Pharmaceutics

4 pages, 176 KiB

Open AccessEditorial

Biopolymers Take Center Stage in Wound Healing Advancements

by Gorka Orive and Martín Federico Desimone

Pharmaceutics 2024, 16(6), 755; https://doi.org/10.3390/pharmaceutics16060755 (registering DOI) - 3 Jun 2024

Abstract

The human body possesses a remarkable ability to heal itself from injuries [...] Full article

(This article belongs to the Special Issue Biopolymer Materials for Wound Healing, 2nd Edition)

19 pages, 3674 KiB

Open AccessArticle

Antitumoral-Embedded Biopolymeric Spheres for Implantable Devices

by Valentina Grumezescu, Oana Gherasim, Bianca Gălățeanu and Ariana Hudiță

Pharmaceutics 2024, 16(6), 754; https://doi.org/10.3390/pharmaceutics16060754 (registering DOI) - 3 Jun 2024

Abstract

The bioactive surface modification of implantable devices paves the way towards the personalized healthcare practice by providing a versatile and tunable approach that increase the patient outcome, facilitate the medical procedure, and reduce the indirect or secondary effects. The purpose of our study [...] Read more.

The bioactive surface modification of implantable devices paves the way towards the personalized healthcare practice by providing a versatile and tunable approach that increase the patient outcome, facilitate the medical procedure, and reduce the indirect or secondary effects. The purpose of our study was to assess the performance of composite coatings based on biopolymeric spheres of poly(lactide-co-glycolide) embedded with hydroxyapatite (HA) and methotrexate (MTX). Bio-simulated tests performed for up to one week evidenced the gradual release of the antitumor drug and the biomineralization potential of PLGA/HA-MTX sphere coatings. The composite materials proved superior biocompatibility and promoted enhanced cell adhesion and proliferation with respect to human preosteoblast and osteosarcoma cell lines when compared to pristine titanium. Full article

(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery, 3rd Edition)

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28 pages, 6006 KiB

Open AccessArticle

Design and Biocompatibility of Biodegradable Poly(octamethylene suberate) Nanoparticles to Treat Skin Diseases

by Dragana P. C. de Barros, Luís P. Fonseca, Luís G. Gonçalves, Diogo S. Serrano and Abel Oliva

Pharmaceutics 2024, 16(6), 753; https://doi.org/10.3390/pharmaceutics16060753 (registering DOI) - 3 Jun 2024

Abstract

Biodegradable aliphatic polyester formulations as carriers for topical drug delivery show the potential to encapsulate structurally different therapeutic compounds. Poly(octamethylene suberate) (POS) nanoparticles (POS-NPs) were used as a matrix to encapsulate four therapeutic molecules used to treat skin disorders: caffeine (CF), quercetin (QR), [...] Read more.

Biodegradable aliphatic polyester formulations as carriers for topical drug delivery show the potential to encapsulate structurally different therapeutic compounds. Poly(octamethylene suberate) (POS) nanoparticles (POS-NPs) were used as a matrix to encapsulate four therapeutic molecules used to treat skin disorders: caffeine (CF), quercetin (QR), hydrocortisone (HC), and adapalene (AD). Hydrophobicity and chemical structure of bioactive compounds (BCs) influenced the physicochemical stability of drug-loaded nanoparticles. The particle size of drug-loaded nanoparticles was between 254.9 nm for the CF-POS-NP and 1291.3 for QR-POS-NP. Particles had a negative charge from −27.6 mV (QR) to −49.2 mV (HC). Drug loading content for all BC-POS-NPs varies between 36.11 ± 1.48% (CF-POS-NP) and 66.66 ± 4.87% (AD-POS-NP), and their entrapment efficiency is relatively high (28.30 ± 1.81% and 99.95 ± 0.04%, respectively). Calorimetric analysis showed the appearance of polymorphism for AD- and HC-loaded systems and the drug’s complete solubilisation into all nanoparticle formulations. FTIR and NMR spectra showed apparent drug incorporation into the polymer matrix of NPs. The encapsulation of BCs enhanced the antioxidative effect. The prepared POS nanoparticles’ cytotoxicity was studied using two dermal cell lines, keratinocyte (HaCaT) cells and fibroblasts (HDFn). The nanoparticle cytotoxic effect was more substantial on HaCaT cell lines. A reconstructed human epidermis (RHE) was successfully used to investigate the penetration of polymeric NPs. Based on permeation and histology studies, HC-POS-NPs and CF-POS-NPs were shown not to be suitable for dermal applications with the explored drug concentrations. AD presents a high permeation rate and no toxic impact on RHE. Full article

(This article belongs to the Special Issue Topical Drug Carriers: Recent Advances and Future Challenges)

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13 pages, 2825 KiB

Open AccessArticle

Surface-Available HER2 Levels Alone Are Not Indicative of Cell Response to HER2-Targeted Antibody–Drug Conjugate Therapies

by Molly Major, Christine S. Nervig, Annette Gerland and Shawn C. Owen

Pharmaceutics 2024, 16(6), 752; https://doi.org/10.3390/pharmaceutics16060752 (registering DOI) - 2 Jun 2024

Abstract

HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on tumor cell surfaces through immunohistochemistry or by gene regulation through fluorescence in situ hybridization. HER2 therapies are not always effective [...] Read more.

HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on tumor cell surfaces through immunohistochemistry or by gene regulation through fluorescence in situ hybridization. HER2 therapies are not always effective in patients with elevated levels of HER2, questioning whether the amount of HER2 is sufficiently predictive of patient outcomes. Additionally, the HER2-targeting antibody–drug conjugate (ADC) Enhertu^® was recently approved for metastasized HER2-low cancers, confirming the benefits of HER2 treatment for patients with low HER2 levels. To evaluate the correlation between HER2 levels and treatment efficacy, we quantified HER2 on eight cell lines using flow cytometry while simultaneously determining the toxicity of two HER2-targeting ADCs. Both HER2-high cell lines and HER2-low cell lines had significant toxicity responses to ADCs. We quantified HER2 internalization and found no correlation between HER2 levels and the percentage of internalization. We found a useful metric suggesting that a minimum number of HER2 receptors trafficked to lysosomes is sufficient to provide effective treatment. Our results indicate that the current standards of determining eligibility for HER2 therapy could limit patients’ access to effective treatment. In conclusion, HER2 levels are not wholly adequate to determine the response to ADC treatment. Full article

(This article belongs to the Section Biologics and Biosimilars)

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28 pages, 3300 KiB

Open AccessArticle

Inhibition of SARS-CoV-2-Induced NLRP3 Inflammasome-Mediated Lung Cell Inflammation by Triphala-Loaded Nanoparticle Targeting Spike Glycoprotein S1

by Chuda Chittasupho, Sonthaya Umsumarng, Kamonwan Srisawad, Punnida Arjsri, Rungsinee Phongpradist, Weerasak Samee, Wipawan Tingya, Chadarat Ampasavate and Pornngarm Dejkriengkraikul

Pharmaceutics 2024, 16(6), 751; https://doi.org/10.3390/pharmaceutics16060751 (registering DOI) - 2 Jun 2024

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, poses a significant global health threat. The spike glycoprotein S1 of the SARS-CoV-2 virus is known to induce the production of pro-inflammatory mediators, contributing to hyperinflammation in COVID-19 patients. Triphala, an ancient Ayurvedic remedy composed of dried [...] Read more.

