Pharmaceutics

14 pages, 4153 KiB

Open AccessArticle

ZIF-8 and Its Magnetic Functionalization as Vehicle for the Transport and Release of Ciprofloxacin

by Ventura Castillo Ramos, Cinthia Berenice García Reyes, Guillermo Mangas García, María Inmaculada Sampedro Quesada, Fernando José Martínez-Checa Barrero, Jacob Josafat Salazar Rábago and Manuel Sánchez Polo

Pharmaceutics 2022, 14(11), 2546; https://doi.org/10.3390/pharmaceutics14112546 - 21 Nov 2022

Cited by 13 | Viewed by 3038

Abstract

The use of nanomaterials for the controlled release of drugs aims to enhance their effectiveness, especially when poorly soluble in water, and achieve their rapid, localized, and effective administration. The present study focuses on the use of a Zeolitic Imidazolate Framework-8 (ZIF-8) as [...] Read more.

The use of nanomaterials for the controlled release of drugs aims to enhance their effectiveness, especially when poorly soluble in water, and achieve their rapid, localized, and effective administration. The present study focuses on the use of a Zeolitic Imidazolate Framework-8 (ZIF-8) as vehicle for the transport and controlled release of the antibiotic ciprofloxacin (CIP) as model due to its favorable physicochemical characteristics. The objective is to synthesize the ZIF-8 material loaded with CIP through encapsulation for subsequent release of the drug in neutral and acid physiological media. In addition, functionalization of the CIP/ZIF compound with magnetic nanoparticles (NP) was sought to increase its traceability through the possible use of magnetic fields. Characterizations by XRD, FT-IR, SEM-EDX, and TGA showed a satisfactory synthesis of both pure ZIF-8 and ciprofloxacin-loaded ZIF-8, with high crystallinity and thermal stability. The release profiles showed an abrupt initial release that stabilized over time. A much higher release (20–80% greater) was obtained in acid versus neutral pH in all cases, attributable to the collapse of the ZIF-8 structure in acid media. In addition, functionalization of the material with iron NPs did not affect the behavior of the system during drug release. Antimicrobial activity tests against E. coli and S. aureus showed that ZIF-8 per se exerts antimicrobial activity, while the compounds CIP/ZIF and magnetic CIP/ZIF increased the antimicrobial capacity of pure CIP by 10–20%. The ZIF-8 system has high potential as a drug carrier and release agent for the treatment of diseases, especially those that cause acidification of the cellular environment, achieving a rapid, localized, and targeted action with the possibility of achieving traceability of the system after its magnetic functionalization. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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35 pages, 4801 KiB

Open AccessReview

¹⁸F-Radiolabeled Translocator Protein (TSPO) PET Tracers: Recent Development of TSPO Radioligands and Their Application to PET Study

by Truong Giang Luu and Hee-Kwon Kim

Pharmaceutics 2022, 14(11), 2545; https://doi.org/10.3390/pharmaceutics14112545 - 21 Nov 2022

Cited by 14 | Viewed by 3540

Abstract

Translocator protein 18 kDa (TSPO) is a transmembrane protein in the mitochondrial membrane, which has been identified as a peripheral benzodiazepine receptor. TSPO is generally present at high concentrations in steroid-producing cells and plays an important role in steroid synthesis, apoptosis, and cell [...] Read more.

Translocator protein 18 kDa (TSPO) is a transmembrane protein in the mitochondrial membrane, which has been identified as a peripheral benzodiazepine receptor. TSPO is generally present at high concentrations in steroid-producing cells and plays an important role in steroid synthesis, apoptosis, and cell proliferation. In the central nervous system, TSPO expression is relatively modest under normal physiological circumstances. However, some pathological disorders can lead to changes in TSPO expression. Overexpression of TSPO is associated with several diseases, such as neurodegenerative diseases, neuroinflammation, brain injury, and cancers. TSPO has therefore become an effective biomarker of related diseases. Positron emission tomography (PET), a non-invasive molecular imaging technique used for the clinical diagnosis of numerous diseases, can detect diseases related to TSPO expression. Several radiolabeled TSPO ligands have been developed for PET. In this review, we describe recent advances in the development of TSPO ligands, and ¹⁸F-radiolabeled TSPO in particular, as PET tracers. This review covers pharmacokinetic studies, preclinical and clinical trials of ¹⁸F-labeled TSPO PET ligands, and the synthesis of TSPO ligands. Full article

(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)

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11 pages, 2233 KiB

Open AccessArticle

Leveraging Dissolution by Autoinjector Designs

by Christoph Spangardt, Christoph Keßler, Ramona Dobrzewski, Antonia Tepler, Simon Hanio, Bernd Klaubert and Lorenz Meinel

Pharmaceutics 2022, 14(11), 2544; https://doi.org/10.3390/pharmaceutics14112544 - 21 Nov 2022

Viewed by 1600

Abstract

Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions. Antidotes, such as the oxime HI-6, which must be formulated as a powder for reconstitution reflecting the molecule’s light sensitivity and instability in aqueous solutions, [...] Read more.

Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions. Antidotes, such as the oxime HI-6, which must be formulated as a powder for reconstitution reflecting the molecule’s light sensitivity and instability in aqueous solutions, dramatically improve recovery—but only if used soon after exposure. Muscle tremors, anxiety, and loss of consciousness after exposure jeopardize proper administration, translating into demanding specifications for the dissolution of HI-6. Reflecting the patients’ catastrophic situation and anticipated desire to react immediately to chemical weapon exposure, the dissolution should be completed within ten seconds. We are developing multi-dose and single-dose autoinjectors to reliably meet these dissolution requirements. The temporal and spatial course of dissolution within the various autoinjector designs was profiled colorimetrically. Based on these colorimetric insights with model dyes, we developed experimental setups integrating online conductometry to push experiments toward the relevant molecule, HI-6. The resulting blueprints for autoinjector designs integrated small-scale rotor systems, boosting dissolution across a wide range of viscosities, and meeting the required dissolution specifications driven by the use of these drug products in extreme situations. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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26 pages, 762 KiB

Open AccessReview

Gut Dysbiosis and Diabetic Foot Ulcer: Role of Probiotics

by Ankit Awasthi, Leander Corrie, Sukriti Vishwas, Monica Gulati, Bimlesh Kumar, Dinesh Kumar Chellappan, Gaurav Gupta, Rajaraman D. Eri, Kamal Dua and Sachin Kumar Singh

Pharmaceutics 2022, 14(11), 2543; https://doi.org/10.3390/pharmaceutics14112543 - 21 Nov 2022

Cited by 11 | Viewed by 3520

Abstract

Diabetic foot ulcer (DFU) is a multifactorial disease and one of the complications of diabetes. The global burden of DFU in the health sector is increasing at a tremendous rate due to its cost management related to hospitalization, medical costs and foot amputation. [...] Read more.

Diabetic foot ulcer (DFU) is a multifactorial disease and one of the complications of diabetes. The global burden of DFU in the health sector is increasing at a tremendous rate due to its cost management related to hospitalization, medical costs and foot amputation. Hence, to manage DFU/DWs, various attempts have been made, including treating wounds systematically/topically using synthetic drugs, herbal drugs, or tissue engineering based surgical dressings. However, less attention has been paid to the intrinsic factors that are also the leading cause of diabetes mellitus (DM) and its complications. One such factor is gut dysbiosis, which is one of the major causes of enhancing the counts of Gram-negative bacteria. These bacteria produce lipopolysaccharides, which are a major contributing factor toward insulin resistance and inflammation due to the generation of oxidative stress and immunopathy. These all lead to DM and DFU. Probiotics are the commercial form of beneficial gut microbes that are taken as nutraceuticals by people of all ages to improve gut immunity and prevent gut dysbiosis. However, the role of probiotics has been less explored in the management of DFU. Hence, the therapeutic potential of probiotics in managing DFU is fully described in the current review. This report covers the linkage between gut dysbiosis and DFU, sources of probiotics, the mechanisms of probiotics in DW healing, and the impact of probiotic supplementation in treating DFU. In addition, techniques for the stabilization of probiotics, market status, and patents related to probiotics have been also covered. The relevant data were gathered from PubMed, Scopus, Taylor and Francis, Science Direct, and Google Scholar. Our systematic review discusses the utilization of probiotic supplementation as a nutraceutical for the management of DFU. Full article

(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)

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27 pages, 9759 KiB

Open AccessArticle

Dendritic Cell-Derived Artificial Microvesicles Inhibit RLS₄₀ Lymphosarcoma Growth in Mice via Stimulation of Th1/Th17 Immune Response

by Oleg V. Markov, Aleksandra V. Sen’kova, Islam S. Mohamed, Elena V. Shmendel, Mikhail A. Maslov, Anastasiya L. Oshchepkova, Evgeniy V. Brenner, Nadezhda L. Mironova and Marina A. Zenkova

Pharmaceutics 2022, 14(11), 2542; https://doi.org/10.3390/pharmaceutics14112542 - 21 Nov 2022

Cited by 2 | Viewed by 1998

Abstract

Cell-free antitumor vaccines represent a promising approach to immunotherapy of cancer. Here, we compare the antitumor potential of cell-free vaccines based on microvesicles derived from dendritic cells (DCs) with DC- and cationic-liposome-based vaccines using a murine model of drug-resistant lymphosarcoma RLS₄₀ in [...] Read more.

