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Pharmaceutics, Volume 16, Issue 7 (July 2024) – 121 articles

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37 pages, 40998 KiB  
Article
Development and Evaluation of Docetaxel-Loaded Nanostructured Lipid Carriers for Skin Cancer Therapy
by Florentina-Iuliana Cocoș, Valentina Anuța, Lăcrămioara Popa, Mihaela Violeta Ghica, Mihaela-Alexandra Nica, Mirela Mihăilă, Radu Claudiu Fierăscu, Bogdan Trică, Cristian Andi Nicolae and Cristina-Elena Dinu-Pîrvu
Pharmaceutics 2024, 16(7), 960; https://doi.org/10.3390/pharmaceutics16070960 - 19 Jul 2024
Viewed by 44
Abstract
This study focuses on the design, characterization, and optimization of nanostructured lipid carriers (NLCs) loaded with docetaxel for the treatment of skin cancer. Employing a systematic formulation development process guided by Design of Experiments (DoE) principles, key parameters such as particle size, polydispersity [...] Read more.
This study focuses on the design, characterization, and optimization of nanostructured lipid carriers (NLCs) loaded with docetaxel for the treatment of skin cancer. Employing a systematic formulation development process guided by Design of Experiments (DoE) principles, key parameters such as particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency were optimized to ensure the stability and drug-loading efficacy of the NLCs. Combined XRD and cryo-TEM analysis were employed for NLC nanostructure evaluation, confirming the formation of well-defined nanostructures. In vitro kinetics studies demonstrated controlled and sustained docetaxel release over 48 h, emphasizing the potential for prolonged therapeutic effects. Cytotoxicity assays on human umbilical vein endothelial cells (HUVEC) and SK-MEL-24 melanoma cell line revealed enhanced efficacy against cancer cells, with significant selective cytotoxicity and minimal impact on normal cells. This multidimensional approach, encompassing formulation optimization and comprehensive characterization, positions the docetaxel-loaded NLCs as promising candidates for advanced skin cancer therapy. The findings underscore the potential translational impact of these nanocarriers, paving the way for future preclinical investigations and clinical applications in skin cancer treatment. Full article
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20 pages, 5201 KiB  
Article
A Novel Lactose/MCC/L-HPC Triple-Based Co-Processed Excipients with Improved Tableting Performance Designed for Metoclopramide Orally Disintegrating Tablets
by Xiaorong Dai, Jiamin Wang, Bo Yan, Qian Wang, Yan Shen, Yongkang Chen and Yu Tian
Pharmaceutics 2024, 16(7), 959; https://doi.org/10.3390/pharmaceutics16070959 - 19 Jul 2024
Viewed by 115
Abstract
New co-processed excipients comprising lactose (filler and sweetener), microcrystalline cellulose (MCC, filler), and low-substituted hydroxypropyl cellulose (L-HPC, disintegrant and binder) were developed via solvent evaporation for the preparation of metoclopramide orally disintegrating tablets (MCP ODTs). Single-factor and Box–Behnken experimental designs were employed to [...] Read more.
New co-processed excipients comprising lactose (filler and sweetener), microcrystalline cellulose (MCC, filler), and low-substituted hydroxypropyl cellulose (L-HPC, disintegrant and binder) were developed via solvent evaporation for the preparation of metoclopramide orally disintegrating tablets (MCP ODTs). Single-factor and Box–Behnken experimental designs were employed to optimize the formulation. The optimized formulation ratios were water: MCC: lactose (g/g) = 17.26:2.79:4.54:1. The results demonstrated that particles formed by solvent evaporation had superior flowability and compressibility compared to the physical mixture. Tablets compressed with these co-processed excipients exhibited a significantly reduced disintegration time of less than 25 s and achieved complete dissolution within 5 min. Pharmacokinetic studies revealed that MCP ODTs significantly improved Cmax, which was 1.60-fold higher compared to conventional tablets. In summary, the lactose/L-HPC/MCC triple-based co-processed excipients developed in this study are promising and could be successfully utilized in orally disintegrating and fast-release tablets. Full article
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22 pages, 5421 KiB  
Article
Investigation of Stabilized Amorphous Solid Dispersions to Improve Oral Olaparib Absorption
by Taehan Yun, Sumin Lee, Seowan Yun, Daeyeong Cho, Kyuho Bang and Kyeongsoo Kim
Pharmaceutics 2024, 16(7), 958; https://doi.org/10.3390/pharmaceutics16070958 - 19 Jul 2024
Viewed by 147
Abstract
In this study, we investigated the formulation of stable solid dispersions to enhance the bioavailability of olaparib (OLA), a therapeutic agent for ovarian cancer and breast cancer characterized as a BCS class IV drug with low solubility and low permeability. Various polymers were [...] Read more.
In this study, we investigated the formulation of stable solid dispersions to enhance the bioavailability of olaparib (OLA), a therapeutic agent for ovarian cancer and breast cancer characterized as a BCS class IV drug with low solubility and low permeability. Various polymers were screened based on solubility tests, and OLA-loaded solid dispersions were prepared using spray drying. The physicochemical properties of these dispersions were investigated via scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier Transform Infrared Spectroscopy (FT-IR). Subsequent dissolution tests, along with assessments of morphological and crystallinity changes in aqueous solutions, led to the selection of a hypromellose (HPMC)-based OLA solid dispersion as the optimal formulation. HPMC was effective at maintaining the supersaturation of OLA in aqueous solutions and exhibited a stable amorphous state without recrystallization. In an in vivo study, this HPMC-based OLA solid dispersion significantly enhanced bioavailability, increasing AUC0–24 by 4.19-fold and Cmax by more than 10.68-fold compared to OLA drug powder (crystalline OLA). Our results highlight the effectiveness of HPMC-based solid dispersions in enhancing the oral bioavailability of OLA and suggest that they could be an effective tool for the development of oral drug formulations. Full article
(This article belongs to the Special Issue Novel Anti-cancer Compounds: Drug Metabolism and Absorption)
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18 pages, 3543 KiB  
Article
Synergistic Effect of Essential Oils and Antifungal Agents in Fighting Resistant Clinical Isolates of Candida auris
by Lorenza Cavallo, Francesca Menotti, Janira Roana, Cristina Costa, Fabio Longo, Claudia Pagano, Antonio Curtoni, Alessandro Bondi, Giuliana Banche, Valeria Allizond and Narcisa Mandras
Pharmaceutics 2024, 16(7), 957; https://doi.org/10.3390/pharmaceutics16070957 - 19 Jul 2024
Viewed by 188
Abstract
Recently, a large number of nosocomial infections have been caused by an emerging pathogen that is rising as a worldwide issue in human health: Candida auris. This yeast is considered resistant to antifungals of the first-line therapies, and consequently it is related [...] Read more.
