNA vaccines, were the first to be rolled out. However, the traditional methods used for virus inactivation [...] Read more.
The COVID-19 pandemic has made clear the need for effective and rapid vaccine development methods. Conventional inactivated virus vaccines, together with new technologies like vector and mRNA vaccines, were the first to be rolled out. However, the traditional methods used for virus inactivation can affect surface-exposed antigen, thereby reducing vaccine efficacy. Gamma rays have been used in the past to inactivate viruses. We recently proposed that high-energy heavy ions may be more suitable as an inactivation method because they increase the damage ratio between the viral nucleic acid and surface proteins. Here, we demonstrate that irradiation of the influenza virus using heavy ion beams constitutes a suitable method to develop effective vaccines, since immunization of mice by the intranasal route with the inactivated virus resulted in the stimulation of strong antigen-specific humoral and cellular immune responses. Full article
(This article belongs to the Special Issue Emerging Pharmaceutical Strategies against Infectious Diseases)
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40 pages, 20578 KiB  
Review
Recent Advances in Alginate-Based Hydrogels for Cell Transplantation Applications
by Alireza Kavand, François Noverraz and Sandrine Gerber-Lemaire
Pharmaceutics 2024, 16(4), 469; https://doi.org/10.3390/pharmaceutics16040469 - 27 Mar 2024
Cited by 1 | Viewed by 4164
Abstract
With its exceptional biocompatibility, alginate emerged as a highly promising biomaterial for a large range of applications in regenerative medicine. Whether in the form of microparticles, injectable hydrogels, rigid scaffolds, or bioinks, alginate provides a versatile platform for encapsulating cells and fostering an [...] Read more.
With its exceptional biocompatibility, alginate emerged as a highly promising biomaterial for a large range of applications in regenerative medicine. Whether in the form of microparticles, injectable hydrogels, rigid scaffolds, or bioinks, alginate provides a versatile platform for encapsulating cells and fostering an optimal environment to enhance cell viability. This review aims to highlight recent studies utilizing alginate in diverse formulations for cell transplantation, offering insights into its efficacy in treating various diseases and injuries within the field of regenerative medicine. Full article
(This article belongs to the Special Issue Recent Advances in Hydrogels for Biomedical Applications)
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18 pages, 9211 KiB  
Article
Nanonization and Deformable Behavior of Fattigated Peptide Drug in Mucoadhesive Buccal Films
by Woojun Kim, Hai V. Ngo, Hy D. Nguyen, Ji-Min Park, Kye Wan Lee, Chulhun Park, Jun-Bom Park and Beom-Jin Lee
Pharmaceutics 2024, 16(4), 468; https://doi.org/10.3390/pharmaceutics16040468 - 27 Mar 2024
Cited by 1 | Viewed by 1486
Abstract
This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) [...] Read more.
This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) were developed. Additionally, a deformable variant of LON (d-LON) was originally developed by incorporating l-α-phosphatidylcholine into LON as an edge activator. The physicochemical properties of LON and d-LON, encompassing particle size, zeta potential, and deformability index (DI), were evaluated. MBFs containing LEU, LOC, and NPs (LON, d-LON) were prepared using the solvent casting method by varying the ratio of Eudragit RLPO and hydroxypropyl methylcellulose, with propylene glycol used as a plasticizer. The optimization of MBF formulations was based on their physicochemical properties, including in vitro residence time, dissolution, and permeability. The dissolution results demonstrated that the conjugation of oleic acid to LEU exhibited a more sustained LEU release pattern by cleaving the ester bond of the conjugate, as compared to the native LEU, with reduced variability. Moreover, the LOC and its self-assembled NPs (LON, d-LON), equivalent to 1 mg LEU doses in MBF, exhibited an amorphous state and demonstrated better permeability through the nanonization process than LEU alone, regardless of membrane types. The incorporation of lauroyl-L-carnitine into the films as a permeation enhancer synergistically augmented drug permeability. Most importantly, the d-LON-loaded buccal films showed the highest permeability, due to the deformability of NPs. Overall, MBF-containing peptide NPs and permeation enhancers have the potential to replace parenteral LEU administration by improving LEU druggability and patient compliance. Full article
(This article belongs to the Special Issue Mucoadhesive and Mucosal Drug Delivery Systems, 2nd Edition)
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18 pages, 3281 KiB  
Article
AmBisome® Formulations for Pediatrics: Stability, Cytotoxicity, and Cost-Effectiveness Studies
by Guendalina Zuccari, Carla Villa, Valentina Iurilli, Paola Barabino, Alessia Zorzoli, Danilo Marimpietri, Debora Caviglia and Eleonora Russo
Pharmaceutics 2024, 16(4), 466; https://doi.org/10.3390/pharmaceutics16040466 - 27 Mar 2024
Viewed by 2663
Abstract
Liposomal amphotericin B (Ambisome®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be [...] Read more.