The COVID-19 pandemic, caused by SARS-CoV-2, poses a significant global health threat. The spike glycoprotein S1 of the SARS-CoV-2 virus is known to induce the production of pro-inflammatory mediators, contributing to hyperinflammation in COVID-19 patients. Triphala, an ancient Ayurvedic remedy composed of dried fruits from three plant species—Emblica officinalis (Family Euphorbiaceae), Terminalia bellerica (Family Combretaceae), and Terminalia chebula (Family Combretaceae)—shows promise in addressing inflammation. However, the limited water solubility of its ethanolic extract impedes its bioavailability. In this study, we aimed to develop nanoparticles loaded with Triphala extract, termed “nanotriphala”, as a drug delivery system. Additionally, we investigated the in vitro anti-inflammatory properties of nanotriphala and its major compounds, namely gallic acid, chebulagic acid, and chebulinic acid, in lung epithelial cells (A549) induced by CoV2-SP. The nanotriphala formulation was prepared using the solvent displacement method. The encapsulation efficiency of Triphala in nanotriphala was determined to be 87.96 ± 2.60% based on total phenolic content. In terms of in vitro release, nanotriphala exhibited a biphasic release profile with zero-order kinetics over 0–8 h. A549 cells were treated with nanotriphala or its active compounds and then induced with 100 ng/mL of spike S1 subunit (CoV2-SP). The results demonstrate that chebulagic acid and chebulinic acid are the active compounds in nanotriphala, which significantly reduced cytokine release (IL-6, IL-1β, and IL-18) and suppressed the expression of inflammatory genes (IL-6, IL-1β, IL-18, and NLRP3) (p < 0.05). Mechanistically, nanotriphala and its active compounds notably attenuated the expression of inflammasome machinery proteins (NLRP3, ASC, and Caspase-1) (p < 0.05). In conclusion, the nanoparticle formulation of Triphala enhances its stability and exhibits anti-inflammatory properties against CoV2-SP-induction. This was achieved by suppressing inflammatory mediators and the NLRP3 inflammasome machinery. Thus, nanotriphala holds promise as a supportive preventive anti-inflammatory therapy for COVID-19-related chronic inflammation. Full article

(This article belongs to the Special Issue Application of Nanocarrier Systems for the Delivery of Bioactive Natural Products and Derivatives Thereof)

31 pages, 1074 KiB

Open AccessReview

Translational Challenges in Drug Therapy and Delivery Systems for Treating Chronic Lower Extremity Wounds

by Danny Aljamal, Priya S. Iyengar and Tammy T. Nguyen

Pharmaceutics 2024, 16(6), 750; https://doi.org/10.3390/pharmaceutics16060750 (registering DOI) - 2 Jun 2024

Abstract

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound [...] Read more.

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound treatments. Current targeted drug treatments and delivery systems for lower extremity wounds rely heavily on preclinical animal models meant to mimic human chronic wounds. However, there are several key differences between animal preclinical wound models and the human chronic wound microenvironment, which can impact the design of targeted drug treatments and delivery systems. To explore these differences, this review delves into recent new drug technologies and delivery systems designed to address the chronic wound microenvironment. It also highlights preclinical models used to test drug treatments specific for the wound microenvironments of lower extremity diabetic, venous, ischemic, and burn wounds. We further discuss key differences between preclinical wound models and human chronic wounds that may impact successful translational drug treatment design. Full article

(This article belongs to the Special Issue Advances in the Development of Cutting-Edge Drug Delivery Systems for the Effective Treatment of Chronic Skin Wounds, 2nd Edition)

14 pages, 1847 KiB

Open AccessArticle

Impact of Time on Parameters for Assessing the Microstructure Equivalence of Topical Products: Diclofenac 1% Emulsion as a Case Study

by Andreu Mañez-Asensi, Mª Jesús Hernández, Víctor Mangas-Sanjuán, Ana Salvador, Matilde Merino-Sanjuán and Virginia Merino

Pharmaceutics 2024, 16(6), 749; https://doi.org/10.3390/pharmaceutics16060749 (registering DOI) - 1 Jun 2024

Abstract

The demonstration of bioequivalence proposed in the European Medicines Agency’s (EMA’s) draft guideline for topical products with the same qualitative and quantitative composition requires the confirmation of the internal structure equivalence. The impact of the shelf-life on the parameters proposed for internal structure [...] Read more.

The demonstration of bioequivalence proposed in the European Medicines Agency’s (EMA’s) draft guideline for topical products with the same qualitative and quantitative composition requires the confirmation of the internal structure equivalence. The impact of the shelf-life on the parameters proposed for internal structure comparison has not been studied. The objectives of this work were: (1) to quantify the effect of the time since manufacturing on the mean value and variability of the parameters proposed by the EMA to characterize the internal structure and performance of topical formulations of a complex topical formulation, and (2) to evaluate the impact of these changes on the assessment of the microstructure equivalence. A total of 5 batches of a topical emulgel containing 1% diclofenac diethylamine were evaluated 5, 14, and 23 months after manufacture. The zero-shear viscosity (η₀), viscosity at 100 s⁻¹ (η₁₀₀), yield stress (σ₀), elastic (G′) and viscous (G″) moduli, internal phase droplet size and in vitro release of the active ingredient were characterized. While no change in variability over time was detected, the mean value of all the parameters changed, especially the droplet size and in vitro release. Thus, combining data from batches of different manufacturing dates may compromise the determination of bioequivalence. The results confirm that to assess the microstructural similarity of complex formulations (such as emulgel), the 90% confidence interval limit for the mean difference in rheological and in vitro release parameters should be 20% and 25%, respectively. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Current Status and Perspectives)

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24 pages, 1259 KiB

Open AccessReview

Comprehensive Insight into Cutaneous Application of Hemp

by Ana Žugić, Milica Martinović, Vanja Tadić, Miloš Rajković, Gordana Racić, Ivana Nešić and Anamarija Koren

Pharmaceutics 2024, 16(6), 748; https://doi.org/10.3390/pharmaceutics16060748 (registering DOI) - 31 May 2024

Abstract

Known for its natural bio-compounds and therapeutic properties, hemp is being utilized in the development of skin products. These products offer a wide range of applications and benefits in the fields of natural bio-compounds, pharmaceutical technology, topical delivery systems, and cosmeceuticals. This manuscript [...] Read more.