Cell-free antitumor vaccines represent a promising approach to immunotherapy of cancer. Here, we compare the antitumor potential of cell-free vaccines based on microvesicles derived from dendritic cells (DCs) with DC- and cationic-liposome-based vaccines using a murine model of drug-resistant lymphosarcoma RLS₄₀ in vivo. The vaccines were the following: microvesicle vaccines—cytochalasin B-induced membrane vesicles (CIMVs) obtained from DCs loaded with total tumor RNA using cholesterol/spermine-containing cationic liposomes L or mannosylated liposomes ML; DC vaccines—murine DCs loaded with total tumor-derived RNA using the same liposomes; and liposomal vaccines—lipoplexes of total tumor-derived RNA with liposomes L or ML. Being non-hepatotoxic, CIMV- and DC-based vaccines administered subcutaneously exhibited comparable potential to stimulate highly efficient antitumor CTLs in vivo, whereas liposomal vaccines were 25% weaker CTL inducers. Nevertheless, the antitumor efficiencies of the different types of the vaccines were similar: sizes of tumor nodes and the number of liver metastases were significantly decreased, regardless of the vaccine type. Notably, the booster vaccination did not improve the overall antitumor efficacy of the vaccines under the study. CIMV- and DC- based vaccines more efficiently than liposome-based ones decreased mitotic activity of tumor cells and induced their apoptosis, stimulated accumulation of neutrophil inflammatory infiltration in tumor tissue, and had a more pronounced immunomodulatory activity toward the spleen and thymus. Administration of CIMV-, DC-, and liposome-based vaccines resulted in activation of Th1/Th17 cells as well as the induction of positive immune checkpoint 4-1BBL and downregulation of suppressive immune checkpoints in a raw PD-1 >>> TIGIT > CTLA4 > TIM3. We demonstrated that cell-free CIMV-based vaccines exhibited superior antitumor and antimetastatic activity in a tumor model in vivo. The obtained results can be considered as the basis for developing novel strategies for oncoimmunotherapy. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)

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19 pages, 6966 KiB

Open AccessArticle

Phytochemical-Stabilized Platinum-Decorated Silver Nanocubes INHIBIT Adenocarcinoma Cells and Enhance Antioxidant Effects by Promoting Apoptosis via Cell Cycle Arrest

by Adewale Odunayo Oladipo, Jeremiah Oshiomame Unuofin, Sogolo Lucky Lebelo and Titus Alfred Makudali Msagati

Pharmaceutics 2022, 14(11), 2541; https://doi.org/10.3390/pharmaceutics14112541 - 21 Nov 2022

Cited by 8 | Viewed by 2010

Abstract

(1) Background: The increasing use of silver and platinum bimetallic nanoparticles in the diagnosis and treatment of cancer presents significant advances in biomedical applications due to their extraordinary physicochemical properties. This study investigated the role of aqueous phytochemical extract in stabilizing platinum nanodots-decorated [...] Read more.

(1) Background: The increasing use of silver and platinum bimetallic nanoparticles in the diagnosis and treatment of cancer presents significant advances in biomedical applications due to their extraordinary physicochemical properties. This study investigated the role of aqueous phytochemical extract in stabilizing platinum nanodots-decorated silver nanocubes (w-Pt@AgNPs) for enhancing antioxidant activities and their mechanism. (2) Methods: UV-Vis, Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM) were used to characterize the formed w-Pt@AgNPs. LC-QToF-MS/MS was used to analyze the bioactive compounds, while DPPH, ABTS, and FRAP were used to detect the scavenging potential. Flow cytometric assays were performed to investigate the cytotoxicity and the mechanism of cell death. (3) Results: Morphological studies indicated that w-Pt@AgNPs were cube in shape, decorated by platinum nanodots on the surfaces. Compared to ethanolic extract-synthesized e-Pt@AgNPs, w-Pt@AgNPs exhibited the strongest antioxidant and cytotoxic activity, as data from Annexin V and Dead cell labeling indicated higher induction of apoptosis. Despite the high proportion of early apoptotic cells, the w-Pt@AgNPs triggered a decrease in G1/G0 cell cycle phase distribution, thereby initiating a G2/M arrest. (4) Conclusions: By enhancing the antioxidant properties and promoting apoptosis, w-Pt@AgNPs exhibited remarkable potential for improved cancer therapy outcomes. Full article

(This article belongs to the Special Issue Antitumor Activity of Silver Nanoparticles and Its Implications on Global Health)

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14 pages, 2115 KiB

Open AccessArticle

Antibacterial Potential Analysis of Novel α-Helix Peptides in the Chinese Wolf Spider Lycosa sinensis

by Huaxin Tan, Junyao Wang, Yuxin Song, Sisi Liu, Ziyan Lu, Haodang Luo and Xing Tang

Pharmaceutics 2022, 14(11), 2540; https://doi.org/10.3390/pharmaceutics14112540 - 21 Nov 2022

Cited by 7 | Viewed by 2146

Abstract

The spider Lycosa sinensis represents a burrowing wolf spider (family Lycosidae) widely distributed in the cotton region of northern China, whose venom is rich in various bioactive peptides. In previous study, we used a combination strategy of peptidomic and transcriptomic analyses to [...] Read more.

The spider Lycosa sinensis represents a burrowing wolf spider (family Lycosidae) widely distributed in the cotton region of northern China, whose venom is rich in various bioactive peptides. In previous study, we used a combination strategy of peptidomic and transcriptomic analyses to systematically screen and identify potential antimicrobial peptides (AMPs) in Lycosa sinensis venom that matched the α-helix structures. In this work, the three peptides (LS-AMP-E1, LS-AMP-F1, and LS-AMP-G1) were subjected to sequence analysis of the physicochemical properties and helical wheel projection, and then six common clinical pathogenic bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) with multiple drug-resistance were isolated and cultured for the evaluation and analysis of antimicrobial activity of these peptides. The results showed that two peptides (LS-AMP-E1 and LS-AMP-F1) had different inhibitory activity against six clinical drug-resistant bacteria; they can effectively inhibit the formation of biofilm and have no obvious hemolytic effect. Moreover, both LS-AMP-E1 and LS-AMP-F1 exhibited varying degrees of synergistic therapeutic effects with traditional antibiotics (azithromycin, erythromycin, and doxycycline), significantly reducing the working concentration of antibiotics and AMPs. In terms of antimicrobial mechanisms, LS-AMP-E1 and LS-AMP-F1 destroyed the integrity of bacterial cell membranes in a short period of time and completely inhibited bacterial growth within 10 min of action. Meanwhile, high concentrations of Mg²⁺ effectively reduced the antibacterial activity of LS-AMP-E1 and LS-AMP-F1. Together, it suggested that the two peptides interact directly on bacterial cell membranes. Taken together, bioinformatic and functional analyses in the present work sheds light on the structure–function relationships of LS-AMPs, and facilitates the discovery and clinical application of novel AMPs. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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12 pages, 2502 KiB

Open AccessArticle

Formulation of SARS-CoV-2 Spike Protein with CpG Oligodeoxynucleotides and Squalene Nanoparticles Modulates Immunological Aspects Following Intranasal Delivery

by Hui-Min Ho, Chiung-Yi Huang, Chung-Hsiang Yang, Shih-Jen Liu, Hsin-Wei Chen, Guann-Yi Yu, Jen-Kun Chen, Tsung-Hsien Chuang and Ming-Hsi Huang

Pharmaceutics 2022, 14(11), 2539; https://doi.org/10.3390/pharmaceutics14112539 - 21 Nov 2022

Cited by 3 | Viewed by 2569

Abstract

Nasal spray vaccination is viewed as a promising strategy for inducing both mucosal and systemic protection against respiratory SARS-CoV-2 coronavirus. Toward this goal, a safe and efficacious mucosal adjuvant is necessary for the transportation of the antigen across the mucosal membrane and antigen [...] Read more.