Liposomal amphotericin B (Ambisome®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be challenging due to the spontaneous tendency of amphotericin B to form aggregates with different biological activity. In this study, the colloidal stability of the liposomes and the chemical stability of amphotericin B were investigated over time at storage conditions. Three liposomal formulations of amphotericin B at 4.0 mg/mL, 2.0 mg/mL, and 0.2 mg/mL were prepared and assayed for changes regarding the dimensional distribution, zeta potential, drug aggregation state, and onset of by-products. Our analyses highlighted that the most diluted formulation, kept at room temperature, showed the greatest changes in the aggregation state of the drug and accordingly the highest cytotoxicity. These findings are clinically relevant since the lower dosages are addressed to the more vulnerable patients. Therefore, the centralization of the dilution of AmBisome® at the pharmacy is of fundamental importance for assuring patient safety, and at the same time for reducing medication waste, as we demonstrated using the cost-saving analysis of drug expense per therapy carried out at the G. Gaslini children hospital. Full article
(This article belongs to the Special Issue Recent Advances in Therapeutic Strategies for the Treatment of Pediatric Diseases)
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21 pages, 4411 KiB  
Review
Polysaccharides as a Hydrophilic Building Block of Amphiphilic Block Copolymers for the Conception of Nanocarriers
by Aijing Lu and Suming Li
Pharmaceutics 2024, 16(4), 467; https://doi.org/10.3390/pharmaceutics16040467 - 27 Mar 2024
Viewed by 1263
Abstract
Polysaccharides are gaining increasing attention for their relevance in the production of sustainable materials. In the domain of biomaterials, polysaccharides play an important role as hydrophilic components in the design of amphiphilic block copolymers for the development of drug delivery systems, in particular [...] Read more.
Polysaccharides are gaining increasing attention for their relevance in the production of sustainable materials. In the domain of biomaterials, polysaccharides play an important role as hydrophilic components in the design of amphiphilic block copolymers for the development of drug delivery systems, in particular nanocarriers due to their outstanding biocompatibility, biodegradability, and structural versatility. The presence of a reducing end in polysaccharide chains allows for the synthesis of polysaccharide-based block copolymers. Compared with polysaccharide-based graft copolymers, the structure of block copolymers can be more precisely controlled. In this review, the synthesis methods of polysaccharide-based amphiphilic block copolymers are discussed in detail, taking into consideration the structural characteristics of polysaccharides. Various synthetic approaches, including reductive amination, oxime ligation, and other chain-end modification reactions, are explored. This review also focuses on the advantages of polysaccharides as hydrophilic blocks in polymeric nanocarriers. The structure and unique properties of different polysaccharides such as cellulose, hyaluronic acid, chitosan, alginate, and dextran are described along with examples of their applications as hydrophilic segments in the synthesis of amphiphilic copolymers to construct nanocarriers for sustained drug delivery. Full article
(This article belongs to the Special Issue Design of Novel Polymeric Systems for Controlled Drug Delivery, 2nd Edition)
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19 pages, 2919 KiB  
Article
Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns
by Tomas L. Roldan, Shike Li, Christophe Guillon, Ned D. Heindel, Jeffrey D. Laskin, In Heon Lee, Dayuan Gao and Patrick J. Sinko
Pharmaceutics 2024, 16(4), 471; https://doi.org/10.3390/pharmaceutics16040471 - 27 Mar 2024
Cited by 1 | Viewed by 1854
Abstract
NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in [...] Read more.
NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in the presence of a Vitamin E TPGS aqueous stabilizer solution. Critical processing parameters and material attributes were optimized to reduce particle size and determine the effect on dissolution rate and burn healing efficacy. The antisolvent/solvent ratio (A/S), dose concentration (DC), and drug/stabilizer ratio (D/S) were the critical sonoprecipitation factors that control particle size. These factors were subjected to a Box–Behnken design and response surface analysis, and model quality was assessed. Maximize desirability and simulation experiment optimization approaches were used to determine nanosuspension parameters with the smallest size and the lowest defect rate within the 10–50 nm specification limits. Optimized and unoptimized nanosuspensions were prepared and characterized. An established depilatory double-disc mouse model was used to evaluate the healing of nitrogen mustard-induced dermal injuries. Optimized nanosuspensions (A/S = 6.2, DC = 2% w/v, D/S = 2.8) achieved a particle size of 31.46 nm with a narrow size range (PDI = 0.110) and a reduced defect rate (42.2 to 6.1%). The optimized nanosuspensions were stable and re-dispersible, and they showed a ~45% increase in cumulative drug release and significant edema reduction in mice. Optimized NDH-4338 nanosuspensions were smaller with more uniform sizes that led to improved physical stability, faster dissolution, and enhanced burn healing efficacy compared to unoptimized nanosuspensions. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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14 pages, 4006 KiB  
Article
The Impact of Polymers on Enzalutamide Solid Self-Nanoemulsifying Drug Delivery System and Improved Bioavailability
by Su-Min Lee, Jeong-Gyun Lee, Tae-Han Yun, Chul-Ho Kim, Jung-Hyun Cho and Kyeong-Soo Kim
Pharmaceutics 2024, 16(4), 457; https://doi.org/10.3390/pharmaceutics16040457 - 26 Mar 2024
Cited by 1 | Viewed by 1729
Abstract
Enzalutamide (ENZ), marketed under the brand name Xtandi® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ’s low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. [...] Read more.
Enzalutamide (ENZ), marketed under the brand name Xtandi® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ’s low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. In previous studies, a liquid self-nanoemulsifying drug delivery system (L-SNEDDS) containing ENZ was developed among various solubilization technologies. However, powder formulations that included colloidal silica rapidly formed crystal nuclei in aqueous solutions, leading to a significant decrease in dissolution. Consequently, this study evaluated the efficacy of adding a polymer as a recrystallization inhibitor to a solid SNEDDS (S-SNEDDS) to maintain the drug in a stable, amorphous state in aqueous environments. Polymers were selected based on solubility tests, and the S-SNEDDS formulation was successfully produced via spray drying. The optimized S-SNEDDS formulation demonstrated through X-ray diffraction and differential scanning calorimetry data that it significantly reduced drug crystallinity and enhanced its dissolution rate in simulated gastric and intestinal fluid conditions. In an in vivo study, the bioavailability of orally administered formulations was increased compared to the free drug. Our results highlight the effectiveness of solid-SNEDDS formulations in enhancing the bioavailability of ENZ and outline the potential translational directions for oral drug development. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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21 pages, 3903 KiB  
Article
Daptomycin Liposomes Exhibit Enhanced Activity against Staphylococci Biofilms Compared to Free Drug
by Foteini Gkartziou, Maria Plota, Charikleia Kypraiou, Iti Gauttam, Fevronia Kolonitsiou, Pavlos Klepetsanis, Iris Spiliopoulou and Sophia G. Antimisiaris
Pharmaceutics 2024, 16(4), 459; https://doi.org/10.3390/pharmaceutics16040459 - 26 Mar 2024
Viewed by 1233
Abstract
The purpose of the present study was to investigate the anti-staphylococcal activity of liposomal daptomycin against four biofilm-producing S. aureus and S. epidermidis clinical strains, three of which are methicillin-resistant. Neutral and negatively charged daptomycin-loaded liposomes were prepared using three methods, namely, thin-film [...] Read more.