Known for its natural bio-compounds and therapeutic properties, hemp is being utilized in the development of skin products. These products offer a wide range of applications and benefits in the fields of natural bio-compounds, pharmaceutical technology, topical delivery systems, and cosmeceuticals. This manuscript deals with hemp actives, such as cannabinoids, terpenes, and flavonoids, and their diverse biological properties relative to topical application, including anti-inflammatory, antimicrobial, and antioxidant effects. Also, the paper reviews strategies to overcome poor penetration of hemp actives, as well as the integration of hemp actives in cosmeceuticals that provide natural and sustainable alternatives to traditional skincare products offering a range of benefits, including anti-aging, moisturizing, and soothing properties. The review aims to provide a comprehensive understanding of the development and manufacturing processes of skin products containing hemp actives. By delving into the science behind hemp-based products, the paper provides valuable insights into the potential of hemp as a versatile ingredient in the pharmaceutical and cosmetic industries. The utilization of hemp in these innovative products not only offers therapeutic benefits but also promotes natural and sustainable approaches to skincare. Full article

(This article belongs to the Special Issue Advances in Natural Products for Cutaneous Application)

26 pages, 7005 KiB

Open AccessArticle

L-Citrullinato-Bipyridine and L-Citrullinato-Phenanthroline Mixed Copper Complexes: Synthesis, Characterization and Potential Anticancer Activity

by Diego Ramírez-Contreras, Sergio Vázquez-Rodríguez, Amalia García-García, Lisset Noriega, Angel Mendoza, Brenda L. Sánchez-Gaytán, Francisco J. Meléndez, María Eugenia Castro, Maura Cárdenas-García and Enrique González-Vergara

Pharmaceutics 2024, 16(6), 747; https://doi.org/10.3390/pharmaceutics16060747 (registering DOI) - 31 May 2024

Abstract

Citrulline (C₆H₁₃N₃O₃) is an amino acid found in the body as a zwitterion. This means its carboxylic and amine groups can act as Lewis donors to chelate metal cations. In addition, citrulline possesses a terminal [...] Read more.

Citrulline (C₆H₁₃N₃O₃) is an amino acid found in the body as a zwitterion. This means its carboxylic and amine groups can act as Lewis donors to chelate metal cations. In addition, citrulline possesses a terminal ureido group on its aliphatic chain, which also appears to coordinate. Here, two new mixed complexes of citrulline were made with 1,10-phenanthroline and 2,2′-bipyridine. These compounds, once dissolved in water, gave aquo-complexes that were subject to DFT studies and in vitro toxicity studies on cancer cell lines (HeLa, MDA-MB-231, HCT 15, and MCF7) showed promising results. Docking studies with DNA were also conducted, indicating potential anticancer properties. Full article

(This article belongs to the Special Issue Application of Metal-Based Complexes in Cancer Treatment)

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34 pages, 2873 KiB

Open AccessReview

Chitosan Nanoparticles for Intranasal Drug Delivery

by Hossein Omidian, Erma J. Gill, Sumana Dey Chowdhury and Luigi X. Cubeddu

Pharmaceutics 2024, 16(6), 746; https://doi.org/10.3390/pharmaceutics16060746 (registering DOI) - 31 May 2024

Abstract

This manuscript explores the use of nanostructured chitosan for intranasal drug delivery, targeting improved therapeutic outcomes in neurodegenerative diseases, psychiatric care, pain management, vaccination, and diabetes treatment. Chitosan nanoparticles are shown to enhance brain delivery, improve bioavailability, and minimize systemic side effects by [...] Read more.

This manuscript explores the use of nanostructured chitosan for intranasal drug delivery, targeting improved therapeutic outcomes in neurodegenerative diseases, psychiatric care, pain management, vaccination, and diabetes treatment. Chitosan nanoparticles are shown to enhance brain delivery, improve bioavailability, and minimize systemic side effects by facilitating drug transport across the blood–brain barrier. Despite substantial advancements in targeted delivery and vaccine efficacy, challenges remain in scalability, regulatory approval, and transitioning from preclinical studies to clinical applications. The future of chitosan-based nanomedicines hinges on advancing clinical trials, fostering interdisciplinary collaboration, and innovating in nanoparticle design to overcome these hurdles and realize their therapeutic potential. Full article

(This article belongs to the Special Issue Recent Advances in Nanoparticles for Mucosal Drug Delivery)

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11 pages, 5736 KiB

Open AccessArticle

Co-Amorphization of Acemetacin with Basic Amino Acids as Co-Formers for Solubility Improvement and Gastric Ulcer Mitigation

by Jiayue Hou, Peixu Zhao, Yanfei Wang, Xiwei Jiang and Qiang Fu

Pharmaceutics 2024, 16(6), 745; https://doi.org/10.3390/pharmaceutics16060745 (registering DOI) - 31 May 2024

Abstract

Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and [...] Read more.

Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and basic amino acids have the potential to protect the gastrointestinal tract. In order to develop a highly efficient and low-toxic ACM formulation, we prepared ACM CAM systems, with basic amino acids (lysine, arginine, and histidine) as co-formers, using a cryo-milling method. The solid-state behaviors of the ACM CAM systems were characterized by polarizing light microscopy, differential scanning calorimetry, and powder X-ray diffraction. Fourier transform infrared spectroscopy and molecular docking were carried out to understand the formation mechanism. Moreover, the gastro-protective effects of ACM CAM systems were evaluated in a rat gastric ulcer model. The results demonstrated that the CAM systems improved the dissolution rates of ACM compared with the neat amorphous counterpart. Furthermore, ACM CAM systems are significantly effective in mitigating the ACM-induced gastric ulcer in rats, and the ulcer inhibition rates were almost 90%. More importantly, this study provided a useful method for mitigating drug-induced gastrointestinal damage and broadened the applications of drug–amino acid CAM systems. Full article

(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)

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Graphical abstract

17 pages, 2450 KiB

Open AccessArticle

Effects of Surface IR783 Density on the In Vivo Behavior and Imaging Performance of Liposomes

by Qianqian Long, Xinmin Zhao, Lili Gao, Mengyuan Liu, Feng Pan, Xihui Gao, Changyou Zhan, Yang Chen, Jialei Wang and Jun Qian

Pharmaceutics 2024, 16(6), 744; https://doi.org/10.3390/pharmaceutics16060744 (registering DOI) - 30 May 2024

Abstract

Background: Nanoparticles conjugated with fluorescent probes have versatile applications, serving not only for targeted fluorescent imaging but also for evaluating the in vivo profiles of designed nanoparticles. However, the relationship between fluorophore density and nanoparticle behavior remains unexplored. Methods: The IR783-modified liposomes (IR783-sLip) [...] Read more.

Background: Nanoparticles conjugated with fluorescent probes have versatile applications, serving not only for targeted fluorescent imaging but also for evaluating the in vivo profiles of designed nanoparticles. However, the relationship between fluorophore density and nanoparticle behavior remains unexplored. Methods: The IR783-modified liposomes (IR783-sLip) were prepared through a modified ethanol injection and extrusion method. The cellular uptake efficiency of IR783-sLip was characterized by flow cytometry and fluorescence microscope imaging. The effects of IR783 density on liposomal in vivo behavior were investigated by pharmacokinetic studies, biodistribution studies, and in vivo imaging. The constitution of protein corona was analyzed by the Western blot assay. Results: Dense IR783 modification improved cellular uptake of liposomes in vitro but hindered their blood retention and tumor imaging performance in vivo. We found a correlation between IR783 density and protein corona absorption, particularly IgM, which significantly impacted the liposome performance. Meanwhile, we observed that increasing IR783 density did not consistently improve the effectiveness of tumor imaging. Conclusions: Increasing the density of modified IR783 on liposomes is not always beneficial for tumor near-infrared (NIR) imaging yield. It is not advisable to prematurely evaluate novel nanomaterials through fluorescence dye conjugation without carefully optimizing the density of the modifications. Full article

(This article belongs to the Special Issue Lipid/Polymer-Based Drug Delivery Systems)

71 pages, 1645 KiB

Open AccessReview

Liquid Chromatography-Mass Spectrometry Analytical Methods for the Quantitation of p-Cresol Sulfate and Indoxyl Sulfate in Human Matrices: Biological Applications and Diagnostic Potentials

by Ala’a R. Al-Dajani, Qi Kun Hou and Tony K. L. Kiang

Pharmaceutics 2024, 16(6), 743; https://doi.org/10.3390/pharmaceutics16060743 (registering DOI) - 30 May 2024

Abstract

Indoxyl sulfate (IxS) and p-cresyl sulfate (pCS) are toxic uremic compounds with documented pathological outcomes. This review critically and comprehensively analyzes the available liquid chromatography-mass spectrometry methods quantifying IxS and pCS in human matrices and the biological applications of [...] Read more.