Nasal spray vaccination is viewed as a promising strategy for inducing both mucosal and systemic protection against respiratory SARS-CoV-2 coronavirus. Toward this goal, a safe and efficacious mucosal adjuvant is necessary for the transportation of the antigen across the mucosal membrane and antigen recognition by the mucosal immune system to generate broad-spectrum immune responses. This study describes the immunological aspects of SARS-CoV-2 spike (S)-protein after being formulated with CpG oligodeoxynucleotides (ODNs) and squalene nanoparticles (termed PELC). Following intranasal delivery in mice, higher expression levels of major histocompatibility complex (MHC) class II and costimulatory molecules CD40 and CD86 on CD11c⁺ cells were observed at the draining superficial cervical lymph nodes in the CpG-formulated S protein group compared with those vaccinated with S protein alone. Subsequently, the activated antigen-presenting cells downstream modulated the cytokine secretion profiles and expanded the cytotoxic T lymphocyte activity of S protein-restimulated splenocytes. Interestingly, the presence of PELC synergistically enhanced cell-mediated immunity and diminished individual differences in S protein-specific immunogenicity. Regarding humoral responses, the mice vaccinated with the PELC:CpG-formulated S protein promoted the production of S protein-specific IgG in serum samples and IgA in nasal and bronchoalveolar lavage fluids. These results indicate that PELC:CpG is a potential mucosal adjuvant that promotes mucosal/systemic immune responses and cell-mediated immunity, a feature that has implications for the development of a nasal spray vaccine against COVID-19. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)

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19 pages, 5515 KiB

Open AccessReview

FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis

by Davide Benedetto Tiz, Luana Bagnoli, Ornelio Rosati, Francesca Marini, Claudio Santi and Luca Sancineto

Pharmaceutics 2022, 14(11), 2538; https://doi.org/10.3390/pharmaceutics14112538 - 21 Nov 2022

Cited by 33 | Viewed by 20159

Abstract

This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for [...] Read more.

This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases. The diverse small molecules are described according to the date of approval and their syntheses is discussed. This review comprises classical chemical scaffolds together with innovative drugs such as a deuterium-containing drug. Full article

(This article belongs to the Special Issue Recent Advances in the Development of Hybrid Drugs)

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16 pages, 3425 KiB

Open AccessArticle

Combination of Nanovectorized siRNA Directed against Survivin with Doxorubicin for Efficient Anti-Cancer Activity in HER2+ Breast Cancer Cells

by Sahar Eljack, Emilie Allard-Vannier, Yoann Misericordia, Katel Hervé-Aubert, Nicolas Aubrey, Igor Chourpa, Areeg Faggad and Stephanie David

Pharmaceutics 2022, 14(11), 2537; https://doi.org/10.3390/pharmaceutics14112537 - 21 Nov 2022

Cited by 10 | Viewed by 2502

Abstract

According to Globocan 2020, breast cancer is considered one of the most common cancers affecting women and is one of the leading causes of death in over 100 countries. The available classical treatment options do not always give satisfactory outcomes, and some patients [...] Read more.

According to Globocan 2020, breast cancer is considered one of the most common cancers affecting women and is one of the leading causes of death in over 100 countries. The available classical treatment options do not always give satisfactory outcomes, and some patients develop resistance to these treatments. This study aims to investigate the combination of nanovectorized siRNA directed against anti-apoptotic protein Survivin (siSurvivin) by targeted stealth magnetic siRNA nanovectors (TS-MSN), designed in our lab, with Doxorubicin (DOX), as an option for HER2+ breast cancer treatment. The hypothesis is that the pretreatment of the HER2+ breast cancer cell line SK-BR-3 with siSurvivin will induce apoptosis in the cancer cells and enhance the therapeutic efficacy of DOX, allowing a dose reduction of DOX and hence a reduction of potential side effects. TS-MSN are based on superparamagnetic iron oxide nanoparticles (SPIONs) covalently coupled with a fluorophore sulfocyanine-5 and polyethylene glycol 5000 (PEG₅₀₀₀) and functionalized with single-chain variable fragments (scFv) of an antibody targeting the HER2 membrane receptor. These covalently functionalized SPIONs are then complexed via electrostatic interactions with therapeutic siRNA and the cationic polymers, chitosan, and poly-L-arginine. TS-MSN_siSurvivin had an average size of 144 ± 30 nm, a PDI of 0.3, and a slightly positive zeta potential value of 10.56 ± 05.70 mV. The agarose gel electrophoresis assay confirmed that the siRNA is well-complexed into TS-MSN without leakage, as no free siRNA was detected. Moreover, siRNA in TS-MSN was protected from RNAse A degradation for up to 6 h at 37 °C. Formulations of TS-MSN with siSurvivin demonstrated in vitro gene knockdown up to 89% in the HER2+ breast cancer cell line SK-BR-3. Furthermore, qRT-PCR confirmed a significant Survivin mRNA relative expression inhibition (about 50%) compared to control siRNA or untreated cells. A combination protocol was evaluated between TS-MSN and Doxorubicin (DOX) for the first time. Therefore, SK-BR-3 cells were pretreated with TS-MSN formulated with siSurvivin at 50 nM for 24 h alone, before a DOX treatment at a concentration of 0.5 µM (corresponding to the IC₅₀) was added for 48 h. The MTT cytotoxicity tests, performed after 72 h of treatment, revealed that the combination had a significant synergistic cytotoxic effect on SK-BR-3 cells compared to monotherapies or untreated cells. We confirmed that pretreatment of cells with siSurvivin potentializes the cytotoxic effect of DOX as an alternative approach for treating HER2+ breast cancer. In conclusion, a combination of anti-Survivin siRNA and DOX would be a good alternative in HER2+ breast cancer therapy. Full article

(This article belongs to the Special Issue Therapeutic RNA Delivery Systems for Treatment of Cancer)

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17 pages, 2985 KiB

Open AccessArticle

Bioadhesive Tannic-Acid-Functionalized Zein Coating Achieves Engineered Colonic Delivery of IBD Therapeutics via Reservoir Microdevices

by Khorshid Kamguyan, Rolf Bech Kjeldsen, Saeed Zajforoushan Moghaddam, Melanie Randahl Nielsen, Esben Thormann, Kinga Zór, Line Hagner Nielsen and Anja Boisen

Pharmaceutics 2022, 14(11), 2536; https://doi.org/10.3390/pharmaceutics14112536 - 21 Nov 2022

Cited by 7 | Viewed by 2674

Abstract

The biggest challenge in oral delivery of anti-inflammatory drugs such as 5-aminosalicylic acid (5-ASA) is to (i) prevent rapid absorption in the small intestine and (ii) achieve localized release at the site of inflammation in the lower gut, i.e., the colon. Here, we [...] Read more.

The biggest challenge in oral delivery of anti-inflammatory drugs such as 5-aminosalicylic acid (5-ASA) is to (i) prevent rapid absorption in the small intestine and (ii) achieve localized release at the site of inflammation in the lower gut, i.e., the colon. Here, we present an advanced biopolymeric coating comprising of tannic-acid-functionalized zein protein to provide a sustained, colon-targeted release profile for 5-ASA and enhance the mucoadhesion of the dosage form via a mussel-inspired mechanism. To enable localized delivery and provide high local concentration, 5-ASA is loaded into the microfabricated drug carriers (microcontainers) and sealed with the developed coating. The functionality and drug release profile of the coating are characterized and optimized in vitro, showing great tunability, scalability, and stability toward proteases. Further, ex vivo experiments demonstrate that the tannic acid functionalization can significantly enhance the mucoadhesion of the coating, which is followed up by in vivo investigations on the intestinal retention, and pharmacokinetic evaluation of the 5-ASA delivery system. Results indicate that the developed coating can provide prolonged colonic delivery of 5-ASA. Therefore, the here-developed biodegradable coating can be an eco-friendly substitute to the state-of-the-art commercial counterparts for targeted delivery of 5-ASA and other small molecule drugs. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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20 pages, 1308 KiB

Open AccessReview

Dengue, West Nile, and Zika Viruses: Potential Novel Antiviral Biologics Drugs Currently at Discovery and Preclinical Development Stages

by Ivo C. Martins, Rafaela C. Ricardo and Nuno C. Santos

Pharmaceutics 2022, 14(11), 2535; https://doi.org/10.3390/pharmaceutics14112535 - 20 Nov 2022

Cited by 15 | Viewed by 2610

Abstract

Dengue, West Nile and Zika viruses are vector-borne flaviviruses responsible for numerous disease outbreaks in both Hemispheres. Despite relatively low mortality, infection may lead to potentially severe situations such as (depending on the virus): hypovolemic shock, encephalitis, acute flaccid paralysis, Guillain-Barré syndrome, congenital [...] Read more.