Recently, a large number of nosocomial infections have been caused by an emerging pathogen that is rising as a worldwide issue in human health: Candida auris. This yeast is considered resistant to antifungals of the first-line therapies, and consequently it is related to morbidity and mortality. Therefore, the aim of this research was to determine the in vitro anti-C. auris activity against twenty-three resistant clinical strains of different essential oils (EOs), pure or in combination with traditional antifungal agents, mainly caspofungin, fluconazole, micafungin and 5-flucytosine. Broth dilution assay was performed to evaluate the fungistatic and fungicidal effectiveness of fifteen EOs towards all the C. auris isolates. The data demonstrated that EOs were able to prevent C. auris growth, with MIC values ranging from 0.03 to 1% for the efficacious EOs (thyme, cinnamon, geranium, clove bud, lemongrass and mentha of Pancalieri), whereas the MICs were >1% for the ineffective ones. Thereafter, the six most effective EOs were used to perform the checkerboard experiments by assaying simultaneously the activity of EOs and traditional antifungals towards two selected strains. The most promising synergic combinations towards C. auris, depending on the isolate, were those with micafungin and geranium, thyme, cinnamon, lemongrass or clove bud EOs, with fluconazole and mentha of Pancalieri EO, and with 5-flucytosine and mentha of Pancalieri EO. These EOs and their combinations with antifungal drugs may provide a useful therapeutic alternative that could reduce the dose of the individual components, limiting the overall side effects. These associations might be a prospective option for the future treatment of infections, thus helping to overcome the challenging issue of resistance in C. auris. Full article
(This article belongs to the Section Drug Targeting and Design)
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18 pages, 2431 KiB  
Article
Novel Genetic Variants Explaining Severe Adverse Drug Events after Clinical Implementation of DPYD Genotype-Guided Therapy with Fluoropyrimidines: An Observational Study
by Xando Díaz-Villamarín, María Martínez-Pérez, María Teresa Nieto-Sánchez, Gabriela Ruiz-Tueros, Emilio Fernández-Varón, Alicia Torres-García, Beatriz González Astorga, Isabel Blancas, Antonio J. Iáñez, José Cabeza-Barrera and Rocío Morón
Pharmaceutics 2024, 16(7), 956; https://doi.org/10.3390/pharmaceutics16070956 - 19 Jul 2024
Viewed by 177
Abstract
Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical [...] Read more.
Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35–23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41–28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice. Full article
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19 pages, 7460 KiB  
Article
Uncovering the Therapeutic Potential of Lithium Chloride in Type 2 Diabetic Cardiomyopathy: Targeting Tau Hyperphosphorylation and TGF-β Signaling via GSK-3β Inhibition
by Layal Abou Assi, Sahar Alkhansa, Rachel Njeim, Jaafar Ismail, Mikel Madi, Hilda E. Ghadieh, Sarah Al Moussawi, Tanya S. Azar, Maurice Ayoub, William S. Azar, Sarah Hamade, Rashad Nawfal, Nina-Rossa Haddad, Frederic Harb, Wissam Faour, Mahmoud I. Khalil and Assaad A. Eid
Pharmaceutics 2024, 16(7), 955; https://doi.org/10.3390/pharmaceutics16070955 - 19 Jul 2024
Viewed by 249
Abstract
Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus (T2DM) that leads to significant morbidity and mortality. The alteration in the signaling mechanism in diabetes leading to cardiomyopathy remains unclear. The purpose of this study is to investigate the role [...] Read more.
Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus (T2DM) that leads to significant morbidity and mortality. The alteration in the signaling mechanism in diabetes leading to cardiomyopathy remains unclear. The purpose of this study is to investigate the role of tauopathy in myocardial dysfunction observed in T2DM. In that regard, diabetic Sprague Dawley rats were treated with intraperitoneal injections of lithium chloride (LiCl), inhibiting tau phosphorylation. Cardiac function was evaluated, and molecular markers of myocardial fibrosis and the TGF-β signaling were analyzed. T2DM rats exhibited a decline in ejection fraction and fractional shortening that revealed cardiac function abnormalities and increased myocardial fibrosis. These changes were associated with tau hyperphosphorylation. Treating diabetic rats with LiCl attenuated cardiac fibrosis and improved myocardial function. Inhibition of GSK-3β leads to the suppression of tau phosphorylation, which is associated with a decrease in TGF-β expression and regulation of the pro-inflammatory markers, suggesting that tau hyperphosphorylation is parallelly associated with fibrosis and inflammation in the diabetic heart. Our findings provide evidence of a possible role of tau hyperphosphorylation in the pathogenesis of DCM through the activation of TGF-β and by inducing inflammation. Targeting the inhibition of tau phosphorylation may offer novel therapeutic approaches to reduce DCM burden in T2DM patients. Full article
(This article belongs to the Special Issue Targeted Therapies in Cardiovascular and Kidney Diseases)
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11 pages, 2183 KiB  
Article
Glioma-Associated Sialoglycans Drive the Immune Suppressive Phenotype and Function of Myeloid Cells
by Lenneke A. M. Cornelissen, Kim C. M. Santegoets, Esther D. Kers-Rebel, Sandra A. J. F. H. Bossmann, Mark Ter Laan, Daniel Granado and Gosse J. Adema
Pharmaceutics 2024, 16(7), 953; https://doi.org/10.3390/pharmaceutics16070953 - 19 Jul 2024
Viewed by 221
Abstract
The tumor microenvironment of glioblastoma IDH-wildtype is highly immune suppressive and is characterized by a strong component of myeloid-derived suppressor cells (MDSCs). To interfere with the immune suppressive functions of MDSCs, a comprehensive understanding on how MDSCs acquire their suppressive phenotype is essential. [...] Read more.
The tumor microenvironment of glioblastoma IDH-wildtype is highly immune suppressive and is characterized by a strong component of myeloid-derived suppressor cells (MDSCs). To interfere with the immune suppressive functions of MDSCs, a comprehensive understanding on how MDSCs acquire their suppressive phenotype is essential. Previously, we and others have shown a distinct Sialic acid-binding immunoglobulin-like lectin (Siglec) receptor expression profile for MDSCs in glioblastoma. Siglec receptors can transmit inhibitory signals comparable to PD-1 and are suggested to act as glyco-immune checkpoints. Here, we investigated how glioma specific Siglec-sialic acid interactions influence myeloid immune suppressive functions. Co-culturing monocytes with glioblastoma cells induced CD163 expression on the monocytes. Upon desialylation of the glioblastoma cells, this induction of CD163 was hampered, and furthermore, the monocytes were now able to secrete higher amounts of IL-6 and TNFα compared to fully sialylated glioblastoma cells. Additionally, Siglec-specific triggering using anti-Siglec-7 or Siglec-9 antibodies displayed a decreased TNFα secretion by the monocytes, validating the role of the Siglec–Sialic axis in the co-culture experiments. Together, our results demonstrate that glioblastoma cells induce a myeloid immune-suppressive phenotype that could be partly rescued by lowering the glioblastoma-associated sialic acid levels. This manuscript supports further research of the Siglec–Sialic acid axis in the context of glioblastoma and its potential to improve clinical outcome. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies for Glioblastoma)
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25 pages, 3975 KiB  
Article
Exploring a New Generation of Pyrimidine and Pyridine Derivatives as Anti-Influenza Agents Targeting the Polymerase PA–PB1 Subunits Interaction
by Ilaria Giacchello, Annarita Cianciusi, Chiara Bertagnin, Anna Bonomini, Valeria Francesconi, Mattia Mori, Anna Carbone, Francesca Musumeci, Arianna Loregian and Silvia Schenone
Pharmaceutics 2024, 16(7), 954; https://doi.org/10.3390/pharmaceutics16070954 - 18 Jul 2024
Viewed by 249
Abstract
The limited range of available flu treatments due to virus mutations and drug resistance have prompted the search for new therapies. RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex of three subunits, i.e., polymerase acidic protein (PA) and polymerase basic proteins 1 and [...] Read more.