Indoxyl sulfate (IxS) and p-cresyl sulfate (pCS) are toxic uremic compounds with documented pathological outcomes. This review critically and comprehensively analyzes the available liquid chromatography-mass spectrometry methods quantifying IxS and pCS in human matrices and the biological applications of these validated assays. Embase, Medline, PubMed, Scopus, and Web of Science were searched until December 2023 to identify assays with complete analytical and validation data (N = 23). Subsequently, citation analysis with PubMed and Scopus was utilized to identify the biological applications for these assays (N = 45). The extraction methods, mobile phase compositions, chromatography, and ionization methods were evaluated with respect to overall assay performance (e.g., sensitivity, separation, interference). Most of the assays focused on human serum/plasma, utilizing acetonitrile or methanol (with ammonium acetate/formate or formic/acetic acid), liquid–liquid extraction, reverse phase (e.g., C18) chromatography, and gradient elution for analyte separation. Mass spectrometry conditions were also consistent in the identified papers, with negative electrospray ionization, select multiple reaction monitoring transitions and deuterated internal standards being the most common approaches. The validated biological applications indicated IxS and/or pCS were correlated with renal disease progression and cardiovascular outcomes, with limited data on central nervous system disorders. Methods for reducing IxS and/or pCS concentrations were also identified (e.g., drugs, natural products, diet, dialysis, transplantation) where inconsistent findings have been reported. The clinical monitoring of IxS and pCS is gaining significant interest, and this review will serve as a useful compendium for scientists and clinicians. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

18 pages, 1774 KiB

Open AccessArticle

Use of Transient Transfection for cGMP Manufacturing of eOD-GT8 60mer, a Self-Assembling Nanoparticle Germline-Targeting HIV-1 Vaccine Candidate

by Vaneet K. Sharma, Sergey Menis, Evan T. Brower, Eddy Sayeed, Jim Ackland, Angela Lombardo, Christopher A. Cottrell, Jonathan L. Torres, Thomas Hassell, Andrew B. Ward, Vadim Tsvetnitsky and William R. Schief

Pharmaceutics 2024, 16(6), 742; https://doi.org/10.3390/pharmaceutics16060742 (registering DOI) - 30 May 2024

Abstract

We describe the current Good Manufacturing Practice (cGMP) production and subsequent characterization of eOD-GT8 60mer, a glycosylated self-assembling nanoparticle HIV-1 vaccine candidate and germline targeting priming immunogen. Production was carried out via transient expression in the human embryonic kidney 293 (HEK293) cell line [...] Read more.

We describe the current Good Manufacturing Practice (cGMP) production and subsequent characterization of eOD-GT8 60mer, a glycosylated self-assembling nanoparticle HIV-1 vaccine candidate and germline targeting priming immunogen. Production was carried out via transient expression in the human embryonic kidney 293 (HEK293) cell line followed by a combination of purification techniques. A large-scale cGMP (200 L) production run yielded 354 mg of the purified eOD-GT8 60mer drug product material, which was formulated at 1 mg/mL in 10% sucrose in phosphate-buffered saline (PBS) at pH 7.2. The clinical trial material was comprehensively characterized for purity, antigenicity, glycan composition, amino acid sequence, and aggregation and by several safety-related tests during cGMP lot release. A comparison of the purified products produced at the 1 L scale and 200 L cGMP scale demonstrated the consistency and robustness of the transient transfection upstream process and the downstream purification strategies. The cGMP clinical trial material was tested in a Phase 1 clinical trial (NCT03547245), is currently being stored at −80 °C, and is on a stability testing program as per regulatory guidelines. The methods described here illustrate the utility of transient transfection for cGMP production of complex products such as glycosylated self-assembling nanoparticles. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

19 pages, 10041 KiB

Open AccessArticle

Cerebroprotective Effects of the TLR4-Binding DNA Aptamer ApTOLL in a Rat Model of Ischemic Stroke and Thrombectomy Recanalization

by Alicia Aliena-Valero, Macarena Hernández-Jiménez, Mikahela A. López-Morales, Eva Tamayo-Torres, María Castelló-Ruiz, David Piñeiro, Marc Ribó and Juan B. Salom

Pharmaceutics 2024, 16(6), 741; https://doi.org/10.3390/pharmaceutics16060741 (registering DOI) - 30 May 2024

Abstract

ApTOLL, a TLR4 modulator aptamer, has demonstrated cerebroprotective effects in a permanent ischemic stroke mouse model, as well as safety and efficacy in early phase clinical trials. We carried out reverse translation research according to STAIR recommendations to further characterize the effects and [...] Read more.

ApTOLL, a TLR4 modulator aptamer, has demonstrated cerebroprotective effects in a permanent ischemic stroke mouse model, as well as safety and efficacy in early phase clinical trials. We carried out reverse translation research according to STAIR recommendations to further characterize the effects and mechanisms of ApTOLL after transient ischemic stroke in rats and to better inform the design of pivotal clinical trials. Adult male rats subjected to transient middle cerebral artery occlusion were treated either with ApTOLL or the vehicle intravenously at different doses and time-points. ApTOLL was compared with TAK-242 (a TLR4 inhibitor). Female rats were also studied. After neurofunctional evaluation, brains were removed for infarct/edema volume, hemorrhagic transformation, and histologic determinations. Peripheral leukocyte populations were assessed via flow cytometry. ApTOLL showed U-shaped dose-dependent cerebroprotective effects. The maximum effective dose (0.45 mg/kg) was cerebroprotective when given both before reperfusion and up to 12 h after reperfusion and reduced the hemorrhagic risk. Similar effects occurred in female rats. Both research and clinical ApTOLL batches induced slightly superior cerebroprotection when compared with TAK-242. Finally, ApTOLL modulated circulating leukocyte levels, reached the brain ischemic tissue to bind resident and infiltrated cell types, and reduced the neutrophil density. These results show the cerebroprotective effects of ApTOLL in ischemic stroke by reducing the infarct/edema volume, neurofunctional impairment, and hemorrhagic risk, as well as the peripheral and local immune response. They provide information about ApTOLL dose effects and its therapeutic time window and target population, as well as its mode of action, which should be considered in the design of pivotal clinical trials. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation: Novel Drug Formulation and Delivery Systems)

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41 pages, 2188 KiB

Open AccessArticle

Vaccinium myrtillus L. Leaf Waste as a Source of Biologically Potent Compounds: Optimization of Polyphenol Extractions, Chemical Profile, and Biological Properties of the Extracts

by Muna Rajab Elferjane, Violeta Milutinović, Milica Jovanović Krivokuća, Mohammad J. Taherzadeh, Witold Pietrzak, Aleksandar Marinković and Aleksandra A. Jovanović

Pharmaceutics 2024, 16(6), 740; https://doi.org/10.3390/pharmaceutics16060740 (registering DOI) - 30 May 2024

Abstract

The aims of the present research include (1) optimization of extraction from Vaccinium myrtillus leaf waste via investigation of plant material:medium ratio, extraction medium, and extraction period, employing extractions at room and high temperatures, or using ultrasound and microwaves (M, HAE, UAE, and [...] Read more.