Dengue, West Nile and Zika viruses are vector-borne flaviviruses responsible for numerous disease outbreaks in both Hemispheres. Despite relatively low mortality, infection may lead to potentially severe situations such as (depending on the virus): hypovolemic shock, encephalitis, acute flaccid paralysis, Guillain-Barré syndrome, congenital malformations (e.g., microcephaly) and, in some situations, death. Moreover, outbreaks also have major socioeconomic repercussions, especially in already vulnerable societies. Thus far, only generic symptoms relief is possible, as there are no specific treatments available yet. Dengvaxia was the world’s first dengue vaccine. However, it is not fully effective. Prophylactic approaches against West Nile and Zika viruses are even more limited. Therefore, therapeutic strategies are required and will be discussed hereafter. We will first briefly present these viruses’ epidemiology, life cycle and structure. Then, we introduce the clinical presentation, diagnosis approaches and available vaccines. Finally, we list and discuss promising compounds at discovery and preclinical development stages already deposited at the GlobalData database and divided into three main types, according to therapeutic molecule: antibody-based, peptide-based molecules and, other compounds. To conclude, we discuss and compare promising developments, useful for future therapies against these three flaviviruses of major concern to human health. Full article

(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)

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14 pages, 4907 KiB

Open AccessArticle

Ganglioside GM3-Functionalized Reconstituted High-Density Lipoprotein (GM3-rHDL) as a Novel Nanocarrier Enhances Antiatherosclerotic Efficacy of Statins in apoE^−/− C57BL/6 Mice

by Bo Wei, Yuanfang Li, Meiying Ao, Wenxiang Shao, Kun Wang, Tong Rong, Yun Zhou and Yong Chen

Pharmaceutics 2022, 14(11), 2534; https://doi.org/10.3390/pharmaceutics14112534 - 20 Nov 2022

Cited by 7 | Viewed by 1959

Abstract

Previously, we found that exogenous ganglioside GM3 had an antiatherosclerotic efficacy and that its antiatherosclerotic efficacy could be enhanced by reconstituted high-density lipoprotein (rHDL). In this study, we hypothesized that GM3-functionalized rHDL (i.e., GM3-rHDL) as a nanocarrier can promote the efficacy of traditional [...] Read more.

Previously, we found that exogenous ganglioside GM3 had an antiatherosclerotic efficacy and that its antiatherosclerotic efficacy could be enhanced by reconstituted high-density lipoprotein (rHDL). In this study, we hypothesized that GM3-functionalized rHDL (i.e., GM3-rHDL) as a nanocarrier can promote the efficacy of traditional antiatherosclerotic drugs (e.g., statins). To test this hypothesis, lovastatin (LT) was used as a representative of statins, and LT-loaded GM3-rHDL nanoparticle (LT-GM3-rHDL or LT@GM3-rHDL; a mean size of ~142 nm) and multiple controls (e.g., GM3-rHDL without LT, LT-loaded rHDL or LT-rHDL, and other nanoparticles) were prepared. By using two different microsphere-based methods, the presences of apolipoprotein A-I (apoA-I) and/or GM3 in nanoparticles and the apoA-I-mediated macrophage-targeting ability of apoA-I/rHDL-containing nanoparticles were verified in vitro. Moreover, LT-GM3-rHDL nanoparticle had a slowly sustained LT release in vitro and the strongest inhibitory effect on the foam cell formation of macrophages (a key event of atherogenesis). After single administration of rHDL-based nanoparticles, a higher LT concentration was detected shortly in the atherosclerotic plaques of apoE^−/− mice than non-rHDL-based nanoparticles, suggesting the in vivo plaque-targeting ability of apoA-I/rHDL-containing nanoparticles. Finally, among all nanoparticles LT-GM3-rHDL induced the largest decreases in the contents of blood lipids and in the areas of atherosclerotic plaques at various aortic locations in apoE^−/− mice fed a high-fat diet for 12 weeks, supporting that LT-GM3-rHDL has the best in vivo antiatherosclerotic efficacy among the tested nanoparticles. Our data imply that GM3-functionalized rHDL (i.e., GM3-rHDL) can be utilized as a novel nanocarrier to enhance the efficacy of traditional antiatherosclerotic drugs (e.g., statins). Full article

(This article belongs to the Special Issue Nanotechnology in Drug Delivery and Controlled Release)

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38 pages, 2987 KiB

Open AccessReview

Instability Challenges and Stabilization Strategies of Pharmaceutical Proteins

by Mohsen Akbarian and Shu-Hui Chen

Pharmaceutics 2022, 14(11), 2533; https://doi.org/10.3390/pharmaceutics14112533 - 20 Nov 2022

Cited by 31 | Viewed by 5475

Abstract

Maintaining the structure of protein and peptide drugs has become one of the most important goals of scientists in recent decades. Cold and thermal denaturation conditions, lyophilization and freeze drying, different pH conditions, concentrations, ionic strength, environmental agitation, the interaction between the surface [...] Read more.

Maintaining the structure of protein and peptide drugs has become one of the most important goals of scientists in recent decades. Cold and thermal denaturation conditions, lyophilization and freeze drying, different pH conditions, concentrations, ionic strength, environmental agitation, the interaction between the surface of liquid and air as well as liquid and solid, and even the architectural structure of storage containers are among the factors that affect the stability of these therapeutic biomacromolecules. The use of genetic engineering, side-directed mutagenesis, fusion strategies, solvent engineering, the addition of various preservatives, surfactants, and additives are some of the solutions to overcome these problems. This article will discuss the types of stress that lead to instabilities of different proteins used in pharmaceutics including regulatory proteins, antibodies, and antibody-drug conjugates, and then all the methods for fighting these stresses will be reviewed. New and existing analytical methods that are used to detect the instabilities, mainly changes in their primary and higher order structures, are briefly summarized. Full article

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18 pages, 3810 KiB

Open AccessArticle

Probing Pharmaceutical Strategies to Promote the Skin Delivery of Asiatic Acid from Hydrogels: Enhancement Effects of Organic Amine Counterions, Chemical Enhancers, and Microneedle Pretreatment

by Mingming Li, Qiuyue Wang, Naiying Chen, Sicheng Yao, Xinxing Sun, Peng Quan and Yang Chen

Pharmaceutics 2022, 14(11), 2532; https://doi.org/10.3390/pharmaceutics14112532 - 20 Nov 2022

Cited by 5 | Viewed by 2161

Abstract

Asiatic acid (AA) is a pentacyclic triterpene isolated from Centella asiatica, holding great promise for treating a variety of skin disorders. However, the dermal application of AA is limited by its poor solubility and permeability. This study aimed to identify a hydrogel formulation [...] Read more.

Asiatic acid (AA) is a pentacyclic triterpene isolated from Centella asiatica, holding great promise for treating a variety of skin disorders. However, the dermal application of AA is limited by its poor solubility and permeability. This study aimed to identify a hydrogel formulation for AA and improve its skin penetration by various penetration enhancement methods. Four kinds of hydrogel bases were selected to prepare the AA hydrogel, in which different organic amines and chemical enhancers were incorporated in combination with microneedle pretreatment. The results showed that AA had good release profiles in the presence of hyaluronic acid as the hydrogel base and organic amines as the counter-ions. Diethylamine and Span 80 could promote drug penetration into the skin, and pretreatment with microneedles could further increase the drug permeability. In conclusion, the optimized hyaluronic acid hydrogel has great potential for use in the topical delivery of AA, and its penetration via the skin can be further improved by different pharmaceutical approaches. Full article

(This article belongs to the Special Issue New Trends for Transdermal and Dermal Delivery)

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18 pages, 1318 KiB

Open AccessArticle

Development of Oral Microemulsion Spray Containing Pentacyclic Triterpenes-Rich Centella asiatica (L.) Urb. Extract for Healing Mouth Ulcers

by Vilasinee Sanguansajapong, Pajaree Sakdiset and Panupong Puttarak

Pharmaceutics 2022, 14(11), 2531; https://doi.org/10.3390/pharmaceutics14112531 - 20 Nov 2022

Cited by 6 | Viewed by 3433

Abstract

Several publications have shown that Centella asiatica (L.) Urb. and its active constituents (pentacyclic triterpenes) are effective in wound healing. The pentacyclic triterpenes-rich C. asiatica extract (PRE) was prepared following a previous study by microwave-assisted extraction (MAE) and fractionation with macroporous resin. This method [...] Read more.