The limited range of available flu treatments due to virus mutations and drug resistance have prompted the search for new therapies. RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex of three subunits, i.e., polymerase acidic protein (PA) and polymerase basic proteins 1 and 2 (PB1 and PB2). It is widely recognized as one of the most promising anti-flu targets because of its critical role in influenza infection and high amino acid conservation. In particular, the disruption of RdRp complex assembly through protein–protein interaction (PPI) inhibition has emerged as a valuable strategy for discovering a new therapy. Our group previously identified the 3-cyano-4,6-diphenyl-pyridine core as a privileged scaffold for developing PA–PB1 PPI inhibitors. Encouraged by these findings, we synthesized a small library of pyridine and pyrimidine derivatives decorated with a thio-N-(m-tolyl)acetamide side chain (compounds 2an) or several amino acid groups (compounds 3an) at the C2 position. Interestingly, derivative 2d, characterized by a pyrimidine core and a phenyl and 4-chloro phenyl ring at the C4 and C6 positions, respectively, showed an IC50 value of 90.1 μM in PA–PB1 ELISA, an EC50 value of 2.8 μM in PRA, and a favorable cytotoxic profile, emerging as a significant breakthrough in the pursuit of new PPI inhibitors. A molecular modeling study was also completed as part of this project, allowing us to clarify the biological profile of these compounds. Full article
(This article belongs to the Section Drug Targeting and Design)
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13 pages, 1719 KiB  
Article
Comparative Efficacy of Inhaled and Intravenous Corticosteroids in Managing COVID-19-Related Acute Respiratory Distress Syndrome
by Ahmed A. Abdelkader, Bshra A. Alsfouk, Asmaa Saleh, Mohamed E. A. Abdelrahim and Haitham Saeed
Pharmaceutics 2024, 16(7), 952; https://doi.org/10.3390/pharmaceutics16070952 - 18 Jul 2024
Viewed by 266
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which the lungs fail to provide sufficient oxygen to the body’s vital organs. It is commonly associated with COVID-19 patients. Severe cases of COVID-19 can lead to lung damage and organ failure due [...] Read more.
Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which the lungs fail to provide sufficient oxygen to the body’s vital organs. It is commonly associated with COVID-19 patients. Severe cases of COVID-19 can lead to lung damage and organ failure due to an immune response in the body. To mitigate these effects, corticosteroids, which are known for their anti-inflammatory properties, have been suggested as a potential treatment option. The primary focus of this study was to assess the impact of various corticosteroid administration methods on the outcomes of patients with COVID-19. Methods: The current study was conducted on COVID-19 patients divided into three groups. The first group was administered 6 mg of intravenous (IV) dexamethasone; the second group received 1 mg/kg of IV methylprednisolone (methylprednisolone); and the third group received budesonide respirable solution at a dosage of 1mg twice daily. The neubilizer used was a vibrating mesh nebulizer (VMN). All patients received standard care. We found that dexamethasone administered intravenously led to a significant reduction in C-reactive protein levels, surpassing the effectiveness of both IV methylprednisolone and inhaled budesonide. Oxygen saturation without mask change over time showed statistically significant differences (p = 0.004) in favor of the budesonide and dexamethasone groups for all days. Individuals who received methylprednisolone showed a significant decrease in mortality rate and an extended survival duration, with statistical significance observed at p = 0.024. The rest of the parameters, including ferritin, lymphocytes, total leukocyte count, platelets, hemoglobin, urea, serum potassium, serum sodium, serum creatinine, serum glutamic-pyruvic transaminase, serum glutamic-oxaloacetic transaminase, uric acid, albumin, globulin, erythrocyte sedimentation rate, international normalized ratio, oxygen saturation with flow, and oxygen flow, showed no statistically significant differences between the three drugs. In conclusion, treatment with IV methylprednisolone (1 mg/kg) resulted in a shorter hospital stay, decreased reliance on ventilation, and improved health outcomes for COVID-19 patients compared to using dexamethasone at a daily dosage of 6 mg or budesonide respirable solution at a dosage of 1mg twice daily. Full article
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17 pages, 2338 KiB  
Article
Design of Novel TRPA1 Agonists Based on Structure of Natural Vasodilator Carvacrol—In Vitro and In Silico Studies
by Đorđe Đukanović, Relja Suručić, Milica Gajić Bojić, Saša M. Trailović, Ranko Škrbić and Žarko Gagić
Pharmaceutics 2024, 16(7), 951; https://doi.org/10.3390/pharmaceutics16070951 - 18 Jul 2024
Viewed by 297
Abstract
Considering the escalating global prevalence and the huge therapeutic demand for the treatment of hypertension, there is a persistent need to identify novel target sites for vasodilator action. This study aimed to investigate the role of TRPA1 channels in carvacrol-induced vasodilation and to [...] Read more.
Considering the escalating global prevalence and the huge therapeutic demand for the treatment of hypertension, there is a persistent need to identify novel target sites for vasodilator action. This study aimed to investigate the role of TRPA1 channels in carvacrol-induced vasodilation and to design novel compounds based on carvacrol structure with improved activities. In an isolated tissue bath experiment, it was shown that 1 µM of the selective TRPA1 antagonist A967079 significantly (p < 0.001) reduced vasodilation induced by 3 mM of carvacrol. A reliable 3D-QSAR model with good statistical parameters was created (R2 = 0.83; Q2 = 0.59 and Rpred2 = 0.84) using 29 TRPA1 agonists. Obtained results from this model were used for the design of novel TRPA1 activators, and to predict their activity against TRPA1. Predicted pEC50 activities of these molecules range between 4.996 to 5.235 compared to experimental pEC50 of 4.77 for carvacrol. Molecular docking studies showed that designed molecules interact with similar amino acid residues of the TRPA1 channel as carvacrol, with eight compounds showing lower binding energies. In conclusion, carvacrol-induced vasodilation is partly mediated by the activation of TRPA1 channels. Combining different in silico approaches pointed out that the molecule D27 (2-[2-(hydroxymethyl)-4-methylphenyl]acetamide) is the best candidate for further synthesis and experimental evaluation in in vitro conditions. Full article
(This article belongs to the Section Drug Targeting and Design)
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18 pages, 3368 KiB  
Article
Mitochondria-Targeted Liposomes for Drug Delivery to Tumor Mitochondria
by Aysegul Ekmekcioglu, Ozgul Gok, Devrim Oz-Arslan, Meryem Sedef Erdal, Yasemin Yagan Uzuner and Meltem Muftuoglu
Pharmaceutics 2024, 16(7), 950; https://doi.org/10.3390/pharmaceutics16070950 - 17 Jul 2024
Viewed by 215
Abstract
The special bilayer structure of mitochondrion is a promising therapeutic target in the diagnosis and treatment of diseases such as cancer and metabolic diseases. Nanocarriers such as liposomes modified with mitochondriotropic moieties can be developed to send therapeutic molecules to mitochondria. In this [...] Read more.