The aims of the present research include (1) optimization of extraction from Vaccinium myrtillus leaf waste via investigation of plant material:medium ratio, extraction medium, and extraction period, employing extractions at room and high temperatures, or using ultrasound and microwaves (M, HAE, UAE, and MAE, respectively), (2) physicochemical characterization, and (3) investigation of extract biological potential. The statistical analysis revealed that optimal levels of parameters for the greatest polyphenolic yield were a proportion of 1:30 g/mL, ethyl alcohol 50% (v/v) during 2 min of microwave irradiation. By LC-MS analysis, 29 phenolic components were detected; HAE showed the highest richness of almost all determined polyphenols, while chlorogenic acid and quercetin 3-O-glucuronide were dominant. All extracts showed a high inhibition of Staphylococcus aureus growth. The effect of different parameters on extracts’ antioxidant capacity depended on the used tests. The extracts also showed a stimulative influence on keratinocyte viability and anti-inflammatory activity (proven in cell-based ELISA and erythrocyte stabilization assays). The extraction procedure significantly affected the extraction yield (MAE ≥ maceration ≥ UAE ≥ HAE), whereas conductivity, density, surface tension, and viscosity varied in a narrow range. The presented research provides evidence on the optimal extraction conditions and technique, chemical composition, and antioxidant, antimicrobial, anti-inflammatory, and keratinocyte viability properties of bilberry extracts for potential applications in pharmacy and cosmetics. Full article

(This article belongs to the Special Issue Natural Pharmaceuticals Focused on Anti-inflammatory Activities)

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22 pages, 8692 KiB

Open AccessArticle

Hybrid Nanosystem Formed by DOX-Loaded Liposomes and Extracellular Vesicles from MDA-MB-231 Is Effective against Breast Cancer Cells with Different Molecular Profiles

by Luiza Marques Paschoal Barbosa, Eliza Rocha Gomes, André Luis Branco de Barros, Geovanni Dantas Cassali, Andréa Teixeira de Carvalho, Juliana de Oliveira Silva, Ana Luiza Pádua and Mônica Cristina Oliveira

Pharmaceutics 2024, 16(6), 739; https://doi.org/10.3390/pharmaceutics16060739 (registering DOI) - 30 May 2024

Abstract

Drug delivery selectivity is a challenge for cancer treatment. A hybrid pegylated pH-sensitive liposome–extracellular vesicle isolated from human breast cancer cell MDA-MB-231 was developed to investigate its in vitro activity against breast cancer cells of different molecular profiles to overcome this inconvenience. The [...] Read more.

Drug delivery selectivity is a challenge for cancer treatment. A hybrid pegylated pH-sensitive liposome–extracellular vesicle isolated from human breast cancer cell MDA-MB-231 was developed to investigate its in vitro activity against breast cancer cells of different molecular profiles to overcome this inconvenience. The hybrid nanosystem was produced by film hydration, and doxorubicin (DOX) was encapsulated in this system using the ammonium sulfate gradient method. The characterization of this hybrid nanosystem revealed a mean diameter of 140.20 ± 2.70 nm, a polydispersity index of 0.102 ± 0.033, an encapsulation efficiency of doxorubicin of 88.9% ± 2.4, and a great storage stability for 90 days at 4 °C. The fusion of extracellular vesicles with liposomes was confirmed by nanoflow cytometry using PE-conjugated human anti-CD63. This hybrid nanosystem demonstrated cytotoxicity against human breast cancer cell lines with different molecular subtypes, enhanced anti-migration properties, and exhibited similar cellular uptake to the free DOX treatment. Preliminary acute toxicity assessments using Balb/C female mice indicated a median lethal dose of 15–17.5 mg/kg, with no evidence of splenic, liver, heart, bone marrow, and renal damage at a dose of 15 mg/kg. These findings suggest the hybrid formulation as a versatile nanocarrier for the treatment of various breast cancer subtypes. Full article

(This article belongs to the Special Issue Advanced Liposomes for Drug Delivery, 2nd Edition)

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14 pages, 2060 KiB

Open AccessReview

The Different Strategies for the Radiolabeling of [²¹¹At]-Astatinated Radiopharmaceuticals

by Jie Gao, Mei Li, Jingjing Yin, Mengya Liu, Hongliang Wang, Jin Du and Jianguo Li

Pharmaceutics 2024, 16(6), 738; https://doi.org/10.3390/pharmaceutics16060738 (registering DOI) - 30 May 2024

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Abstract

Astatine-211 (²¹¹At) has emerged as a promising radionuclide for targeted alpha therapy of cancer by virtue of its favorable nuclear properties. However, the limited in vivo stability of ²¹¹At-labeled radiopharmaceuticals remains a major challenge. This review provides a comprehensive overview [...] Read more.

Astatine-211 (²¹¹At) has emerged as a promising radionuclide for targeted alpha therapy of cancer by virtue of its favorable nuclear properties. However, the limited in vivo stability of ²¹¹At-labeled radiopharmaceuticals remains a major challenge. This review provides a comprehensive overview of the current strategies for ²¹¹At radiolabeling, including nucleophilic and electrophilic substitution reactions, as well as the recent advances in the development of novel bifunctional coupling agents and labeling approaches to enhance the stability of ²¹¹At-labeled compounds. The preclinical and clinical applications of ²¹¹At-labeled radiopharmaceuticals, including small molecules, peptides, and antibodies, are also discussed. Looking forward, the identification of new molecular targets, the optimization of ²¹¹At production and quality control methods, and the continued evaluation of ²¹¹At-labeled radiopharmaceuticals in preclinical and clinical settings will be the key to realizing the full potential of ²¹¹At-based targeted alpha therapy. With the growing interest and investment in this field, ²¹¹At-labeled radiopharmaceuticals are poised to play an increasingly important role in future cancer treatment. Full article

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25 pages, 5791 KiB

Open AccessArticle

Applying Physiologically Based Pharmacokinetic Modeling to Interpret Carbamazepine’s Nonlinear Pharmacokinetics and Its Induction Potential on Cytochrome P450 3A4 and Cytochrome P450 2C9 Enzymes

by Xuefen Yin, Brian Cicali, Leyanis Rodriguez-Vera, Viera Lukacova, Rodrigo Cristofoletti and Stephan Schmidt

Pharmaceutics 2024, 16(6), 737; https://doi.org/10.3390/pharmaceutics16060737 (registering DOI) - 30 May 2024

Viewed by 93

Abstract

Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of other drugs, including itself, potentially leading to the undertreatment of co-administered drugs. Additionally, CBZ exhibits nonlinear pharmacokinetics (PK), but the [...] Read more.

Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of other drugs, including itself, potentially leading to the undertreatment of co-administered drugs. Additionally, CBZ exhibits nonlinear pharmacokinetics (PK), but the root causes have not been fully studied. This study aims to investigate the mechanisms behind CBZ’s nonlinear PK and its induction potential on CYP3A4 and CYP2C9 enzymes. To achieve this, we developed and validated a physiologically based pharmacokinetic (PBPK) parent–metabolite model of CBZ and its active metabolite Carbamazepine-10,11-epoxide in GastroPlus^®. The model was utilized for Drug–Drug Interaction (DDI) prediction with CYP3A4 and CYP2C9 victim drugs and to further explore the underlying mechanisms behind CBZ’s nonlinear PK. The model accurately recapitulated CBZ plasma PK. Good DDI performance was demonstrated by the prediction of CBZ DDIs with quinidine, dolutegravir, phenytoin, and tolbutamide; however, with midazolam, the predicted/observed DDI AUC_last ratio was 0.49 (slightly outside of the two-fold range). CBZ’s nonlinear PK can be attributed to its nonlinear metabolism caused by autoinduction, as well as nonlinear absorption due to poor solubility. In further applications, the model can help understand DDI potential when CBZ serves as a CYP3A4 and CYP2C9 inducer. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics and Drug Interactions)

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21 pages, 3283 KiB

Open AccessArticle

Applicability of MDR1 Overexpressing Abcb1KO-MDCKII Cell Lines for Investigating In Vitro Species Differences and Brain Penetration Prediction

by Emőke Sóskuti, Nóra Szilvásy, Csilla Temesszentandrási-Ambrus, Zoltán Urbán, Olivér Csíkvári, Zoltán Szabó, Gábor Kecskeméti, Éva Pusztai and Zsuzsanna Gáborik

Pharmaceutics 2024, 16(6), 736; https://doi.org/10.3390/pharmaceutics16060736 (registering DOI) - 29 May 2024

Viewed by 216

Abstract

Implementing the 3R initiative to reduce animal experiments in brain penetration prediction for CNS-targeting drugs requires more predictive in vitro and in silico models. However, animal studies are still indispensable to obtaining brain concentration and determining the prediction performance of in vitro models. [...] Read more.

Implementing the 3R initiative to reduce animal experiments in brain penetration prediction for CNS-targeting drugs requires more predictive in vitro and in silico models. However, animal studies are still indispensable to obtaining brain concentration and determining the prediction performance of in vitro models. To reveal species differences and provide reliable data for IVIVE, in vitro models are required. Systems overexpressing MDR1 and BCRP are widely used to predict BBB penetration, highlighting the impact of the in vitro system on predictive performance. In this study, endogenous Abcb1 knock-out MDCKII cells overexpressing MDR1 of human, mouse, rat or cynomolgus monkey origin were used. Good correlations between ERs of 83 drugs determined in each cell line suggest limited species specificities. All cell lines differentiated CNS-penetrating compounds based on ERs with high efficiency and sensitivity. The correlation between in vivo and predicted K_p,uu,brain was the highest using total ER of human MDR1 and BCRP and optimized scaling factors. MDR1 interactors were tested on all MDR1 orthologs using digoxin and quinidine as substrates. We found several examples of inhibition dependent on either substrate or transporter abundance. In summary, this assay system has the potential for early-stage brain penetration screening. IC₅₀ comparison between orthologs is complex; correlation with transporter abundance data is not necessarily proportional and requires the understanding of modes of transporter inhibition. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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18 pages, 2196 KiB

Open AccessArticle

Comparative In Vitro Study: Assessing Phytochemical, Antioxidant, Antimicrobial, and Anticancer Properties of Vaccinium macrocarpon Aiton and Vaccinium oxycoccos L. Fruit Extracts

by Rima Šedbarė, Valdimaras Janulis, Alvydas Pavilonis and Vilma Petrikaite

Pharmaceutics 2024, 16(6), 735; https://doi.org/10.3390/pharmaceutics16060735 (registering DOI) - 29 May 2024

Viewed by 147

Abstract

The phytochemical diversity and potential health benefits of V. oxycoccos and V. macrocarpon fruits call for further scientific inquiry. Our study aimed to determine the phytochemical composition of extracts from these fruits and assess their antioxidant, antibacterial, and anticancer properties in vitro. It [...] Read more.

The phytochemical diversity and potential health benefits of V. oxycoccos and V. macrocarpon fruits call for further scientific inquiry. Our study aimed to determine the phytochemical composition of extracts from these fruits and assess their antioxidant, antibacterial, and anticancer properties in vitro. It was found that the ethanolic extracts of V. oxycoccos and V. macrocarpon fruits, which contained more lipophilic compounds, had 2–14 times lower antioxidant activity compared to the dry aqueous extracts of cranberry fruit, which contained more hydrophilic compounds. All tested cranberry fruit extracts (OE, OW, ME, and MW) significantly inhibited the growth of bacterial strains S. aureus, S. epidermidis, E. coli, and K. pneumoniae in vitro compared to the control. Cytotoxic activity against the human prostate carcinoma PPC-1 cell line, human renal carcinoma cell line (CaKi-1), and human foreskin fibroblasts (HF) was determined using an MTT assay. Furthermore, the effect of the cranberry fruit extract samples on cell migration activity, cancer spheroid growth, and viability was examined. The ethanolic extract from V. macrocarpon fruits (ME) showed higher selectivity in inhibiting the viability of prostate and renal cancer cell lines compared to fibroblasts. It also effectively hindered the migration of these cancer cell lines. Additionally, the V. macrocarpon fruit extract (ME) demonstrated potent cytotoxicity against PPC-1 and CaKi-1 spheroids, significantly reducing the size of PPC-1 spheroids compared to the control. These findings suggest that cranberry fruit extracts, particularly the ethanolic extract from V. macrocarpon fruits, have promising potential as natural remedies for bacterial infections and cancer therapy. Full article

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

17 pages, 3570 KiB

Open AccessReview

Review of Prodrug and Nanodelivery Strategies to Improve the Treatment of Colorectal Cancer with Fluoropyrimidine Drugs

by Santu Sarkar, Sezgin Kiren and William H. Gmeiner

Pharmaceutics 2024, 16(6), 734; https://doi.org/10.3390/pharmaceutics16060734 (registering DOI) - 29 May 2024

Viewed by 189

Abstract

Fluoropyrimidine (FP) drugs are central components of combination chemotherapy regimens for the treatment of colorectal cancer (CRC). FP-based chemotherapy has improved survival outcomes over the last several decades with much of the therapeutic benefit derived from the optimization of dose and delivery. To [...] Read more.

Fluoropyrimidine (FP) drugs are central components of combination chemotherapy regimens for the treatment of colorectal cancer (CRC). FP-based chemotherapy has improved survival outcomes over the last several decades with much of the therapeutic benefit derived from the optimization of dose and delivery. To provide further advances in therapeutic efficacy, next-generation prodrugs and nanodelivery systems for FPs are being developed. This review focuses on recent innovative nanodelivery approaches for FP drugs that display therapeutic promise. We summarize established, clinically useful FP prodrug strategies, including capecitabine, which exploit tumor-specific enzyme expression for optimal anticancer activity. We then describe the use of FP DNA-based polymers (e.g., CF10) for the delivery of activated FP nucleotides as a nanodelivery approach with proven activity in pre-clinical models and with clinical potential. Multiple nanodelivery systems for FP delivery show promise in CRC pre-clinical models and we review advances in albumin-mediated FP delivery, the development of mesoporous silica nanoparticles, emulsion-based nanoparticles, metal nanoparticles, hydrogel-based delivery, and liposomes and lipid nanoparticles that display particular promise for therapeutic development. Nanodelivery of FPs is anticipated to impact CRC treatment in the coming years and to improve survival for cancer patients. Full article

(This article belongs to the Special Issue Recent Advances in Drug Delivery for the Treatment of Colorectal Cancer)

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28 pages, 12430 KiB

Open AccessReview

Atomic Force Microscopy for the Study of Cell Mechanics in Pharmaceutics

by Henrik Siboni, Ivana Ruseska and Andreas Zimmer

Pharmaceutics 2024, 16(6), 733; https://doi.org/10.3390/pharmaceutics16060733 (registering DOI) - 29 May 2024

Viewed by 180

Abstract

Cell mechanics is gaining attraction in drug screening, but the applicable methods have not yet become part of the standardized norm. This review presents the current state of the art for atomic force microscopy, which is the most widely available method. The field [...] Read more.