Several publications have shown that Centella asiatica (L.) Urb. and its active constituents (pentacyclic triterpenes) are effective in wound healing. The pentacyclic triterpenes-rich C. asiatica extract (PRE) was prepared following a previous study by microwave-assisted extraction (MAE) and fractionation with macroporous resin. This method provided the pentacyclic triterpene content in the extract up to 59.60% w/w. The PRE showed potent anti-inflammatory activity by inhibiting nitric oxide (NO) production with an IC₅₀ value of 20.59 ± 3.48 μg/mL and a potent fibroblast proliferative effect (165.67%) at concentrations of 10 μg/mL. The prepared microemulsion consisted of a water: oil: surfactant mixture of 2: 2: 6, using coconut oil: clove oil (1:1) as the oil phase and Tween 20: Span 20 (2:1) as the surfactant mixture and 1.0, 2.5, and 5.0% PRE. Cell proliferation, migration, and collagen production of the microemulsion base and microemulsions containing 1.0%, 2.5%, and 5.0% PRE were evaluated. The results revealed that the microemulsion containing 1% PRE had the highest proliferation effect (136.30 ± 3.93% to 152.65 ± 3.48% at concentrations of 10 μg/mL), migration activities (100.00 ± 0.0% at 24 h), and collagen production in human dermal fibroblast (HDF) and human gingival fibroblast (HGF) cells when compared with other formulations or blank. Moreover, the anti-inflammatory activity of microemulsions containing 1% PRE was slightly lower than standard indomethacin. Anti-inflammation of the microemulsion containing PRE exhibited a dose-dependent trend, while 5% PRE was more potent than the standard drug. Considering the potent wound-healing activities and the good anti-inflammatory activity of the microemulsion containing PRE, the microemulsion with 1% PRE was identified as the most suitable oral spray formulation for oral ulcer treatment. Full article

(This article belongs to the Special Issue Dosage Form Design for Oral Drug Delivery)

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24 pages, 2329 KiB

Open AccessReview

Cyclodextrin-Based Delivery Systems and Hydroxycinnamic Acids: Interactions and Effects on Crucial Parameters Influencing Oral Bioavailability—A Review

by Kleyton Santos Veras, Flávia Nathiely Silveira Fachel, Valquiria Linck Bassani, Helder Ferreira Teixeira and Letícia Scherer Koester

Pharmaceutics 2022, 14(11), 2530; https://doi.org/10.3390/pharmaceutics14112530 - 20 Nov 2022

Cited by 4 | Viewed by 1712

Abstract

Hydroxycinnamic acids (HCAs) are a subclass of phenolic acids presenting caffeic acid (CA), chlorogenic acid (CGA), coumaric acid (COA) isomers, ferulic acid (FA), and rosmarinic acid (RA) as the major representants, being broadly distributed into vegetal species and showing a range of biological [...] Read more.

Hydroxycinnamic acids (HCAs) are a subclass of phenolic acids presenting caffeic acid (CA), chlorogenic acid (CGA), coumaric acid (COA) isomers, ferulic acid (FA), and rosmarinic acid (RA) as the major representants, being broadly distributed into vegetal species and showing a range of biological potentials. Due to the low oral bioavailability of the HCAs, the development of delivery systems to promote better administration by the oral route is demanding. Among the systems, cyclodextrin (CD)-based delivery systems emerge as an important technology to solve this issue. Regarding these aspects, in this review, CD-based delivery systems containing HCAs are displayed, described, and discussed concerning the degree of interaction and their effects on crucial parameters that affect the oral bioavailability of HCAs. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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19 pages, 3869 KiB

Open AccessArticle

Label-Free Assessment of Mannitol Accumulation Following Osmotic Blood–Brain Barrier Opening Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging

by Jing Liu, Chengyan Chu, Jia Zhang, Chongxue Bie, Lin Chen, Safiya Aafreen, Jiadi Xu, David O. Kamson, Peter C. M. van Zijl, Piotr Walczak, Miroslaw Janowski and Guanshu Liu

Pharmaceutics 2022, 14(11), 2529; https://doi.org/10.3390/pharmaceutics14112529 - 20 Nov 2022

Cited by 6 | Viewed by 2889

Abstract

Purpose: Mannitol is a hyperosmolar agent for reducing intracranial pressure and inducing osmotic blood–brain barrier opening (OBBBO). There is a great clinical need for a non-invasive method to optimize the safety of mannitol dosing. The aim of this study was to develop a [...] Read more.

Purpose: Mannitol is a hyperosmolar agent for reducing intracranial pressure and inducing osmotic blood–brain barrier opening (OBBBO). There is a great clinical need for a non-invasive method to optimize the safety of mannitol dosing. The aim of this study was to develop a label-free Chemical Exchange Saturation Transfer (CEST)-based MRI approach for detecting intracranial accumulation of mannitol following OBBBO. Methods: In vitro MRI was conducted to measure the CEST properties of D-mannitol of different concentrations and pH. In vivo MRI and MRS measurements were conducted on Sprague-Dawley rats using a Biospec 11.7T horizontal MRI scanner. Rats were catheterized at the internal carotid artery (ICA) and randomly grouped to receive either 1 mL or 3 mL D-mannitol. CEST MR images were acquired before and at 20 min after the infusion. Results: In vitro MRI showed that mannitol has a strong, broad CEST contrast at around 0.8 ppm with a mM CEST MRI detectability. In vivo studies showed that CEST MRI could effectively detect mannitol in the brain. The low dose mannitol treatment led to OBBBO but no significant mannitol accumulation, whereas the high dose regimen resulted in both OBBBO and mannitol accumulation. The CEST MRI findings were consistent with ¹H-MRS and Gd-enhanced MRI assessments. Conclusion: We demonstrated that CEST MRI can be used for non-invasive, label-free detection of mannitol accumulation in the brain following BBBO treatment. This method may be useful as a rapid imaging tool to optimize the dosing of mannitol-based OBBBO and improve its safety and efficacy. Full article

(This article belongs to the Special Issue Nanoparticle Delivery to Tumors: Challenges and Advances)

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16 pages, 2524 KiB

Open AccessArticle

Repurposing the Antibacterial Agents Peptide 19-4LF and Peptide 19-2.5 for Treatment of Cutaneous Leishmaniasis

by Rima El-Dirany, Celia Fernández-Rubio, José Peña-Guerrero, Esther Moreno, Esther Larrea, Socorro Espuelas, Fadi Abdel-Sater, Klaus Brandenburg, Guillermo Martínez-de-Tejada and Paul Nguewa

Pharmaceutics 2022, 14(11), 2528; https://doi.org/10.3390/pharmaceutics14112528 - 20 Nov 2022

Cited by 7 | Viewed by 2280

Abstract

The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the [...] Read more.