The special bilayer structure of mitochondrion is a promising therapeutic target in the diagnosis and treatment of diseases such as cancer and metabolic diseases. Nanocarriers such as liposomes modified with mitochondriotropic moieties can be developed to send therapeutic molecules to mitochondria. In this study, DSPE-PEG-TPP polymer conjugate was synthesized and used to prepare mitochondria-targeted liposomes (TPPLs) to improve the therapeutic index of chemotherapeutic agents functioning in mitochondria and reduce their side effects. Doxorubicin (Dox) loaded-TPPL and non-targeted PEGylated liposomes (PPLs) were prepared and compared based on physicochemical properties, morphology, release profile, cellular uptake, mitochondrial localization, and anticancer effects. All formulations were spherically shaped with appropriate size, dispersity, and zeta potential. The stability of the liposomes was favorable for two months at 4 °C. TPPLs localize to mitochondria, whereas PPLs do not. The empty TPPLs and PPLs were not cytotoxic to HCT116 cells. The release kinetics of Dox-loaded liposomes showed that Dox released from TPPLs was higher at pH 5.6 than at pH 7.4, which indicates a higher accumulation of the released drug in the tumor environment. The half-maximal inhibitory concentration of Dox-loaded TPPLs and PPLs was 1.62-fold and 1.17-fold lower than that of free Dox due to sustained drug release, respectively. The reactive oxygen species level was significantly increased when HCT116 cells were treated with Dox-loaded TPPLs. In conclusion, TPPLs may be promising carriers for targeted drug delivery to tumor mitochondria. Full article
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18 pages, 4243 KiB  
Article
The Continuous and Reversible Transformation of the Polymorphs of an MGAT2 Inhibitor (S-309309) from the Anhydrate to the Hydrate in Response to Relative Humidity
by Tetsuya Miyano, Katsuji Sugita and Hiroshi Ueda
Pharmaceutics 2024, 16(7), 949; https://doi.org/10.3390/pharmaceutics16070949 - 17 Jul 2024
Viewed by 213
Abstract
Polymorphic control is vital for the quality control of pharmaceutical crystals. Here, we investigated the relationship between the hydrate and anhydrate polymorphs of a monoacylglycerol acyltransferase 2 inhibitor (S-309309). Solvent evaporation and slurry conversion revealed two polymorphs, the hydrate and the solvate. The [...] Read more.
Polymorphic control is vital for the quality control of pharmaceutical crystals. Here, we investigated the relationship between the hydrate and anhydrate polymorphs of a monoacylglycerol acyltransferase 2 inhibitor (S-309309). Solvent evaporation and slurry conversion revealed two polymorphs, the hydrate and the solvate. The solvate was transformed into the hydrate by heating. X-ray powder diffraction demonstrated that the hydrate was transformed into an anhydrate via an intermediate state when heated. These crystal forms were confirmed under controlled humidity conditions; the presence of the anhydrate, the intermediate hydrate, or the hydrate depended on the relative humidity at 25 °C. The stoichiometry of S-309309 in water in the hydrate form was 4:1. The hydrates and anhydrates exhibited similar crystal structures and stability. The water of hydration in the intermediate hydrate was 0.1–0.15 mol according to the dynamic vapor sorption profile. The stability and dissolution profile of the anhydrate and hydrate showed no significant change due to similar crystal lattices and quick rehydration of the anhydrate. A mechanism for the reversible crystal transformation between the anhydrate and pseudo-polymorphs of the hydrate was discovered. We concluded that S-309309 causes a pseudo-polymorphic transformation; however, this is not a critical issue for pharmaceutical use. Full article
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21 pages, 1156 KiB  
Review
Low-Density Lipoprotein Receptor-Related Protein 1 as a Potential Therapeutic Target in Alzheimer’s Disease
by Sabrina Petralla, Maria Panayotova, Elisa Franchina, Gert Fricker and Elena Puris
Pharmaceutics 2024, 16(7), 948; https://doi.org/10.3390/pharmaceutics16070948 - 17 Jul 2024
Viewed by 315
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between the production and Aβ clearance in the brain and across the blood–brain barrier (BBB). In this respect, low-density lipoprotein receptor-related protein 1 (LRP1) plays a significant role by mediating both brain Aβ production and clearance. Due to its important role in AD pathogenesis, LRP1 is considered an attractive drug target for AD therapies. In the present review, we summarize the current knowledge about the role of LRP1 in AD pathogenesis as well as recent findings on changes in LRP1 expression and function in AD. Finally, we discuss the advances in utilizing LRP1 as a drug target for AD treatments as well as future perspectives on LRP1 research. Full article
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30 pages, 6481 KiB  
Article
Enhanced Antibacterial Activity of Clindamycin Using Molecularly Imprinted Polymer Nanoparticles Loaded with Polyurethane Nanofibrous Scaffolds for the Treatment of Acne Vulgaris
by Sammar Fathy Elhabal, Rehab Abdelmonem, Rasha Mohamed El Nashar, Mohamed Fathi Mohamed Elrefai, Ahmed Mohsen Elsaid Hamdan, Nesreen A. Safwat, Mai S. Shoela, Fatma E. Hassan, Amira Rizk, Soad L. Kabil, Nagla Ahmed El-Nabarawy, Amal Anwar Taha and Mohamed El-Nabarawi
Pharmaceutics 2024, 16(7), 947; https://doi.org/10.3390/pharmaceutics16070947 - 17 Jul 2024
Viewed by 322
Abstract
Acne vulgaris, a prevalent skin condition, arises from an imbalance in skin flora, fostering bacterial overgrowth. Addressing this issue, clindamycin molecularly imprinted polymeric nanoparticles (Clin-MIP) loaded onto polyurethane nanofiber scaffolds were developed for acne treatment. Clin-MIP was synthesized via precipitation polymerization using methacrylic [...] Read more.
Acne vulgaris, a prevalent skin condition, arises from an imbalance in skin flora, fostering bacterial overgrowth. Addressing this issue, clindamycin molecularly imprinted polymeric nanoparticles (Clin-MIP) loaded onto polyurethane nanofiber scaffolds were developed for acne treatment. Clin-MIP was synthesized via precipitation polymerization using methacrylic acid (MAA), ethylene glycol dimethacrylate (EGDMA), and azoisobutyronitrile (AIBN) as functional monomers, crosslinkers, and free-radical initiators, respectively. MIP characterization utilized Fourier-transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) before being incorporated into polyurethane nanofibers through electrospinning. Further analysis involved FTIR, scanning electron microscopy (SEM), in vitro release studies, and an ex vivo study. Clin-MIP showed strong antibacterial activity against S. aureus, with inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 0.39 and 6.25 μg/mL, respectively. It significantly dropped the bacterial count from 1 × 108 to 39 × 101 CFU/mL in vivo and has bactericidal activity within 180 min of incubation in vitro. The pharmacodynamic and histopathology studies revealed a significant decrease in infected animal skin inflammation, epidermal hypertrophy, and congestion upon treatment with Clin-MIP polyurethane nanofiber and reduced pro-inflammatory cytokines (NLRP3, TNF-α, IL-1β, and IL-6) conducive to acne healing. Consequently, the recently created Clin-MIP polyurethane nanofibrous scaffold. This innovative approach offers insight into creating materials with several uses for treating infectious wounds caused by acne. Full article
(This article belongs to the Special Issue Advanced Nanomaterials for Drug Delivery)
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13 pages, 1513 KiB  
Article
Development of Norelgestromin Dissolving Bilayer Microarray Patches for Sustained Release of Hormonal Contraceptive
by Lalitkumar K. Vora, Ismaiel A. Tekko, Fabiana Volpe Zanutto, Akmal Sabri, Robert K. M. Choy, Jessica Mistilis, Priscilla Kwarteng, Maggie Kilbourne-Brook, Courtney Jarrahian, Helen O. McCarthy and Ryan F. Donnelly
Pharmaceutics 2024, 16(7), 946; https://doi.org/10.3390/pharmaceutics16070946 - 17 Jul 2024
Viewed by 215
Abstract
Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards [...] Read more.
Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards developing a future potential drug delivery system for sustained hormonal contraception. The fabricated MAPs were designed with the appropriate needle lengths to penetrate the stratum corneum, while remaining minimally stimulating to dermal nociceptors. Ex vivo assessments showed that the MAPs delivered an average of 176 ± 60.9 μg of NGMN per MAP into excised neonatal porcine skin, representing 15.3 ± 5.3% of the loaded drug. In vivo pharmacokinetic analysis in Sprague Dawley rats demonstrated a Tmax of 4 h and a Cmax of 67.4 ± 20.1 ng/mL for the MAP-treated group, compared to a Tmax of 1 h and a Cmax of 700 ± 138 ng/mL for the intramuscular (IM) injection group, with a relative bioavailability of approximately 10% for the MAPs. The MAP-treated rats maintained plasma levels sufficient for therapeutic effects for up to 7 days after a single application. These results indicate the potential of NGMN-loaded dissolving bilayer MAPs, with further development focused on extending the release duration and improving bioavailability for prolonged contraceptive effects. Full article
(This article belongs to the Special Issue Microarray Patches for Transdermal Drug Delivery)
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15 pages, 4965 KiB  
Article
The Increase in the Plasticity of Microcrystalline Cellulose Spheres’ When Loaded with a Plasticizer
by Artūrs Paulausks, Tetiana Kolisnyk and Valentyn Mohylyuk
Pharmaceutics 2024, 16(7), 945; https://doi.org/10.3390/pharmaceutics16070945 - 16 Jul 2024
Viewed by 324
Abstract
Compaction pressure can induce an undesirable solid-state polymorphic transition in drugs, fragmentation, loss of coated pellet integrity, and the decreased viability and vitality of microorganisms. Thus, the excipients with increased plasticity can be considered as an option to decrease the undesirable effects of [...] Read more.
Compaction pressure can induce an undesirable solid-state polymorphic transition in drugs, fragmentation, loss of coated pellet integrity, and the decreased viability and vitality of microorganisms. Thus, the excipients with increased plasticity can be considered as an option to decrease the undesirable effects of compaction pressure. This study aims to increase the plasticity (to reduce the mean yield pressure; Py) of dried microcrystalline cellulose (MCC) by loading it with a specially selected plasticizer. Diethyl citrate (DEC), water, and glycerol were the considered plasticizers. Computation of solubility parameters was used to predict the miscibility of MCC with plasticizers (possible plasticization effect). Plasticizer-loaded MCC spheres with 5.0 wt.% of water, 5.2 wt.% of DEC, and 4.2 wt.% glycerol were obtained via the solvent method, followed by solvent evaporation. Plasticizer-loaded formulations were characterised by TGA, DSC, pXRD, FTIR, pressure-displacement profiles, and in-die Heckel plots. Py was derived from the in-die Heckel analysis and was used as a plasticity parameter. In comparison with non-plasticized MCC (Py = 136.5 MPa), the plasticity of plasticizer-loaded formulations increased (and Py decreased) from DEC (124.7 MPa) to water (106.6 MPa) and glycerol (99.9 MPa), and that was in full accordance with the predicted miscibility likeliness order based on solubility parameters. Therefore, water and glycerol were able to decrease the Py of non-plasticized MCC spheres by 16.3 and 30.0%, respectively. This feasibility study showed the possibility of modifying the plasticity of MCC by loading it with a specially selected plasticizer. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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52 pages, 12014 KiB  
Review
Advancements in Insulin Pumps: A Comprehensive Exploration of Insulin Pump Systems, Technologies, and Future Directions
by Mohammad Towhidul Islam Rimon, Md Wasif Hasan, Mohammad Fuad Hassan and Sevki Cesmeci
Pharmaceutics 2024, 16(7), 944; https://doi.org/10.3390/pharmaceutics16070944 - 15 Jul 2024
Viewed by 363
Abstract
Insulin pumps have transformed the way diabetes is managed by providing a more accurate and individualized method of delivering insulin, in contrast to conventional injection routines. This research explores the progression of insulin pumps, following their advancement from initial ideas to advanced contemporary [...] Read more.
Insulin pumps have transformed the way diabetes is managed by providing a more accurate and individualized method of delivering insulin, in contrast to conventional injection routines. This research explores the progression of insulin pumps, following their advancement from initial ideas to advanced contemporary systems. The report proceeds to categorize insulin pumps according to their delivery systems, specifically differentiating between conventional, patch, and implantable pumps. Every category is thoroughly examined, emphasizing its unique characteristics and capabilities. A comparative examination of commercially available pumps is provided to enhance informed decision making. This section provides a thorough analysis of important specifications among various brands and models. Considered factors include basal rate and bolus dosage capabilities, reservoir size, user interface, and compatibility with other diabetes care tools, such as continuous glucose monitoring (CGM) devices and so on. This review seeks to empower healthcare professionals and patients with the essential information to improve diabetes treatment via individualized pump therapy options. It provides a complete assessment of the development, categorization, and full specification comparisons of insulin pumps. Full article
(This article belongs to the Special Issue Micro/Nano Drug Delivery Systems)
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13 pages, 2032 KiB  
Communication
Antitumor Activity of a Pyrrolobenzodiazepine Antibody–Drug Conjugate Targeting LGR5 in Preclinical Models of Neuroblastoma
by Jianghua Tu, Yukimatsu Toh, Adela M. Aldana, Jake J. Wen, Ling Wu, Joan Jacob, Li Li, Sheng Pan, Kendra S. Carmon and Qingyun J. Liu
Pharmaceutics 2024, 16(7), 943; https://doi.org/10.3390/pharmaceutics16070943 - 15 Jul 2024
Viewed by 306
Abstract
Neuroblastoma (NB) is a cancer of the peripheral nervous system found in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all cancer-related deaths in children. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is [...] Read more.
Neuroblastoma (NB) is a cancer of the peripheral nervous system found in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all cancer-related deaths in children. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a membrane receptor that is associated with the primary tumor formation and metastasis of cancers in the gastrointestinal system. Remarkably, high levels of LGR5 are found in NB tumor cells, and high LGR5 expression is strongly correlated with poor survival. Antibody–drug conjugates (ADCs) are monoclonal antibodies that are covalently linked to cell-killing cytotoxins to deliver the payloads into cancer cells. We generated an ADC with an anti-LGR5 antibody and pyrrolobenzodiazepine (PBD) dimer-based payload SG3199 using a chemoenzymatic conjugation method. The resulting anti-LGR5 ADC was able to inhibit the growth of NB cells expressing LGR5 with high potency and specificity. Importantly, the ADC was able to completely inhibit the growth of NB xenograft tumors in vivo at a clinically relevant dose for the PBD class of ADCs. The findings support the potential of targeting LGR5 using the PBD class of payload for the treatment of high-risk NBs. Full article
(This article belongs to the Special Issue Next-Generation Antibody-Drug Conjugates (ADCs))
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22 pages, 7760 KiB  
Review
Chemodynamic Therapy of Glioblastoma Multiforme and Perspectives
by Zia Ullah, Yasir Abbas, Jingsi Gu, Sai Ko Soe, Shubham Roy, Tingting Peng and Bing Guo
Pharmaceutics 2024, 16(7), 942; https://doi.org/10.3390/pharmaceutics16070942 - 15 Jul 2024
Viewed by 375
Abstract
Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood–brain barrier (BBB) to [...] Read more.
Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood–brain barrier (BBB) to reach the GBM is another endless marathon. In this review, the physiology of the BBB has been elaborated to understand the mechanism of crossing these potential barriers to treat GBM. Moreover, the designing of Fenton-based nanomaterials has been discussed for the production of reactive oxygen species in the tumor area to eradicate the cancer cells. For effective tumor targeting, biological nanomaterials that can cross the BBB via neurovascular transport channels have also been explored. To overcome the neurotoxicity caused by inorganic nanomaterials, the use of smart nanoagents having both enhanced biocompatibility and effective tumor targeting ability to enhance the efficiency of CDT are systematically summarized. Finally, the advancements in intelligent Fenton-based nanosystems for a multimodal therapeutic approach in addition to CDT are demonstrated. Hopefully, this systematic review will provide a better understanding of Fenton-based CDT and insight into GBM treatment. Full article
(This article belongs to the Special Issue Recent Advances in NIR-II Fluorescence Imaging-Based Cancer Treatment)
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20 pages, 16526 KiB  
Article
The Potential of Photodynamic Therapy Using Solid Lipid Nanoparticles with Aluminum Phthalocyanine Chloride as a Nanocarrier for Modulating Immunogenic Cell Death in Murine Melanoma In Vitro
by Marina M. Simões, Karen L. R. Paiva, Isadora Florêncio de Souza, Victor Carlos Mello, Ingrid Gracielle Martins da Silva, Paulo Eduardo Narcizo Souza, Luis Alexandre Muehlmann and Sônia Nair Báo
Pharmaceutics 2024, 16(7), 941; https://doi.org/10.3390/pharmaceutics16070941 - 14 Jul 2024
Viewed by 485
Abstract
Photodynamic therapy (PDT) uses a photosensitizer to generate reactive oxygen species (ROS) that kill target cells. In cancer treatments, PDT can potentially induce immunogenic cell death (ICD), which is characterized by a well-controlled exposure of damage-associated molecular patterns (DAMPs) that activate dendritic cells [...] Read more.
Photodynamic therapy (PDT) uses a photosensitizer to generate reactive oxygen species (ROS) that kill target cells. In cancer treatments, PDT can potentially induce immunogenic cell death (ICD), which is characterized by a well-controlled exposure of damage-associated molecular patterns (DAMPs) that activate dendritic cells (DCs) and consequently modulate the immune response in the tumor microenvironment. However, PDT still has limitations, such as the activity of photosensitizers in aqueous media and poor bioavailability. Therefore, a new photosensitizer system, SLN-AlPc, has been developed to improve the therapeutic efficacy of PDT. In vitro experiments showed that the light-excited nanocarrier increased ROS production in murine melanoma B16-F10 cells and modulated the profile of DCs. PDT induced cell death accompanied by the exposure of DAMPs and the formation of autophagosomes. In addition, the DCs exposed to PDT-treated B16-F10 cells exhibited morphological changes, increased expression of MHCII, CD86, CD80, and production of IL-12 and IFN-γ, suggesting immune activation towards an antitumor profile. These results indicate that the SLNs-AlPc protocol has the potential to improve PDT efficacy by inducing ICD and activating DCs. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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15 pages, 23571 KiB  
Article
α-Lactalbumin mRNA-LNP Evokes an Anti-Tumor Effect Combined with Surgery in Triple-Negative Breast Cancer
by Yun-Ru He, Heng Xia, Peng Yun, Yuandong Xu, Winson M. J. Ma, Ze-Xiu Xiao and Gao-Feng Zha
Pharmaceutics 2024, 16(7), 940; https://doi.org/10.3390/pharmaceutics16070940 - 14 Jul 2024
Viewed by 520
Abstract
Triple-negative breast cancer (TNBC) has been considered a huge clinical unmet need due to its aggressive progression and highly frequent metastasis. mRNA therapeutics supply a potential and versatile immunotherapy of oncology treatment. Here, we developed α-lactalbumin mRNA-lipid nanoparticles (α-LNP) as a potential therapeutical [...] Read more.
Triple-negative breast cancer (TNBC) has been considered a huge clinical unmet need due to its aggressive progression and highly frequent metastasis. mRNA therapeutics supply a potential and versatile immunotherapy of oncology treatment. Here, we developed α-lactalbumin mRNA-lipid nanoparticles (α-LNP) as a potential therapeutical strategy for TNBC. The α-LNP induced the specific IgG antibodies and activated IFN γ-secreting-T cells in vivo. Additionally, the safety of α-LNP also had been demonstrated in vivo. When vaccinated prior to tumor implantation, α-LNP showed a preventive effect against 4T1 tumor growth and extended the survival of the tumor model by activating the memory immune responses. Furthermore, α-LNP administration in combination with surgical removal of neoplasm effectively inhibited the progression and metastasis in the TNBC model. Taken together, our results indicate that the α-LNP vaccine is a promising novel treatment for both therapeutics and prophylactics in TNBC. Full article
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20 pages, 2486 KiB  
Review
Natural Killer-Based Therapy: A Prospective Thought for Cancer Treatment Related to Diversified Drug Delivery Pathways
by Jing Zang, Yijun Mei, Shiguo Zhu, Shaoping Yin, Nianping Feng, Tianyuan Ci and Yaqi Lyu
Pharmaceutics 2024, 16(7), 939; https://doi.org/10.3390/pharmaceutics16070939 - 14 Jul 2024
Viewed by 361
Abstract
Immunotherapy has been a research hotspot due to its low side effects, long-lasting efficacy, and wide anti-tumor spectrum. Recently, NK cell-based immunotherapy has gained broad attention for its unique immunological character of tumor identification and eradication and low risk of graft-versus-host disease and [...] Read more.
Immunotherapy has been a research hotspot due to its low side effects, long-lasting efficacy, and wide anti-tumor spectrum. Recently, NK cell-based immunotherapy has gained broad attention for its unique immunological character of tumor identification and eradication and low risk of graft-versus-host disease and cytokine storm. With the cooperation of a drug delivery system (DDS), NK cells activate tumoricidal activity by adjusting the balance of the activating and inhibitory signals on their surface after drug-loaded DDS administration. Moreover, NK cells or NK-derived exosomes can also be applied as drug carriers for distinct modification to promote NK activation and exert anti-tumor effects. In this review, we first introduce the source and classification of NK cells and describe the common activating and inhibitory receptors on their surface. Then, we summarize the strategies for activating NK cells in vivo through various DDSs. Finally, the application prospects of NK cells in tumor immunotherapy are also discussed. Full article
(This article belongs to the Special Issue Advanced Nanopharmaceutics for Anticancer Therapy)
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20 pages, 11463 KiB  
Article
Targeting Liver Xor by GalNAc-siRNA Is an Effective Strategy for Hyperuricemia Therapy
by Huiyan Sun, Xinxia Wang, Yongqiang Li, Yingzhi Shen, Lin Zhang, Yingjie Xu, Junling Liu and Xuemei Fan
Pharmaceutics 2024, 16(7), 938; https://doi.org/10.3390/pharmaceutics16070938 - 14 Jul 2024
Viewed by 366
Abstract
Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme [...] Read more.
Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy. Full article
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26 pages, 20027 KiB  
Article
Design and Optimization of Sesamol Nanosuspensions to Potentiate the Anti-Tumor Activity of Epirubicin against Ehrlich Solid Carcinoma-Bearing Mice
by Kholoud A. Elzanaty, Gamal A. Omran, Ehab Kotb Elmahallawy, Ashraf Albrakati, Ayman A. Saleh, Naief Dahran, Alaa S. Alhegaili, Ahmad Salahuddin, Heba Abd-El-Azim, Ahmed Noreldin and Tarek M. Okda
Pharmaceutics 2024, 16(7), 937; https://doi.org/10.3390/pharmaceutics16070937 - 13 Jul 2024
Viewed by 446
Abstract
There is a growing interest in discovering natural sources of anti-cancer drugs. Sesamol (SES) is a phenolic compound with antitumor effects. The present study aimed to investigate the anticancer properties of SES and its nano-suspensions (SES-NS) combined with Epirubicin (EPI) in breast cancer [...] Read more.
There is a growing interest in discovering natural sources of anti-cancer drugs. Sesamol (SES) is a phenolic compound with antitumor effects. The present study aimed to investigate the anticancer properties of SES and its nano-suspensions (SES-NS) combined with Epirubicin (EPI) in breast cancer (BC) using mice bearing a solid Ehrlich tumor. The study involved 35 female albino mice and investigated the effects of SES and EPI on tumor growth, proliferation, apoptosis, autophagy, angiogenesis, and oxidative stress. Methods including ELISA, qRT-PCR, and immunohistochemistry were utilized. The findings revealed reductions in tumor growth and proliferation using SES either alone or combined and evidenced by decreased AKT (AKT Serine/Threonine kinase1) levels, angiogenesis indicated by lower levels of VEGFR (vascular endothelial growth factor), and apoptosis demonstrated by elevated caspase3 and BAX levels. Furthermore, autophagy increased and was indicated by increased levels of beclin1 and lc3, along with decreased oxidative stress as evidenced by elevated TAC (total antioxidant capacity) and reduced MDA (malondialdehyde) levels. Interestingly, SES-NS demonstrated more significant effects at lower doses. In summary, this study underscores the potential of SES as a promising agent for BC treatment. Moreover, SES-NS potentiated the beneficial effects of EPI while mitigating its adverse effects. Full article
(This article belongs to the Special Issue Natural Nanoparticle for Cancer Diagnosis and Treatment, 2nd Edition)
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16 pages, 2668 KiB  
Article
ROS–Responsive Ferrocenyl Amphiphilic PAMAM Dendrimers for On–Demand Delivery of siRNA Therapeutics to Cancer Cells
by Peng Chen, Zhihui Wang, Xinmo Wang, Junni Gong, Ju Sheng, Yufei Pan, Dandan Zhu and Xiaoxuan Liu
Pharmaceutics 2024, 16(7), 936; https://doi.org/10.3390/pharmaceutics16070936 - 13 Jul 2024
Viewed by 338
Abstract
Small interfering RNA (siRNA) therapeutics, characterized by high specificity, potency, and durability, hold great promise in the treatment of cancer and other diseases. However, the clinic implementation of siRNA therapeutics critically depends on the safe and on–demand delivery of siRNA to the target [...] Read more.
Small interfering RNA (siRNA) therapeutics, characterized by high specificity, potency, and durability, hold great promise in the treatment of cancer and other diseases. However, the clinic implementation of siRNA therapeutics critically depends on the safe and on–demand delivery of siRNA to the target cells. Here, we reported a family of ferrocenyl amphiphilic dendrimers (Fc-AmDs) for on–demand delivery of siRNA in response to the high ROS content in cancer cells. These dendrimers bear ROS–sensitive ferrocene moieties in the hydrophobic components and positively chargeable poly(amidoamine) dendrons as the hydrophilic entities, possessing favorable safety profiles and ROS responsive properties. One of these ferrocenyl amphiphilic dendrimers, Fc-C8-AmD 8A, outperforms in siRNA delivery, benefiting from its optimal balance of hydrophobicity and hydrophilicity. Its ROS feature facilitates specific and efficient disassembly of its complex with siRNA in ROS–rich cancer cells for effective siRNA delivery and gene silencing. Moreover, Fc-C8-AmD 8A also integrates the features and beneficial properties of both lipid and dendrimer vectors. Therefore, it represents a novel on–demand delivery system for cancer cell–specific siRNA delivery. This work opens new perspectives for designing self–assembly nanosystems for on–demand drug delivery. Full article
(This article belongs to the Special Issue Applications of Dendrimers in Biomedicine, 2nd Edition)
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17 pages, 4917 KiB  
Article
Engineered Exosomes Biopotentiated Hydrogel Promote Hair Follicle Growth via Reprogramming the Perifollicular Microenvironment
by Hairui Zhang, Jiali Yao, Qianyang Jiang, Yurou Shi, Weihong Ge and Xiaoling Xu
Pharmaceutics 2024, 16(7), 935; https://doi.org/10.3390/pharmaceutics16070935 - 13 Jul 2024
Viewed by 291
Abstract
Androgenetic alopecia (AGA) is a highly prevalent condition in contemporary society. The conventional treatment of minoxidil tincture is hindered by issues such as skin irritation caused by ethanol, non-specific accumulation in hair follicles, and short retention due to its liquid form. Herein, we [...] Read more.
Androgenetic alopecia (AGA) is a highly prevalent condition in contemporary society. The conventional treatment of minoxidil tincture is hindered by issues such as skin irritation caused by ethanol, non-specific accumulation in hair follicles, and short retention due to its liquid form. Herein, we have developed a novel minoxidil-incorporated engineered exosomes biopotentiated hydrogel (Gel@MNs) that has the capability to modulate the perifollicular microenvironment for the treatment of AGA. Leveraging the exceptional skin penetration abilities of flexible liposomes and the targeting properties of exosomes, the encapsulated minoxidil can be effectively delivered to the hair follicles. In comparison to free minoxidil, Gel@MNs demonstrated accelerated hair regeneration in an AGA mouse model without causing significant skin irritation. This was evidenced by an increase in both the number and size of hair follicles within the dermal layer, enhanced capillary formation surrounding the follicles, and the regulation of the transition of hair follicle cells from the telogen phase to the anagen growth phase. Therefore, this safe and microenvironment-modifying hybrid exosome-embedded hydrogel shows promising potential for clinical treatment of AGA. Full article
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21 pages, 2207 KiB  
Article
Pharmacokinetics and Enterohepatic Circulation of 2-(Quinoline-8-carboxamido)benzoic Acid (2-QBA) in Mice
by Ji-Hyeon Jeon, So-Yeon Jeon, Yeon-Ju Baek, Chan-E Park, Min-Koo Choi, Young Taek Han and Im-Sook Song
Pharmaceutics 2024, 16(7), 934; https://doi.org/10.3390/pharmaceutics16070934 - 12 Jul 2024
Viewed by 314
Abstract
The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson’s disease. We developed an analytical method for 2-QBA using a liquid chromatography–tandem mass spectrometry [...] Read more.