The purpose of the present study was to investigate the anti-staphylococcal activity of liposomal daptomycin against four biofilm-producing S. aureus and S. epidermidis clinical strains, three of which are methicillin-resistant. Neutral and negatively charged daptomycin-loaded liposomes were prepared using three methods, namely, thin-film hydration (TFH), a dehydration–rehydration vesicle (DRV) method, and microfluidic mixing (MM); moreover, they were characterized for drug encapsulation (EE%), size distribution, zeta-potential, vesicle stability, drug release, and drug integrity. Interestingly, whilst drug loading in THF and DRV nanosized (by extrusion) vesicles was around 30–35, very low loading (~4%) was possible in MM vesicles, requiring further explanatory investigations. Liposomal encapsulation protected daptomycin from degradation and preserved its bioactivity. Biofilm mass (crystal violet, CV), biofilm viability (MTT), and growth curve (GC) assays evaluated the antimicrobial activity of neutral and negatively charged daptomycin-liposomes towards planktonic bacteria and biofilms. Neutral liposomes exhibited dramatically enhanced inhibition of bacterial growth (compared to the free drug) for all species studied, while negatively charged liposomes were totally inactive. Biofilm prevention and treatment studies revealed high antibiofilm activity of liposomal daptomycin. Neutral liposomes were more active for prevention and negative charge ones for treating established biofilms. Planktonic bacteria as well as the matured biofilms of low daptomycin-susceptible, methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) strains were almost completely eradicated by liposomal-daptomycin, indicating the need for their further exploration as antimicrobial therapeutics. Full article
(This article belongs to the Special Issue Advances in Liposomes for Drug Delivery)
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30 pages, 2633 KiB  
Review
Polymersomes as Innovative, Stimuli-Responsive Platforms for Cancer Therapy
by Irina Negut and Bogdan Bita
Pharmaceutics 2024, 16(4), 463; https://doi.org/10.3390/pharmaceutics16040463 - 26 Mar 2024
Cited by 1 | Viewed by 1646
Abstract
This review addresses the urgent need for more targeted and less toxic cancer treatments by exploring the potential of multi-responsive polymersomes. These advanced nanocarriers are engineered to deliver drugs precisely to tumor sites by responding to specific stimuli such as pH, temperature, light, [...] Read more.
This review addresses the urgent need for more targeted and less toxic cancer treatments by exploring the potential of multi-responsive polymersomes. These advanced nanocarriers are engineered to deliver drugs precisely to tumor sites by responding to specific stimuli such as pH, temperature, light, hypoxia, and redox conditions, thereby minimizing the side effects associated with traditional chemotherapy. We discuss the design, synthesis, and recent applications of polymersomes, emphasizing their ability to improve therapeutic outcomes through controlled drug release and targeted delivery. Moreover, we highlight the critical areas for future research, including the optimization of polymersome–biological interactions and biocompatibility, to facilitate their clinical adoption. Multi-responsive polymersomes emerge as a promising development in nanomedicine, offering a pathway to safer and more effective cancer treatments. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery, 2nd Edition)
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44 pages, 2418 KiB  
Review
Recent Approaches for the Topical Treatment of Psoriasis Using Nanoparticles
by Krisztina Bodnár, Pálma Fehér, Zoltán Ujhelyi, Ildikó Bácskay and Liza Józsa
Pharmaceutics 2024, 16(4), 449; https://doi.org/10.3390/pharmaceutics16040449 - 25 Mar 2024
Cited by 6 | Viewed by 4604
Abstract
Psoriasis (PSO) is a chronic autoimmune skin condition characterized by the rapid and excessive growth of skin cells, which leads to the formation of thick, red, and scaly patches on the surface of the skin. These patches can be itchy and painful, and [...] Read more.
Psoriasis (PSO) is a chronic autoimmune skin condition characterized by the rapid and excessive growth of skin cells, which leads to the formation of thick, red, and scaly patches on the surface of the skin. These patches can be itchy and painful, and they may cause discomfort for patients affected by this condition. Therapies for psoriasis aim to alleviate symptoms, reduce inflammation, and slow down the excessive skin cell growth. Conventional topical treatment options are non-specific, have low efficacy and are associated with adverse effects, which is why researchers are investigating different delivery mechanisms. A novel approach to drug delivery using nanoparticles (NPs) shows promise in reducing toxicity and improving therapeutic efficacy. The unique properties of NPs, such as their small size and large surface area, make them attractive for targeted drug delivery, enhanced drug stability, and controlled release. In the context of PSO, NPs can be designed to deliver active ingredients with anti-inflammatory effect, immunosuppressants, or other therapeutic compounds directly to affected skin areas. These novel formulations offer improved access to the epidermis and facilitate better absorption, thus enhancing the therapeutic efficacy of conventional anti-psoriatic drugs. NPs increase the surface-to-volume ratio, resulting in enhanced penetration through the skin, including intracellular, intercellular, and trans-appendage routes. The present review aims to discuss the latest approaches for the topical therapy of PSO using NPs. It is intended to summarize the results of the in vitro and in vivo examinations carried out in the last few years regarding the effectiveness and safety of nanoparticles. Full article
(This article belongs to the Special Issue Nanoparticles for Local Drug Delivery)
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27 pages, 4839 KiB  
Article
Investigating the Effects of Mixing Dynamics on Twin-Screw Granule Quality Attributes via the Development of a Physics-Based Process Map
by Lalith Kotamarthy, Subhodh Karkala, Ashley Dan, Andrés D. Román-Ospino and Rohit Ramachandran
Pharmaceutics 2024, 16(4), 456; https://doi.org/10.3390/pharmaceutics16040456 - 25 Mar 2024
Viewed by 1443
Abstract
Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing [...] Read more.
Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing dynamics on the granule quality attributes (PSD, content uniformity, and microstructure). Mixing is an important dynamic process that simultaneously occurs along with the granulation rate mechanisms during the wet granulation process. An improved mechanistic understanding was achieved by identifying and quantifying the physically relevant intermediate parameters that affect the mixing dynamics in TSG, and then their effects on the granule attributes were analyzed by investigating their effects on the granulation rate mechanisms. The fill level, granule liquid saturation, extent of nucleation, and powder wettability were found to be the key physically relevant intermediate parameters that affect the mixing inside the twin-screw granulator. An improved geometrical model for the fill level was developed and validated against existing experimental data. Finally, a process map was developed to depict the effects of mixing on the temporal and spatial evolution of the materials inside the twin-screw granulator. This process map illustrates the mechanism of nucleation and the growth of the granules based on the fundamental material properties of the primary powders (solubility and wettability), liquid binders (viscosity), and mixing dynamics present in the system. Furthermore, it was shown that the process map can be used to predict the granule product quality based on the granule growth mechanism. Full article
(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)
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28 pages, 3797 KiB  
Article
Gold(I) and Silver(I) Complexes Containing Hybrid Sulfonamide/Thiourea Ligands as Potential Leishmanicidal Agents
by Alice P. Borges, Malu M. S. Obata, Silvia H. Libardi, Rafael O. Trevisan, Victor M. Deflon, Ulrich Abram, Francis B. Ferreira, Luiz Antônio S. Costa, Antonio O. T. Patrocínio, Marcos V. da Silva, Júlio C. Borges and Pedro I. S. Maia
Pharmaceutics 2024, 16(4), 452; https://doi.org/10.3390/pharmaceutics16040452 - 25 Mar 2024
Cited by 1 | Viewed by 1323
Abstract
Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from [...] Read more.
Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from MI metal ions with thioureas, aiming to obtain potential leishmanicidal agents. The thiourea ligands (HLR) were obtained by reactions of p-toluenesulfohydrazide with R-isothiocyanates and were used in complexation reactions with AgI and AuI, leading to the formation of complexes of composition [M(HLR)2]X (M = Ag or Au; X = NO3− or Cl−). All compounds were characterized by FTIR, 1H NMR, UV-vis, emission spectroscopy and elemental analysis. Some representatives were additionally studied by ESI-MS and single-crystal XRD. Their properties were further analyzed by DFT calculations. Their cytotoxicity on Vero cells and the extracellular leishmanicidal activity on Leishmania infantum and Leishmania braziliensis cells were evaluated. Additionally, the interaction of the complexes with the Old Yellow enzyme of the L. braziliensis (LbOYE) was examined. The biological tests showed that some compounds present remarkable leishmanicidal activity, even higher than that of the standard drug Glucantime, with different selectivity for the two species of Leishmania. Finally, the interaction studies with LbOYE revealed that this enzyme could be one of their biological targets. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Metal Complexes and Derived Materials)
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16 pages, 937 KiB  
Review
Impact of Drug-Mediated Inhibition of Intestinal Transporters on Nutrient and Endogenous Substrate Disposition…an Afterthought?
by Kshitee Kharve, Andrew S. Engley, Mary F. Paine and Jason A. Sprowl
Pharmaceutics 2024, 16(4), 447; https://doi.org/10.3390/pharmaceutics16040447 - 24 Mar 2024
Viewed by 1492
Abstract
A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of [...] Read more.
A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of nutrients or endogenous substrates. Several investigations have provided links between nutrient, endogenous substrate, or drug absorption and the activity of certain membrane transporters. This knowledge has been key in the development of new therapeutics that can alleviate various symptoms of select diseases, such as cholestasis and diabetes. Despite this progress, recent studies revealed potential clinical dangers of unintended altered nutrient or endogenous substrate disposition due to the drug-mediated disruption of intestinal transport activity. This review outlines reports of glucose, folate, thiamine, lactate, and bile acid (re)absorption changes and consequent adverse events as examples. Finally, the need to comprehensively expand research on intestinal transporter-mediated drug interactions to avoid the unwanted disruption of homeostasis and diminish therapeutic adverse events is highlighted. Full article
(This article belongs to the Special Issue New Insights into Transporters in Drug Development)
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14 pages, 16075 KiB  
Article
Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury
by Takuma Ikeda, Masahito Kawabori, Yuyuan Zheng, Sho Yamaguchi, Shuho Gotoh, Yo Nakahara, Erika Yoshie and Miki Fujimura
Pharmaceutics 2024, 16(4), 446; https://doi.org/10.3390/pharmaceutics16040446 - 23 Mar 2024
Cited by 4 | Viewed by 2876
Abstract
Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous [...] Read more.
Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a promising approach. In this study, we investigate the effects of intranasally administered exosomes in an animal model. Exosomes were isolated from the cell supernatants using the ultracentrifugation method. Brain injury was induced in Sprague-Dawley rats through a transient four-vessel occlusion model. Intranasal administration was conducted with 3 × 108 exosome particles in 20 µL of PBS or PBS alone, administered daily for 7 days post-injury. Long-term cognitive behavioral assessments, biodistribution of exosomes, and histological evaluations of apoptosis and neuroinflammation were conducted. Exosomes were primarily detected in the olfactory bulb one hour after intranasal administration, subsequently distributing to the striatum and midbrain. Rats treated with exosomes exhibited substantial improvement in cognitive function up to 28 days after the insult, and demonstrated significantly fewer apoptotic cells along with higher neuronal cell survival in the hippocampus. Exosomes were found to be taken up by microglia, leading to a decrease in the expression of cytotoxic inflammatory markers. Full article
(This article belongs to the Special Issue Pharmaceutical Formulations and Bioavailability Enhancement Techniques for Transmucosal Drug Delivery)
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26 pages, 2897 KiB  
Review
3D Printing Direct Powder Extrusion in the Production of Drug Delivery Systems: State of the Art and Future Perspectives
by Ángela Aguilar-de-Leyva, Marta Casas, Carmen Ferrero, Vicente Linares and Isidoro Caraballo
Pharmaceutics 2024, 16(4), 437; https://doi.org/10.3390/pharmaceutics16040437 - 22 Mar 2024
Cited by 3 | Viewed by 2615
Abstract
The production of tailored, on-demand drug delivery systems has gained attention in pharmaceutical development over the last few years, thanks to the application of 3D printing technology in the pharmaceutical field. Recently, direct powder extrusion (DPE) has emerged among the extrusion-based additive manufacturing [...] Read more.
The production of tailored, on-demand drug delivery systems has gained attention in pharmaceutical development over the last few years, thanks to the application of 3D printing technology in the pharmaceutical field. Recently, direct powder extrusion (DPE) has emerged among the extrusion-based additive manufacturing techniques. It is a one-step procedure that allows the direct processing of powdered formulations. The aim of this systematic literature review is to analyze the production of drug delivery systems using DPE. A total of 27 articles have been identified through scientific databases (Scopus, PubMed, and ScienceDirect). The main characteristics of the three types of 3D printers based on DPE have been discussed. The selection of polymers and auxiliary excipients, as well as the flowability of the powder mixture, the rheological properties of the molten material, and the printing temperatures have been identified as the main critical parameters for successful printing. A wide range of drug delivery systems with varied geometries and different drug release profiles intended for oral, buccal, parenteral, and transdermal routes have been produced. The ability of this technique to manufacture personalized, on-demand drug delivery systems has been proven. For all these reasons, its implementation in hospital settings in the near future seems promising. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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22 pages, 2106 KiB  
Review
In Vivo Applications of Dendrimers: A Step toward the Future of Nanoparticle-Mediated Therapeutics
by Krzysztof Sztandera, José Luis Rodríguez-García and Valentín Ceña
Pharmaceutics 2024, 16(4), 439; https://doi.org/10.3390/pharmaceutics16040439 - 22 Mar 2024
Cited by 3 | Viewed by 2059
Abstract
Over the last few years, the development of nanotechnology has allowed for the synthesis of many different nanostructures with controlled sizes, shapes, and chemical properties, with dendrimers being the best-characterized of them. In this review, we present a succinct view of the structure [...] Read more.