The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the present study, the approach of repurposing AMPs as antileishmanial drugs was applied. The leishmanicidal activity of two synthetic anti-lipopolysaccharide peptides (SALPs), so-called 19-2.5 and 19-4LF was characterized in Leishmania major. In vitro, both peptides were highly active against intracellular Leishmania major in mouse macrophages without exerting toxicity in host cells. Then, q-PCR-based gene profiling, revealed that this activity was related to the downregulation of several genes involved in drug resistance (yip1), virulence (gp63) and parasite proliferation (Cyclin 1 and Cyclin 6). Importantly, the treatment of BALB/c mice with any of the two AMPs caused a significant reduction in L. major infective burden. This effect was associated with an increase in Th1 cytokine levels (IL-12p35, TNF-α, and iNOS) in the skin lesion and spleen of the L. major infected mice while the Th2-associated genes were downregulated (IL-4 and IL-6). Lastly, we investigated the effect of both peptides in the gene expression profile of the P2X7 purinergic receptor, which has been reported as a therapeutic target in several diseases. The results showed significant repression of P2X7R by both peptides in the skin lesion of L. major infected mice to an extent comparable to that of a common anti-leishmanial drug, Paromomycin. Our in vitro and in vivo studies suggest that the synthetic AMPs 19-2.5 and 19-4LF are promising candidates for leishmaniasis treatment and present P2X7R as a potential therapeutic target in cutaneous leishmaniasis (CL). Full article

(This article belongs to the Special Issue Drug Repurposing and Delivery Systems for Immunotherapy)

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29 pages, 7040 KiB

Open AccessArticle

Quercetin Loaded Cationic Solid Lipid Nanoparticles in a Mucoadhesive In Situ Gel—A Novel Intravesical Therapy Tackling Bladder Cancer

by Sylvia Shawky, Shaimaa Makled, Ashraf Awaad and Nabila Boraie

Pharmaceutics 2022, 14(11), 2527; https://doi.org/10.3390/pharmaceutics14112527 - 20 Nov 2022

Cited by 24 | Viewed by 3583

Abstract

The study aim was to develop an intravesical delivery system of quercetin for bladder cancer management in order to improve drug efficacy, attain a controlled release profile and extend the residence time inside the bladder. Either uncoated or chitosan coated quercetin-loaded solid lipid [...] Read more.

The study aim was to develop an intravesical delivery system of quercetin for bladder cancer management in order to improve drug efficacy, attain a controlled release profile and extend the residence time inside the bladder. Either uncoated or chitosan coated quercetin-loaded solid lipid nanoparticles (SLNs) were prepared and evaluated in terms of colloidal, morphological and thermal characteristics. Drug encapsulation efficiency and its release behaviour were assessed. Furthermore, cytotoxicity of SLNs on T-24 cells was evaluated. Ex vivo studies were carried out using bovine bladder mucosa. Spherical SLNs (≈250 nm) ensured good entrapment efficiencies (EE > 97%) and sustained drug release up to 142 h. Cytotoxicity profile revealed concentration-dependent toxicity recording an IC₅₀ in the range of 1.6–8.9 μg/mL quercetin. SLNs were further dispersed in in situ hydrogels comprising poloxamer 407 (20%) with mucoadhesive polymers. In situ gels exhibited acceptable gelation temperatures (around 25 °C) and long erosion time (24–27 h). SLNs loaded gels displayed remarkably enhanced retention on bladder tissues relative to SLNs dispersions. Coated SLNs exhibited better penetration abilities compared to uncoated ones, while coated SLNs dispersed in gel (G₁₀C-St-QCT-SLNs-2) showed the highest penetration up to 350 μm. Hence, G₁₀C-St-QCT-SLNs-2 could be considered as a platform for intravesical quercetin delivery. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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32 pages, 7290 KiB

Open AccessReview

Wetspun Polymeric Fibrous Systems as Potential Scaffolds for Tendon and Ligament Repair, Healing and Regeneration

by Joana Rocha, Joana C. Araújo, Raul Fangueiro and Diana P. Ferreira

Pharmaceutics 2022, 14(11), 2526; https://doi.org/10.3390/pharmaceutics14112526 - 19 Nov 2022

Cited by 6 | Viewed by 2552

Abstract

Tendon and ligament traumatic injuries are among the most common diagnosed musculoskeletal problems. Such injuries limit joint mobility, reduce musculoskeletal performance, and most importantly, lower people’s comfort. Currently, there are various treatments that are used to treat this type of injury, from surgical [...] Read more.

Tendon and ligament traumatic injuries are among the most common diagnosed musculoskeletal problems. Such injuries limit joint mobility, reduce musculoskeletal performance, and most importantly, lower people’s comfort. Currently, there are various treatments that are used to treat this type of injury, from surgical to conservative treatments. However, they’re not entirely effective, as reinjures are frequent and, in some cases, fail to re-establish the lost functionality. Tissue engineering (TE) approaches aim to overcome these disadvantages by stimulating the regeneration and formation of artificial structures that resemble the original tissue. Fabrication and design of artificial fibrous scaffolds with tailored mechanical properties are crucial for restoring the mechanical function of the tissues. Recently, polymeric nanofibers produced by wetspinning have been largely investigated to mimic, repair, and replace the damaged tissue. Wetspun fibrous structures are extensively used due to their exceptional properties, such as the ability to mimic the native tissue, their biodegradability and biocompatibility, and good mechanical properties. In this review, the tendon and ligament structure and biomechanics are presented. Then, promising wetspun multifunctional fibrous structures based on biopolymers, more specifically polyhydroxyalkanoates (PHA), polycaprolactone (PCL), and polyethylenes, will be discussed, as well as reinforcing agents such as cellulose nanocrystals (CNC), nanoparticles, and growth factors. Full article

(This article belongs to the Special Issue Fiber-Based Scaffolds as Drug Carriers: Recent Advances)

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20 pages, 5045 KiB

Open AccessArticle

Piper aduncum Essential Oil Rich in Dillapiole: Development of Hydrogel-Thickened Nanoemulsion and Nanostructured Lipid Carrier Intended for Skin Delivery

by Simone Braga Carneiro, Tainá Kreutz, Renata Pereira Limberger, Helder Ferreira Teixeira, Valdir Florêncio da Veiga Júnior and Letícia Scherer Koester

Pharmaceutics 2022, 14(11), 2525; https://doi.org/10.3390/pharmaceutics14112525 - 19 Nov 2022

Cited by 7 | Viewed by 2598

Abstract

The essential oil extracted from the leaves of Piper aduncum, an aromatic plant from the Amazon region, is rich in dillapiole and presents anti-inflammatory activity. In this study, nanoemulsions (NE) and nanostructured lipid carriers (NLC), which are biocompatible nanostructured systems of a [...] Read more.

The essential oil extracted from the leaves of Piper aduncum, an aromatic plant from the Amazon region, is rich in dillapiole and presents anti-inflammatory activity. In this study, nanoemulsions (NE) and nanostructured lipid carriers (NLC), which are biocompatible nanostructured systems of a lipid nature, were prepared by high-pressure homogenization for the yet unexplored skin delivery of dillapiole. The addition of hydroxyethylcellulose produced hydrogel-thickened NE or NLC in view to improving the viscosity and skin adherence of the nanoformulations. Formulations were characterized with respect to dillapiole content, droplet size, polydispersity index, zeta potential, morphology, rheological behavior, bioadhesion, skin permeation profile, and in vitro irritancy (HET-CAM). The formulations developed presented spherical, homogeneous nanometric particle size (around 130 nm), narrow polydispersity index (<0.3), and negative zeta potential (around −40 mV). Dillapiole content was slightly lower in NLC compared to NE since the production process involves heating. The hydrogels containing nanocarriers showed pseudoplastic behavior with bioadhesive characteristics. The developed formulations exhibited a controlled release profile, dillapiole delivery up to the dermis, the layer of interest for anti-inflammatory potential, and low irritant potential in the chorioallantoic membrane (HET-CAM). Both hydrogels-thickened NE and NLC seemed to be promising formulations for skin delivery of Piper aduncum essential oil. Full article

(This article belongs to the Special Issue Advances in Nanocarriers for Drug Delivery and Targeting)

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18 pages, 5199 KiB

Open AccessArticle

Acceptability of Multiparticulate Dosing Using Sympfiny^® Delivery System with Children (Age 1–12)

by Kate Abeln, Kate Cox, Laura Haggerty and Mary Beth Privitera

Pharmaceutics 2022, 14(11), 2524; https://doi.org/10.3390/pharmaceutics14112524 - 19 Nov 2022

Cited by 1 | Viewed by 1767

Abstract

This study investigated multiparticulate formulation administered over a two-week period of time via the Sympfiny^® system with children of ages 1–12 years. The study was conducted with parent–child pairs (N = 120 total participants) following a specific dose strategy to mimic PURIXAN’s [...] Read more.