The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson’s disease. We developed an analytical method for 2-QBA using a liquid chromatography–tandem mass spectrometry (LC-MS/MS) in mouse plasma, in which a protein precipitation method for the sample preparation of 2-QBA in mouse plasma was used due to its simplicity and good extraction recovery rates (80.49–97.56%). The linearity of the calibration standard sample, inter- and intraday precision and accuracy, and stability of three quality control samples were suitable based on the assessment criteria and the lower limit of quantification (LLOQ) of the 2-QBA was 1 ng/mL. A pharmacokinetic study of 2-QBA was performed in mice divided into oral (2.0, 5.0, and 15 mg/kg) and intravenous (0.5 and 1.0 mg/kg) administration groups. The absolute oral bioavailability (BA) range of 2-QBA was calculated as 68.3–83.7%. Secondary peaks were observed at approximately 4–8 h after the oral administration of 2-QBA at all doses. The elimination half-life of the orally administered 2-QBA was significantly longer than that of the intravenous 2-QBA. In addition, glucuronide metabolites of 2-QBA were identified. They were transformed into 2-QBA using the β-glucuronidase treatment. Furthermore, the 2-QBA was readily absorbed from the jejunum to lower ileum. Taken together, the secondary peaks could be explained by the enterohepatic circulation of 2-QBA. In conclusion, the reabsorption of orally administered 2-QBA could contribute to the high oral BA of 2-QBA and could be beneficial for the efficacy of 2-QBA. Moreover, the simple and validated analytical method for 2-QBA using LC-MS/MS was applied to the pharmacokinetic study and BA assessments of 2-QBA in mice and would be helpful for subsequent pharmacokinetic studies, as well as for evaluations of the toxicokinetics and pharmacokinetic–pharmacodynamic correlation of 2-QBA to assess its potential as a drug. Full article
(This article belongs to the Special Issue Bioanalysis and Metabolomics, 2nd Edition)
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16 pages, 1695 KiB  
Article
Evaluating and Managing the Microbial Contamination of Eye Drops: A Two-Phase Hospital-Based Study
by Léa Roquefeuil, Katia Iskandar, Christine Roques, Loïc Marchin, Mylène Guittard, Hélène Poupet, Marie-Laure Brandely-Piat and Marion Jobard
Pharmaceutics 2024, 16(7), 933; https://doi.org/10.3390/pharmaceutics16070933 - 12 Jul 2024
Viewed by 306
Abstract
The microbial contamination of eye drop tips and caps varies between 7.7% and 100%. In seeking patient protection and continuous improvement, the Pharmacy Department in the Sterile Ophthalmological and Oncological Preparations Unit at Cochin Hospital AP-HP, Paris, France, conducted a two-phase study to [...] Read more.
The microbial contamination of eye drop tips and caps varies between 7.7% and 100%. In seeking patient protection and continuous improvement, the Pharmacy Department in the Sterile Ophthalmological and Oncological Preparations Unit at Cochin Hospital AP-HP, Paris, France, conducted a two-phase study to compare the antimicrobial efficiency and practical use of standard packaging and a marketed eye drop container incorporating a self-decontaminating antimicrobial green technology by Pylote SAS at the tip and cap sites. The first phase was conducted in situ to identify the microbial contaminants of eye drops used in the hospital and community settings. A total of 110 eye drops were included for testing. Staphylococcus species were the most prevalent bacteria. Candida parapsilosis was detected in only one residual content sample and, at the same time, on the cap and tip. The second phase was performed in vitro, according to JIS Z2801. Reductions above one log in Staphylococcus aureus and Pseudomonas aeruginosa counts were noted in Pylote SAS eye drop packaging after 24 h of contact. The practical tests showed satisfactory results. Pylote SAS antimicrobial mineral oxide technology exhibited promising effects that combined effectiveness, safety, and sustainability to protect the patient by preventing infections due to the contamination of eye drop containers. Full article
(This article belongs to the Section Clinical Pharmaceutics)
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20 pages, 4385 KiB  
Review
Recent Advances in Photodynamic Therapy: Metal-Based Nanoparticles as Tools to Improve Cancer Therapy
by Stefania Mariano, Elisabetta Carata, Lucio Calcagnile and Elisa Panzarini
Pharmaceutics 2024, 16(7), 932; https://doi.org/10.3390/pharmaceutics16070932 - 12 Jul 2024
Viewed by 360
Abstract
Cancer remains a significant global health challenge, with traditional therapies like surgery, chemotherapy, and radiation often accompanied by systemic toxicity and damage to healthy tissues. Despite progress in treatment, these approaches have limitations such as non-specific targeting, systemic toxicity, and resistance development in [...] Read more.
Cancer remains a significant global health challenge, with traditional therapies like surgery, chemotherapy, and radiation often accompanied by systemic toxicity and damage to healthy tissues. Despite progress in treatment, these approaches have limitations such as non-specific targeting, systemic toxicity, and resistance development in cancer cells. In recent years, nanotechnology has emerged as a revolutionary frontier in cancer therapy, offering potential solutions to these challenges. Nanoparticles, due to their unique physical and chemical properties, can carry therapeutic payloads, navigate biological barriers, and selectively target cancer cells. Metal-based nanoparticles, in particular, offer unique properties suitable for various therapeutic applications. Recent advancements have focused on the integration of metal-based nanoparticles to enhance the efficacy and precision of photodynamic therapy. Integrating nanotechnology into cancer therapy represents a paradigm shift, enabling the development of strategies with enhanced specificity and reduced off-target effects. This review aims to provide a comprehensive understanding of the pivotal role of metal-based nanoparticles in photodynamic therapy. We explore the mechanisms, biocompatibility, and applications of metal-based nanoparticles in photodynamic therapy, highlighting the challenges and the limitations in their use, as well as the combining of metal-based nanoparticles/photodynamic therapy with other strategies as a synergistic therapeutic approach for cancer treatment. Full article
(This article belongs to the Special Issue Metal-Based Nanoparticles for Pharmaceutical Applications)
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19 pages, 8763 KiB  
Article
pH-Triggered Hydrogel Nanoparticles for Efficient Anticancer Drug Delivery and Bioimaging Applications
by Keristina Wagdi K. Amin, Ágota Deák, Miklós Csanády, Jr., Nikoletta Szemerédi, Diána Szabó, Árpád Turcsányi, Ditta Ungor, Gabriella Spengler, László Rovó and László Janovák
Pharmaceutics 2024, 16(7), 931; https://doi.org/10.3390/pharmaceutics16070931 - 11 Jul 2024
Viewed by 418
Abstract
In this work, we developed multifunctional hydrogel nanoparticles (NPs) that can encapsulate anticancer drugs and imaging contrast agents as well. Mitomycin C (MMC) and rhodamine B (RB) were selected as models for anticancer drugs and imaging contrasting agents, respectively. Both MMC and RB [...] Read more.
In this work, we developed multifunctional hydrogel nanoparticles (NPs) that can encapsulate anticancer drugs and imaging contrast agents as well. Mitomycin C (MMC) and rhodamine B (RB) were selected as models for anticancer drugs and imaging contrasting agents, respectively. Both MMC and RB were linked to the succinated polyvinyl alcohol polymer (PVA-SA). The selected labeled hydrogel NPs ((0.5% RB)-PVA-SA NPs and (1.5% RB)-PVA-SA NPs) improved the RB quantum yield from 29.8% to a minimum of 42.7%. Moreover, they showed higher emission stability compared to free RB when they were repeatedly excited at 554 nm for 2 h. Furthermore, the dye polymeric interactions significantly increased the RB fluorescence lifetime by approximately twofold. All these optical properties pave the way for our labeled hydrogel NPs to be used in imaging-guided therapy. For the labeled MMC-loaded NPs, the MMC-binding efficiency was found to be exceedingly high in all synthesized samples: a minimum of 92% was achieved. In addition, the obtained pH-dependent drug release profiles as well as the cytotoxicity evaluation demonstrated the high potential of releasing MMC under acidic cancerous conditions. Moreover, the in vitro cellular uptake experiment confirmed the accumulation of MMC NPs throughout the cytoplasm. Full article
(This article belongs to the Special Issue Recent Advances in Hydrogels for Biomedical Applications)
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