Over the last few years, the development of nanotechnology has allowed for the synthesis of many different nanostructures with controlled sizes, shapes, and chemical properties, with dendrimers being the best-characterized of them. In this review, we present a succinct view of the structure and the synthetic procedures used for dendrimer synthesis, as well as the cellular uptake mechanisms used by these nanoparticles to gain access to the cell. In addition, the manuscript reviews the reported in vivo applications of dendrimers as drug carriers for drugs used in the treatment of cancer, neurodegenerative diseases, infections, and ocular diseases. The dendrimer-based formulations that have reached different phases of clinical trials, including safety and pharmacokinetic studies, or as delivery agents for therapeutic compounds are also presented. The continuous development of nanotechnology which makes it possible to produce increasingly sophisticated and complex dendrimers indicates that this fascinating family of nanoparticles has a wide potential in the pharmaceutical industry, especially for applications in drug delivery systems, and that the number of dendrimer-based compounds entering clinical trials will markedly increase during the coming years. Full article
(This article belongs to the Special Issue Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 85th Birthday for His Outstanding Achievements in Advancing the Field of Dendrimers)
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38 pages, 7322 KiB  
Systematic Review
Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers
by Patrizia Garbati, Cristiana Picco, Raffaella Magrassi, Paolo Signorello, Ludovica Cacopardo, Mauro Dalla Serra, Maria Grazia Faticato, Maria De Luca, Francesco Balestra, Maria Principia Scavo and Federica Viti
Pharmaceutics 2024, 16(3), 431; https://doi.org/10.3390/pharmaceutics16030431 - 21 Mar 2024
Cited by 3 | Viewed by 3068
Abstract
The intestine is essential for the modulation of nutrient absorption and the removal of waste. Gut pathologies, such as cancer, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and celiac disease, which extensively impact gut functions, are thus critical for human health. Targeted [...] Read more.
The intestine is essential for the modulation of nutrient absorption and the removal of waste. Gut pathologies, such as cancer, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and celiac disease, which extensively impact gut functions, are thus critical for human health. Targeted drug delivery is essential to tackle these diseases, improve therapy efficacy, and minimize side effects. Recent strategies have taken advantage of both active and passive nanocarriers, which are designed to protect the drug until it reaches the correct delivery site and to modulate drug release via the use of different physical–chemical strategies. In this systematic review, we present a literature overview of the different nanocarriers used for drug delivery in a set of chronic intestinal pathologies, highlighting the rationale behind the controlled release of intestinal therapies. The overall aim is to provide the reader with useful information on the current approaches for gut targeting in novel therapeutic strategies. Full article
(This article belongs to the Special Issue Nanotechnology-Based Pharmaceutical Treatments)
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24 pages, 3524 KiB  
Article
NLC-Based Sunscreen Formulations with Optimized Proportion of Encapsulated and Free Filters Exhibit Enhanced UVA and UVB Photoprotection
by Margarete M. de Araújo, Andressa C. Schneid, Mariana S. Oliveira, Samuel V. Mussi, Miller N. de Freitas, Flávia C. Carvalho, Edson A. Bernes Junior, Renato Faro and Hatylas Azevedo
Pharmaceutics 2024, 16(3), 427; https://doi.org/10.3390/pharmaceutics16030427 - 20 Mar 2024
Cited by 4 | Viewed by 2480
Abstract
The topical use of sunscreens is recommended for avoiding the damaging effects of UV radiation. However, improvements are still needed in the existing products to enhance their photoprotection effectiveness and safety. This involves minimizing the use of chemical UV filters while providing enhanced [...] Read more.