This study investigated multiparticulate formulation administered over a two-week period of time via the Sympfiny^® system with children of ages 1–12 years. The study was conducted with parent–child pairs (N = 120 total participants) following a specific dose strategy to mimic PURIXAN’s dosing guidelines based upon the child’s age. PURIXAN^® (mercaptopurine) and Methotrexate have been identified as potential chemotherapy drugs that could benefit from reformulation into multiparticulate. Multiparticulate drugs have advantages as they can be flavorless, and do not require liquid reconstitution and do not require refrigeration. The study included three parts: initial in-person session, 14 days of at-home use, and a final in-person session. The in-person sessions were conducted at HS Design’s (HSD) (Morristown, NJ, USA) offices located in Morristown, New Jersey, where a study moderator captured and recorded all subjective comments by participants and observed device use to identify use errors. The participants were instructed to administer a dose (placebo) for the next 14 days and at each dose delivery to fill out a daily survey regarding their experience. Overall, the cumulative survey responses and feedback collected during the in-person sessions suggest that child participants ages 5–12 years old found multiparticulate to be an acceptable formulation and would be willing to take this medication if they were sick. Over time, more children ages 1–4 did not open their mouths; consistently around 15–20% of 1–4 years olds spat the placebo. However, approximately 95% of parents found the Sympfiny^® system acceptable and indicated that they would use it to deliver medication to their child. Full article

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43 pages, 9258 KiB

Open AccessReview

Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs

by Arvind Negi, Kavindra Kumar Kesari and Anne Sophie Voisin-Chiret

Pharmaceutics 2022, 14(11), 2523; https://doi.org/10.3390/pharmaceutics14112523 - 19 Nov 2022

Cited by 10 | Viewed by 4260

Abstract

Targeting selective estrogen subtype receptors through typical medicinal chemistry approaches is based on occupancy-driven pharmacology. In occupancy-driven pharmacology, molecules are developed in order to inhibit the protein of interest (POI), and their popularity is based on their virtue of faster kinetics. However, such [...] Read more.

Targeting selective estrogen subtype receptors through typical medicinal chemistry approaches is based on occupancy-driven pharmacology. In occupancy-driven pharmacology, molecules are developed in order to inhibit the protein of interest (POI), and their popularity is based on their virtue of faster kinetics. However, such approaches have intrinsic flaws, such as pico-to-nanomolar range binding affinity and continuous dosage after a time interval for sustained inhibition of POI. These shortcomings were addressed by event-driven pharmacology-based approaches, which degrade the POI rather than inhibit it. One such example is PROTACs (Proteolysis targeting chimeras), which has become one of the highly successful strategies of event-driven pharmacology (pharmacology that does the degradation of POI and diminishes its functions). The selective targeting of estrogen receptor subtypes is always challenging for chemical biologists and medicinal chemists. Specifically, estrogen receptor α (ER-α) is expressed in nearly 70% of breast cancer and commonly overexpressed in ovarian, prostate, colon, and endometrial cancer. Therefore, conventional hormonal therapies are most prescribed to patients with ER + cancers. However, on prolonged use, resistance commonly developed against these therapies, which led to selective estrogen receptor degrader (SERD) becoming the first-line drug for metastatic ER + breast cancer. The SERD success shows that removing cellular ER-α is a promising approach to overcoming endocrine resistance. Depending on the mechanism of degradation of ER-α, various types of strategies of developed. Full article

(This article belongs to the Special Issue State of Art in Protein Degraders and Autophagy Modulators in the Cancer Treatment)

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16 pages, 26739 KiB

Open AccessArticle

Drug Transport System Based on Phospholipid Nanoparticles: Production Technology and Characteristics

by Elena G. Tikhonova, Maxim A. Sanzhakov, Yulia A. Tereshkina, Lyubov V. Kostryukova, Yulia Yu. Khudoklinova, Nadezhda A. Orlova, Daria V. Bobrova and Olga M. Ipatova

Pharmaceutics 2022, 14(11), 2522; https://doi.org/10.3390/pharmaceutics14112522 - 19 Nov 2022

Cited by 7 | Viewed by 1802

Abstract

One of the current trends in modern pharmaceuticals is the supply of drugs by transport systems. The use of delivery systems allows to increase the therapeutic efficacy, tolerability, and safety of drug therapy. Liposomes, polymer nanoparticles, carbon nanoparticles, blood cells, metal nanoparticles, oxides, [...] Read more.

One of the current trends in modern pharmaceuticals is the supply of drugs by transport systems. The use of delivery systems allows to increase the therapeutic efficacy, tolerability, and safety of drug therapy. Liposomes, polymer nanoparticles, carbon nanoparticles, blood cells, metal nanoparticles, oxides, etc., are used as transport systems. This work is aimed at obtaining a finished technological product based on soy phospholipids with particle size in the nanometer range and reproducible characteristics (size, charge). For this purpose, we carried out investigations to select the optimal conditions of technological process. The developed technology makes it possible to obtain phospholipid nanoparticles without the use of any solubilizers and/or surfactants, which increases its practical relevance for further work. The versatility of the technology is demonstrated by the example of incorporation of drugs of various chemical nature and pharmacotherapeutic groups. Full article

(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems)

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23 pages, 5255 KiB

Open AccessArticle

Wound Healing Efficacy of Rosuvastatin Transethosomal Gel, I Optimal Optimization, Histological and In Vivo Evaluation

by Randa Mohammed Zaki, Vidya Devanathadesikan Seshadri, Alanoud S. Mutayran, Lara A. Elsawaf, Abubaker M. Hamad, Alanood S. Almurshedi, Rehab Mohammad Yusif and Mayada Said

Pharmaceutics 2022, 14(11), 2521; https://doi.org/10.3390/pharmaceutics14112521 - 19 Nov 2022

Cited by 20 | Viewed by 3117

Abstract

This study aimed to make a formulation and statistical optimization of transethosomal formulations of rosuvastatin (ROS) to enhance its topical wound healing efficiency. Design-Expert^® software was used to employ I optimal design. The formulation variables in the study were surfactant concentration (% [...] Read more.

This study aimed to make a formulation and statistical optimization of transethosomal formulations of rosuvastatin (ROS) to enhance its topical wound healing efficiency. Design-Expert^® software was used to employ I optimal design. The formulation variables in the study were surfactant concentration (%w/v), ethanol concentration (%w/v) and surfactant type (span 60 or tween 80), while the dependent responses were entrapment efficiency percent (EE%), vesicle size (VS) and zeta potential (ZP). The numerical optimization process employed by the design expert software resulted in an optimum formula composed of 0.819439 (%w/v) span 60, 40 (%w/v) ethanol and 100 mg lecithin with a desirability of 0.745. It showed a predicted EE% value of 66.5517 vs. 277.703 nm and a ZP of −33. When it was prepared and validated, it showed less than a 5% deviation from the predicted values. The optimum formula was subjected to further characterizations, such as DSC, XRD, TEM, in vitro release, the effect of aging and wound healing efficiency. The DSC thermogram made a confirmation of the compatibility of ROS with the ingredients used in the formulation. XRD showed the encapsulation of ROS in the transethosomal vesicles. The TEM image pointed out the spherical nature of the nanovesicles with the absence of aggregation. Additionally, the optimum formula revealed an enhancement of drug release in comparison with the drug suspension. It also showed good stability for one month. Furthermore, it revealed good wound healing efficiency when compared with the standard silver sulphadiazine (1% w/w) ointment or the drug-loaded gel, which could be related to the enhanced penetration of the nanosized vesicles of TESMs into the skin, which enhances the wound healing process. So, it could be regarded as a promising carrier of ROS for the treatment of chronic wounds. Full article

(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)

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35 pages, 4348 KiB

Open AccessReview

siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases

by Tutu Kalita, Saba Abbasi Dezfouli, Lalit M. Pandey and Hasan Uludag

Pharmaceutics 2022, 14(11), 2520; https://doi.org/10.3390/pharmaceutics14112520 - 19 Nov 2022

Cited by 27 | Viewed by 5078

Abstract

RNAi (RNA interference)-based technology is emerging as a versatile tool which has been widely utilized in the treatment of various diseases. siRNA can alter gene expression by binding to the target mRNA and thereby inhibiting its translation. This remarkable potential of siRNA makes [...] Read more.

