Journal Description
Pharmaceutics
Pharmaceutics
is a peer-reviewed, open access journal on the science and technology of pharmaceutics and biopharmaceutics, and is published monthly online by MDPI. The Spanish Society of Pharmaceutics and Pharmaceutical Technology (SEFIG), Pharmaceutical Solid State Research Cluster (PSSRC), Academy of Pharmaceutical Sciences (APS) and Korean Society of Pharmaceutical Sciences and Technology (KSPST) are affiliated with Pharmaceutics and their members receive a discount on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q1 (Pharmacology & Pharmacy) / CiteScore - Q1 (Pharmaceutical Science)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 14.2 days after submission; acceptance to publication is undertaken in 3.6 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Companion journal: Future Pharmacology
Impact Factor:
5.4 (2022);
5-Year Impact Factor:
6.0 (2022)
Latest Articles
Surface-Available HER2 Levels Alone Are Not Indicative of Cell Response to HER2-Targeted Antibody–Drug Conjugate Therapies
Pharmaceutics 2024, 16(6), 752; https://0-doi-org.brum.beds.ac.uk/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
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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.
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(This article belongs to the Section Biologics and Biosimilars)
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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://0-doi-org.brum.beds.ac.uk/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
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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)
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://0-doi-org.brum.beds.ac.uk/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
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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)
Open AccessArticle
Impact of Time on Parameters for Assessing the Microstructure Equivalence of Topical Products: Diclofenac 1% Emulsion as a Case Study
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Andreu Mañez-Asensi, Mª Jesús Hernández, Víctor Mangas-Sanjuán, Ana Salvador, Matilde Merino-Sanjuán and Virginia Merino
Pharmaceutics 2024, 16(6), 749; https://0-doi-org.brum.beds.ac.uk/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
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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.
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(This article belongs to the Special Issue Topical Drug Delivery: Current Status and Perspectives)
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Open AccessReview
Comprehensive Insight into Cutaneous Application of Hemp
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Ana Žugić, Milica Martinović, Vanja Tadić, Miloš Rajković, Gordana Racić, Ivana Nešić and Anamarija Koren
Pharmaceutics 2024, 16(6), 748; https://0-doi-org.brum.beds.ac.uk/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
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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)
Open AccessArticle
L-Citrullinato-Bipyridine and L-Citrullinato-Phenanthroline Mixed Copper Complexes: Synthesis, Characterization and Potential Anticancer Activity
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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://0-doi-org.brum.beds.ac.uk/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
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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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Open AccessReview
Chitosan Nanoparticles for Intranasal Drug Delivery
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Hossein Omidian, Erma J. Gill, Sumana Dey Chowdhury and Luigi X. Cubeddu
Pharmaceutics 2024, 16(6), 746; https://0-doi-org.brum.beds.ac.uk/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
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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.
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(This article belongs to the Special Issue Recent Advances in Nanoparticles for Mucosal Drug Delivery)
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Open AccessArticle
Co-Amorphization of Acemetacin with Basic Amino Acids as Co-Formers for Solubility Improvement and Gastric Ulcer Mitigation
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Jiayue Hou, Peixu Zhao, Yanfei Wang, Xiwei Jiang and Qiang Fu
Pharmaceutics 2024, 16(6), 745; https://0-doi-org.brum.beds.ac.uk/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
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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.
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(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)
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Open AccessArticle
Effects of Surface IR783 Density on the In Vivo Behavior and Imaging Performance of Liposomes
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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://0-doi-org.brum.beds.ac.uk/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)
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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)
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
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Ala’a R. Al-Dajani, Qi Kun Hou and Tony K. L. Kiang
Pharmaceutics 2024, 16(6), 743; https://0-doi-org.brum.beds.ac.uk/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
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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)
Open AccessArticle
Use of Transient Transfection for cGMP Manufacturing of eOD-GT8 60mer, a Self-Assembling Nanoparticle Germline-Targeting HIV-1 Vaccine Candidate
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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://0-doi-org.brum.beds.ac.uk/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
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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)
Open AccessArticle
Cerebroprotective Effects of the TLR4-Binding DNA Aptamer ApTOLL in a Rat Model of Ischemic Stroke and Thrombectomy Recanalization
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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://0-doi-org.brum.beds.ac.uk/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
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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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Vaccinium myrtillus L. Leaf Waste as a Source of Biologically Potent Compounds: Optimization of Polyphenol Extractions, Chemical Profile, and Biological Properties of the Extracts
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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://0-doi-org.brum.beds.ac.uk/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
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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.
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(This article belongs to the Special Issue Natural Pharmaceuticals Focused on Anti-inflammatory Activities)
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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
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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://0-doi-org.brum.beds.ac.uk/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
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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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Open AccessReview
The Different Strategies for the Radiolabeling of [211At]-Astatinated Radiopharmaceuticals
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Jie Gao, Mei Li, Jingjing Yin, Mengya Liu, Hongliang Wang, Jin Du and Jianguo Li
Pharmaceutics 2024, 16(6), 738; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16060738 (registering DOI) - 30 May 2024
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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
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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.
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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://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16060737 (registering DOI) - 30 May 2024
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
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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 AUClast 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.
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(This article belongs to the Special Issue Advances in Pharmacokinetics and Drug Interactions)
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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://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16060736 (registering DOI) - 29 May 2024
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.
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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 Kp,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.
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(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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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://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16060735 (registering DOI) - 29 May 2024
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
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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.
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(This article belongs to the Special Issue Studies on the Cytotoxicity and Antimicrobial Effects of Synthetic and Natural Compounds)
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://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16060734 (registering DOI) - 29 May 2024
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
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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.
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(This article belongs to the Special Issue Recent Advances in Drug Delivery for the Treatment of Colorectal Cancer)
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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://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16060733 (registering DOI) - 29 May 2024
Abstract
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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
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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.
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