Cell mechanics is gaining attraction in drug screening, but the applicable methods have not yet become part of the standardized norm. This review presents the current state of the art for atomic force microscopy, which is the most widely available method. The field is first motivated as a new way of tracking pharmaceutical effects, followed by a basic introduction targeted at pharmacists on how to measure cellular stiffness. The review then moves on to the current state of the knowledge in terms of experimental results and supplementary methods such as fluorescence microscopy that can give relevant additional information. Finally, rheological approaches as well as the theoretical interpretations are presented before ending on additional methods and outlooks. Full article

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27 pages, 2097 KiB

Open AccessReview

Nivolumab and Ipilimumab Acting as Tormentors of Advanced Tumors by Unleashing Immune Cells and Associated Collateral Damage

by Bushra Khan, Rowaid M. Qahwaji, Mashael S. Alfaifi and Mohammad Mobashir

Pharmaceutics 2024, 16(6), 732; https://doi.org/10.3390/pharmaceutics16060732 (registering DOI) - 29 May 2024

Viewed by 188

Abstract

Combining immune checkpoint inhibitors, specifically nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), holds substantial promise in revolutionizing cancer treatment. This review explores the transformative impact of these combinations, emphasizing their potential for enhancing therapeutic outcomes across various cancers. Immune checkpoint proteins, such as PD1 and [...] Read more.

Combining immune checkpoint inhibitors, specifically nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), holds substantial promise in revolutionizing cancer treatment. This review explores the transformative impact of these combinations, emphasizing their potential for enhancing therapeutic outcomes across various cancers. Immune checkpoint proteins, such as PD1 and CTLA4, play a pivotal role in modulating immune responses. Blocking these checkpoints unleashes anticancer activity, and the synergy observed when combining multiple checkpoint inhibitors underscores their potential for enhanced efficacy. Nivolumab and ipilimumab harness the host’s immune system to target cancer cells, presenting a powerful approach to prevent tumor development. Despite their efficacy, immune checkpoint inhibitors are accompanied by a distinct set of adverse effects, particularly immune-related adverse effects affecting various organs. Understanding these challenges is crucial for optimizing treatment strategies and ensuring patient well-being. Ongoing clinical trials are actively exploring the combination of checkpoint inhibitory therapies, aiming to decipher their synergistic effects and efficacy against diverse cancer types. This review discusses the mechanisms, adverse effects, and various clinical trials involving nivolumab and ipilimumab across different cancers, emphasizing their transformative impact on cancer treatment. Full article

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21 pages, 5620 KiB

Open AccessArticle

Study on the Effect of Pharmaceutical Excipient PEG400 on the Pharmacokinetics of Baicalin in Cells Based on MRP2, MRP3, and BCRP Efflux Transporters

by Dan Yang, Min Zhang, Mei Zhao, Chaoji Li, Leyuan Shang, Shuo Zhang, Pengjiao Wang and Xiuli Gao

Pharmaceutics 2024, 16(6), 731; https://doi.org/10.3390/pharmaceutics16060731 (registering DOI) - 29 May 2024

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Abstract

Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can directly or indirectly influence the disposition process of active drugs in vivo, thereby affecting the bioavailability of drugs. In order to reveal the [...] Read more.

Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can directly or indirectly influence the disposition process of active drugs in vivo, thereby affecting the bioavailability of drugs. In order to reveal the pharmacokinetic effect of PEG400 on baicalin in hepatocytes and its mechanism, the present study first started with the effect of PEG400 on the metabolic disposition of baicalin at the hepatocyte level, and then the effect of PEG400 on the protein expression of baicalin-related transporters (BCRP, MRP2, and MRP3) was investigated by using western blot; the effect of MDCKII-BCRP, MDCKII-BCRP, MRP2, and MRP3 was investigated by using MDCKII-BCRP, MDCKII-MRP2, and MDCKII-MRP3 cell monolayer models, and membrane vesicles overexpressing specific transporter proteins (BCRP, MRP2, and MRP3), combined with the exocytosis of transporter-specific inhibitors, were used to study the effects of PEG400 on the transporters in order to explore the possible mechanisms of its action. The results demonstrated that PEG400 significantly influenced the concentration of baicalin in hepatocytes, and the AUC_0–t of baicalin increased from 75.96 ± 2.57 μg·h/mL to 106.94 ± 2.22 μg·h/mL, 111.97 ± 3.98 μg·h/mL, and 130.42 ± 5.26 μg·h/mL (p ˂ 0.05). Furthermore, the efflux rate of baicalin was significantly reduced in the vesicular transport assay and the MDCKII cell model transport assay, which indicated that PEG400 had a significant inhibitory effect on the corresponding transporters. In conclusion, PEG400 can improve the bioavailability of baicalin to some extent by affecting the efflux transporters and thus the metabolic disposition of baicalin in the liver. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

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18 pages, 10969 KiB

Open AccessArticle

Porous Chitosan/Hydroxyapatite Composite Microspheres for Vancomycin Loading and Releasing

by Meng-Ying Wu, Yi-Ting Kuo, I-Fang Kao and Shiow-Kang Yen

Pharmaceutics 2024, 16(6), 730; https://doi.org/10.3390/pharmaceutics16060730 (registering DOI) - 29 May 2024

Viewed by 158

Abstract

Porous chitosan/hydroxyapatite (Chi-HAp) composite microspheres were prepared in an aqueous solution containing chitosan, calcium nitrate, and ammonium dihydrogen phosphate by using a hydrothermal method at various temperatures. The investigation indicated that temperature significantly impacted the final product’s appearance. Hydroxyapatite (HAp) coupled with dicalcium [...] Read more.

Porous chitosan/hydroxyapatite (Chi-HAp) composite microspheres were prepared in an aqueous solution containing chitosan, calcium nitrate, and ammonium dihydrogen phosphate by using a hydrothermal method at various temperatures. The investigation indicated that temperature significantly impacted the final product’s appearance. Hydroxyapatite (HAp) coupled with dicalcium phosphate dihydrate (DCPD) flakes were obviously found at 65 and 70 °C, while the latter gradually disappeared at higher temperatures. Conversely, synthesis at 90 °C led to smaller particle sizes due to the broken chitosan chains. The microspheres synthesized at 75 °C were selected for further analysis, revealing porous structures with specific surface areas of 36.66 m²/g, pores ranging from 3 to 100 nm, and pore volumes of 0.58 cm³/g. Vancomycin (VCM), an antibiotic, was then absorbed on and released from the microspheres derived at 75 °C, with a drug entrapment efficiency of 20% and a release duration exceeding 20 days. The bacteriostatic activity of the VCM/composite microspheres against Staphylococcus aureus increased with the VCM concentration and immersion time, revealing a stable inhibition zone diameter of approximately 4.3 mm from 24 to 96 h, and this indicated the retained stability and efficacy of the VCM during the encapsulating process. Full article

(This article belongs to the Special Issue Design of Mesoporous Materials for Biomedical Application)

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27 pages, 3443 KiB

Open AccessReview

Photodynamic Therapy for Atherosclerosis: Past, Present, and Future

by Yanqing Lin, Ruosen Xie and Tao Yu

Pharmaceutics 2024, 16(6), 729; https://doi.org/10.3390/pharmaceutics16060729 (registering DOI) - 29 May 2024

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Abstract

This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health concern. Atherosclerosis is characterized by the accumulation of lipids and inflammation within arterial walls, leading to significant morbidity and mortality [...] Read more.