RNAi (RNA interference)-based technology is emerging as a versatile tool which has been widely utilized in the treatment of various diseases. siRNA can alter gene expression by binding to the target mRNA and thereby inhibiting its translation. This remarkable potential of siRNA makes it a useful candidate, and it has been successively used in the treatment of diseases, including cancer. However, certain properties of siRNA such as its large size and susceptibility to degradation by RNases are major drawbacks of using this technology at the broader scale. To overcome these challenges, there is a requirement for versatile tools for safe and efficient delivery of siRNA to its target site. Lipid nanoparticles (LNPs) have been extensively explored to this end, and this paper reviews different types of LNPs, namely liposomes, solid lipid NPs, nanostructured lipid carriers, and nanoemulsions, to highlight this delivery mode. The materials and methods of preparation of the LNPs have been described here, and pertinent physicochemical properties such as particle size, surface charge, surface modifications, and PEGylation in enhancing the delivery performance (stability and specificity) have been summarized. We have discussed in detail various challenges facing LNPs and various strategies to overcome biological barriers to undertake the safe delivery of siRNA to a target site. We additionally highlighted representative therapeutic applications of LNP formulations with siRNA that may offer unique therapeutic benefits in such wide areas as acute myeloid leukaemia, breast cancer, liver disease, hepatitis B and COVID-19 as recent examples. Full article

(This article belongs to the Special Issue Functionalized Nanoparticles in Cancer Therapeutics)

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15 pages, 1968 KiB

Open AccessArticle

Biologic Evaluation of a Heterodimeric HER2-Albumin Targeted Affibody Molecule Produced by Chemo-Enzymatic Peptide Synthesis

by Yongsheng Liu, Rezan Güler, Yunqi Liao, Anzhelika Vorobyeva, Olof Widmark, Theodorus J. Meuleman, Anna Koijen, Leendert J. van den Bos, Robert Naasz, Vitalina Bodenko, Anna Orlova, Caroline Ekblad, Vladimir Tolmachev and Fredrik Y. Frejd

Pharmaceutics 2022, 14(11), 2519; https://doi.org/10.3390/pharmaceutics14112519 - 19 Nov 2022

Cited by 14 | Viewed by 2422

Abstract

Targeted molecular radiation therapy is a promising emerging treatment modality in oncology, and peptide synthesis may shorten the time to reach the clinical stage. In this study, we have explored Chemo-Enzymatic Peptide Synthesis, or CEPS, as a new means of producing a therapeutic [...] Read more.

Targeted molecular radiation therapy is a promising emerging treatment modality in oncology, and peptide synthesis may shorten the time to reach the clinical stage. In this study, we have explored Chemo-Enzymatic Peptide Synthesis, or CEPS, as a new means of producing a therapeutic HER2 targeted Affibody^® molecule, comprising a C-terminal albumin binding domain (ABD) for half-life extension and a total length of 108 amino acids. In addition, a DOTA moiety could be incorporated at N-terminus directly during the synthesis step and subsequently utilized for site-specific radiolabeling with the therapeutic radionuclide ¹⁷⁷Lu. Retained thermodynamic stability as well as retained binding to both HER2 and albumin was verified. Furthermore, HER2 binding specificity of the radiolabeled Affibody molecule was confirmed by an in vitro saturation assay showing a significantly higher cell-bound activity of SKOV-3 (high HER2 expression) compared with BxPC3 (low HER2 expression), both in the presence and absence of HSA. In vivo evaluation in mice bearing HER2 expressing xenografts also showed specific tumor targeting as well as extended time in circulation and reduced kidney uptake compared with a HER2 targeted Affibody molecule without the ABD moiety. To conclude, we have demonstrated that CEPS can be used for production of Affibody-fusion molecules with retained in vitro and in vivo functionality. Full article

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24 pages, 4253 KiB

Open AccessArticle

Tackling Antibiotic Resistance: Influence of Aliphatic Branches on Broad-Spectrum Antibacterial Polytriazoles against ESKAPE Group Pathogens

by Cristian Rangel-Núñez, Inmaculada Molina-Pinilla, Cristina Ramírez-Trujillo, Adrián Suárez-Cruz, Samuel Bernal Martínez and Manuel Bueno-Martínez

Pharmaceutics 2022, 14(11), 2518; https://doi.org/10.3390/pharmaceutics14112518 - 19 Nov 2022

Cited by 1 | Viewed by 1715

Abstract

One of the most important threats to public health is the appearance of multidrug-resistant pathogenic bacteria, since they are the cause of a high number of deaths worldwide. Consequently, the preparation of new effective antibacterial agents that do not generate antimicrobial resistance is [...] Read more.

One of the most important threats to public health is the appearance of multidrug-resistant pathogenic bacteria, since they are the cause of a high number of deaths worldwide. Consequently, the preparation of new effective antibacterial agents that do not generate antimicrobial resistance is urgently required. We report on the synthesis of new linear cationic antibacterial polytriazoles that could be a potential source of new antibacterial compounds. These polymers were prepared by thermal- or copper-catalyzed click reactions of azide and alkyne functions. The antibacterial activity of these materials can be modulated by varying the size or nature of their side chains, as this alters the hydrophilic/hydrophobic balance. Antibacterial activity was tested against pathogens of the ESKAPE group. The P3TD polymer, which has butylated side chains, was found to have the highest bactericidal activity. The toxicity of selected polytriazoles was investigated using human red blood cells and a human gingival fibroblast cell line. The propensity of prepared polytriazoles to induce resistance in certain bacteria was studied. Some of them were found to not produce resistance in methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa. The interaction of these polytriazoles with the Escherichia coli membrane produces both depolarization and disruption of the membrane. Full article

(This article belongs to the Special Issue New Strategies for Combating Antibiotic Resistance Based on Organic and Inorganic Nanosystems)

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17 pages, 4909 KiB

Open AccessArticle

Design-of-Experiments (DoE)-Assisted Fabrication of Quercetin-Loaded Nanoemulgel and Its Evaluation against Human Skin Cancer Cell Lines

by Aman Chitkara, Bharti Mangla, Pankaj Kumar, Shamama Javed, Waquar Ahsan and Harvinder Popli

Pharmaceutics 2022, 14(11), 2517; https://doi.org/10.3390/pharmaceutics14112517 - 19 Nov 2022

Cited by 17 | Viewed by 2518

Abstract

Background: Quercetin (QCT) is a natural polyphenolic flavonoid showing great potential in the treatment of skin cancer. However, its use is limited owing to its poor water solubility, poor absorption, quick metabolism and excretion, as well as low stability. Preparation of nanoemulgel has [...] Read more.

Background: Quercetin (QCT) is a natural polyphenolic flavonoid showing great potential in the treatment of skin cancer. However, its use is limited owing to its poor water solubility, poor absorption, quick metabolism and excretion, as well as low stability. Preparation of nanoemulgel has been proven to be an effective approach to deliver the drugs topically due to various advantages associated with it. Objectives: This study aimed to prepare stable nanoemulgel of QCT using a Design-of-Experiments (DoE) tool for optimization, to characterize and to assess its in vivo toxicity and efficacy against human cancer cell lines in vitro. Methods: An ultrasonication emulsification method was used for the preparation of QCT-loaded nanoemulsion (QCT@NE). Box–Behnken design was used for the optimization of developed nanoemulgel. Then, in vitro characterization of prepared nanoemulsion was performed using Fourier Transform-Infra Red (FT-IR) spectroscopy, Scanning Electron Microscopy (SEM), particle size analysis, determination of zeta potential and entrapment efficiency (%EE). Further, the developed QCT-loaded nanoemulgel (QCT@NG) was characterized in vitro using texture profile analysis, viscosity and pH determination. Eventually, the cell cytotoxicity studies of the prepared nanoemulgel were performed on the skin cancer cell lines A431 followed by an acute toxicity and skin irritation study on male wistar rats in vivo. Results: The developed QCT@NE was found to be nanometric in size (173.1 ± 1.2 nm) with low polydispersity index (0.353 ± 0.13), zeta potential (−36.1 ± 5.9 mV), and showed good %EE (90.26%). The QCT@NG was found to be substantially more effective against the human skin carcinoma (A431) cell lines as compared to plain QCT with IC₅₀ values of 108.5 and 579.0 µM, respectively. Skin irritation study showed no sign of toxicity and ensured safety for topical application. Hematological analysis revealed no significant differences between the treatment and control group in any biochemical parameter. In the nanoemulgel treatment group, there were no discernible differences in the liver enzymes, bilirubin, hemoglobin, total leukocyte and platelet counts as compared to the control group. Conclusions: The optimized QCT@NG was found to be an ideal and promising formulation for the treatment of skin cancer without showing skin irritation and organ toxicity. Full article

(This article belongs to the Special Issue Advanced Bio-Hybrid Materials for Drug Delivery Systems - New Trends and Perspectives)

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Pharmaceutics, Volume 14, Issue 11 (November 2022) – 291 articles

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