The topical use of sunscreens is recommended for avoiding the damaging effects of UV radiation. However, improvements are still needed in the existing products to enhance their photoprotection effectiveness and safety. This involves minimizing the use of chemical UV filters while providing enhanced and prolonged photoprotection. This work investigated novel sunscreen formulations and their UV protection effects by encapsulating Uvinul® A, Tinosorb® S, and Uvinul® T150 into nanostructured lipid carriers (NLCs) based on bacuri butter and raspberry seed oil. First, the impact of critical formulation and process parameters on NLCs’ particle size was evaluated using a 22 Face Centered Central Composite Design. Then, formulations were evaluated in terms of critical quality factors, in vitro skin permeation, and in vitro and in vivo photoprotection activities. The developed NLCs-containing formulations exhibited appropriate size (122–135 nm), PdI (<0.3), encapsulation efficiency (>90%), and drug content (>80%), which were preserved for at least 90 days under different stability conditions. Moreover, these NLCs-based formulations had equivalent skin permeation to emulsion-based controls, and the addition of NLCs into sunscreen cream bases in the optimum proportion of 20% (w/w) resulted in enhanced UVA and UVB photoprotection levels, despite a 10% reduction in the total filters content. Altogether, these results describe the application of nanoencapsulated organic UV filters in innovative sunscreen formulations to achieve superior photoprotection and cosmeceutical properties. Full article
(This article belongs to the Special Issue Quality Requirements for Nanomedicines: From Early Development to the Market)
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12 pages, 3738 KiB  
Article
Mannose-Decorated Solid-Lipid Nanoparticles for Alveolar Macrophage Targeted Delivery of Rifampicin
by Hriday Bera, Caizhu Zhao, Xidong Tian, Dongmei Cun and Mingshi Yang
Pharmaceutics 2024, 16(3), 429; https://doi.org/10.3390/pharmaceutics16030429 - 20 Mar 2024
Cited by 1 | Viewed by 1886
Abstract
Alveolar macrophages play a vital role in a variety of lung diseases, including tuberculosis. Thus, alveolar macrophage targeted anti-tubercular drug delivery through nanocarriers could improve its therapeutic response against tuberculosis. The current study aimed at exploring the efficacy of glyceryl monostearate (GMS)-based solid-lipid [...] Read more.
Alveolar macrophages play a vital role in a variety of lung diseases, including tuberculosis. Thus, alveolar macrophage targeted anti-tubercular drug delivery through nanocarriers could improve its therapeutic response against tuberculosis. The current study aimed at exploring the efficacy of glyceryl monostearate (GMS)-based solid-lipid nanoparticles (SLNs) and their mannose functionalized forms on the alveolar macrophage targeting ability of an anti-tubercular model drug, rifampicin (Rif). Rif-loaded SLNs were accomplished by the solvent diffusion method. These carriers with unimodal particle size distribution (~170 nm) were further surface-modified with mannose via Schiff-base reaction, leading to slight enhancement of particle diameter and a decline of drug loading capacity. The encapsulated Rif, which was molecularly dispersed within the matrices as indicated by their XRD patterns, was eluted in a sustained manner with an initial burst release effect. The uptake efficiency of mannose-modified SLNs was remarkably higher than that of corresponding native forms on murine macrophage Raw 264.7 cells and human lung adenocarcinoma A549 cells. Eventually, the mannose-modified SLNs showed a greater cytotoxicity on Raw 264.7 and A549 cells relative to their unmodified forms. Overall, our study demonstrated that mannose modification of SLNs had an influence on their uptake by alveolar macrophages, which could provide guidance for the future development of alveolar macrophage targeted nanoformulations. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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14 pages, 4923 KiB  
Article
Intracellular Delivery of Therapeutic Protein via Ultrathin Layered Double Hydroxide Nanosheets
by He Zhang, Anle Ge, Yulin Wang, Boran Xia, Xichu Wang, Zhonghui Zheng, Changsheng Wei, Bo Ma, Lin Zhu, Rose Amal, Sung Lai Jimmy Yun and Zi Gu
Pharmaceutics 2024, 16(3), 422; https://doi.org/10.3390/pharmaceutics16030422 - 19 Mar 2024
Cited by 1 | Viewed by 1736
Abstract
The therapeutic application of biofunctional proteins relies on their intracellular delivery, which is hindered by poor cellular uptake and transport from endosomes to cytoplasm. Herein, we constructed a two-dimensional (2D) ultrathin layered double hydroxide (LDH) nanosheet for the intracellular delivery of a cell-impermeable [...] Read more.
The therapeutic application of biofunctional proteins relies on their intracellular delivery, which is hindered by poor cellular uptake and transport from endosomes to cytoplasm. Herein, we constructed a two-dimensional (2D) ultrathin layered double hydroxide (LDH) nanosheet for the intracellular delivery of a cell-impermeable protein, gelonin, towards efficient and specific cancer treatment. The LDH nanosheet was synthesized via a facile method without using exfoliation agents and showed a high loading capacity of proteins (up to 182%). Using 2D and 3D 4T1 breast cancer cell models, LDH–gelonin demonstrated significantly higher cellular uptake efficiency, favorable endosome escape ability, and deep tumor penetration performance, leading to a higher anticancer efficiency, in comparison to free gelonin. This work provides a promising strategy and a generalized nanoplatform to efficiently deliver biofunctional proteins to unlock their therapeutic potential for cancer treatment. Full article
(This article belongs to the Special Issue Smart Drug Delivery Strategies Based on Porous Materials)
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