This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health concern. Atherosclerosis is characterized by the accumulation of lipids and inflammation within arterial walls, leading to significant morbidity and mortality through cardiovascular diseases such as myocardial infarction and stroke. Traditional therapeutic approaches have primarily focused on modulating risk factors such as hypertension and hyperlipidemia, with emerging evidence highlighting the pivotal role of inflammation. PDT, leveraging a photosensitizer, specific-wavelength light, and oxygen, offers targeted treatment by inducing cell death in diseased tissues while sparing healthy ones. This specificity, combined with advancements in nanoparticle technology for improved delivery, positions PDT as a promising alternative to traditional interventions. The review explores the mechanistic basis of PDT, its efficacy in preclinical studies, and the potential for enhancing plaque stability and reducing macrophage density within plaques. It also addresses the need for further research to optimize treatment parameters, mitigate adverse effects, and validate long-term outcomes. By detailing past developments, current progress, and future directions, this paper aims to highlight PDT’s potential in revolutionizing atherosclerosis treatment, bridging the gap from experimental research to clinical application. Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

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19 pages, 5579 KiB

Open AccessArticle

Drug-Induced Reorganisation of Lipid Metabolism Limits the Therapeutic Efficacy of Ponatinib in Glioma Stem Cells

by Paula Aldaz, Ana Olias-Arjona, Irene Lasheras-Otero, Karina Ausin, Marta Redondo-Muñoz, Claudia Wellbrock, Enrique Santamaria, Joaquin Fernandez-Irigoyen and Imanol Arozarena

Pharmaceutics 2024, 16(6), 728; https://doi.org/10.3390/pharmaceutics16060728 - 29 May 2024

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Abstract

The standard of care for glioblastoma (GBM) involves surgery followed by adjuvant radio- and chemotherapy, but often within months, patients relapse, and this has been linked to glioma stem cells (GSCs), self-renewing cells with increased therapy resistance. The identification of the epidermal growth [...] Read more.

The standard of care for glioblastoma (GBM) involves surgery followed by adjuvant radio- and chemotherapy, but often within months, patients relapse, and this has been linked to glioma stem cells (GSCs), self-renewing cells with increased therapy resistance. The identification of the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) as key players in gliomagenesis inspired the development of inhibitors targeting these tyrosine kinases (TKIs). However, results from clinical trials testing TKIs have been disappointing, and while the role of GSCs in conventional therapy resistance has been extensively studied, less is known about resistance of GSCs to TKIs. In this study, we have used compartmentalised proteomics to analyse the adaptive response of GSCs to ponatinib, a TKI with activity against PDGFR. The analysis of differentially expressed proteins revealed that GSCs respond to ponatinib by broadly rewiring lipid metabolism, involving fatty acid beta-oxidation, cholesterol synthesis, and sphingolipid degradation. Inhibiting each of these metabolic pathways overcame ponatinib adaptation of GSCs, but interrogation of patient data revealed sphingolipid degradation as the most relevant pathway in GBM. Our data highlight that targeting lipid metabolism, and particularly sphingolipid degradation in combinatorial therapies, could improve the outcome of TKI therapies using ponatinib in GBM. Full article

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

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19 pages, 4217 KiB

Open AccessArticle

Exploring the Regimes of Particle Behavior upon Impact via the Discrete Element Method

by Chanh Nguyen, Jennifer Curtis and Kambiz Salari

Pharmaceutics 2024, 16(6), 727; https://doi.org/10.3390/pharmaceutics16060727 - 28 May 2024

Viewed by 256

Abstract

Discrete element method simulations are conducted to probe the various regimes of post-impact behavior of particles with solid surfaces. The impacting particles are described as spherical agglomerates consisting of smaller constituent (or primary) particles held together via surface adhesion. Under the influence of [...] Read more.

Discrete element method simulations are conducted to probe the various regimes of post-impact behavior of particles with solid surfaces. The impacting particles are described as spherical agglomerates consisting of smaller constituent (or primary) particles held together via surface adhesion. Under the influence of a wide range of impact velocities and particle surface energies, five distinct behavioral regimes—rebounding, vibration, fragmentation, pancaking, and shattering—are identified, and force transmission patterns are linked to post-impact behavior. In the rebounding regime, the coefficient of restitution decreases linearly as impact velocity increases and the particle agglomerate experiences compaction. In the fragmentation regime, rebound velocity generally decreases with increasing fragment size. The rebound velocity of fragments decreases with time except for the smallest fragments, which can increase in velocity due to collisions with other fragments of high velocity. Particle breakage in the pancaking regime does not follow common mechanistic models of breakage. Full article

(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)

27 pages, 6444 KiB

Open AccessArticle

Silversol^® (a Colloidal Nanosilver Formulation) Inhibits Growth of Antibiotic-Resistant Staphylococcus aureus by Disrupting Its Physiology in Multiple Ways

by Nidhi Thakkar, Gemini Gajera, Dilip Mehta and Vijay Kothari

Pharmaceutics 2024, 16(6), 726; https://doi.org/10.3390/pharmaceutics16060726 - 28 May 2024

Viewed by 346

Abstract

Antibiotic-resistant strains of Staphylococcus aureus are being viewed as a serious threat by various public health agencies. Identifying novel targets in this important pathogen is crucial to the development of new effective antibacterial formulations. We investigated the antibacterial effect of a colloidal nanosilver [...] Read more.

Antibiotic-resistant strains of Staphylococcus aureus are being viewed as a serious threat by various public health agencies. Identifying novel targets in this important pathogen is crucial to the development of new effective antibacterial formulations. We investigated the antibacterial effect of a colloidal nanosilver formulation, Silversol^®, against an antibiotic-resistant strain of S. aureus using appropriate in vitro assays. Moreover, we deciphered the molecular mechanisms underlying this formulation’s anti-S. aureus activity using whole transcriptome analysis. Lower concentrations of the test formulation exerted a bacteriostatic effect against this pathogen, and higher concentrations exerted a bactericidal effect. Silversol^® at sub-lethal concentration was found to disturb multiple physiological traits of S. aureus such as growth, antibiotic susceptibility, membrane permeability, efflux, protein synthesis and export, biofilm and exopolysaccharide production, etc. Transcriptome data revealed that the genes coding for transcriptional regulators, efflux machinery, transferases, β-lactam resistance, oxidoreductases, metal homeostasis, virulence factors, and arginine biosynthesis are expressed differently under the influence of the test formulation. Genes (argG and argH) involved in arginine biosynthesis emerged among the major targets of Silversol^®’s antibacterial activity against S. aureus. Full article

(This article belongs to the Special Issue Novel Drugs, Targets and Therapies against Infectious Diseases)

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