Pharmaceutics

13 pages, 1113 KiB

Open AccessArticle

The Impact of Chronic Oral Beta-Blocker Intake on Intravenous Bolus Landiolol Response in Hospitalized Intensive Care Patients with Sudden-Onset Supraventricular Tachycardia—A Post Hoc Analysis of a Cross-Sectional Trial

by Felix Eibensteiner, Emmilie Mosor, Daniel Tihanyi, Sonja Anders, Andrea Kornfehl, Marco Neymayer, Julia Oppenauer, Christoph Veigl, Valentin Al Jalali, Hans Domanovits, Patrick Sulzgruber and Sebastian Schnaubelt

Pharmaceutics 2024, 16(6), 839; https://doi.org/10.3390/pharmaceutics16060839 - 20 Jun 2024

Viewed by 434

Abstract

Background: Landiolol, a highly cardioselective agent with a short half-life (2.4–4 min), is commonly used as a perfusor or bolus application to treat tachycardic arrhythmia. Some small studies suggest that prior oral β-blocker use results in a less effective response to intravenous β-blockers. [...] Read more.

Background: Landiolol, a highly cardioselective agent with a short half-life (2.4–4 min), is commonly used as a perfusor or bolus application to treat tachycardic arrhythmia. Some small studies suggest that prior oral β-blocker use results in a less effective response to intravenous β-blockers. Methods: This study investigated whether prior chronic oral β-blocker (Lβ) or no prior chronic oral β-blocker (L–) intake influences the response to intravenous push-dose Landiolol in intensive care patients with acute tachycardic arrhythmia. Results: The effects in 30 patients (67 [55–72] years) were analyzed, 10 (33.3%) with and 20 (66.7%) without prior oral β-blocker therapy. Arrhythmias were diagnosed as tachycardic atrial fibrillation in 14 patients and regular, non-fluid-dependent, supraventricular tachycardia in 16 cases. Successful heart rate control (Lβ 4 vs. L– 7, p = 1.00) and rhythm control (Lβ 3 vs. L– 6, p = 1.00) did not significantly differ between the two groups. Both groups showed a significant decrease in heart rate when comparing before and after the bolus administration, without significant differences between the two groups (Lβ −26/min vs. L– −33/min, p = 0.528). Oral β-blocker therapy also did not influence the change in mean arterial blood pressure after Landiolol bolus administration (Lβ −5 mmHg vs. L– −4 mmHg, p = 0.761). Conclusions: A prior chronic intake of β-blockers neither affected the effectiveness of push-dose Landiolol in heart rate or rhythm control nor impacted the difference in heart rate or mean arterial blood pressure before and after the Landiolol boli. Full article

(This article belongs to the Special Issue Advances in the Pharmaceutical Treatment of Cardiovascular Disease)

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20 pages, 8708 KiB

Open AccessArticle

In Vitro and In Vivo Antipsoriatic Efficacy of Protected and Unprotected Sugar–Zinc Phthalocyanine Conjugates

by Sebastian Makuch, Piotr Kupczyk, Marta Woźniak, Alicja Makarec, Maja Lipińska, Magdalena Klyta, Joanna Sulecka-Zadka, Wiesław Szeja, Mariachiara Gani, Valentina Rapozzi, Piotr Ziółkowski and Piotr Smoleński

Pharmaceutics 2024, 16(6), 838; https://doi.org/10.3390/pharmaceutics16060838 - 20 Jun 2024

Viewed by 692

Abstract

Psoriasis, a chronic immune-mediated skin disorder affecting over 125 million people globally, is characterized by abnormal keratinocyte proliferation and immune cell infiltration. Photodynamic therapy (PDT) remains underutilized in the treatment of psoriasis despite its potential as a promising and effective therapeutic approach. This [...] Read more.

Psoriasis, a chronic immune-mediated skin disorder affecting over 125 million people globally, is characterized by abnormal keratinocyte proliferation and immune cell infiltration. Photodynamic therapy (PDT) remains underutilized in the treatment of psoriasis despite its potential as a promising and effective therapeutic approach. This study aimed to explore the efficacy of zinc phthalocyanine (ZnPc) and its sugar conjugates as potential antipsoriatic agents. We successfully synthesized protected and unprotected sugar-conjugated zinc phthalocyanines and evaluated their potential against cytokine-stimulated HaCaT keratinocytes, as well as an established IMQ psoriasis-like in vivo model. Tetrasubstituted protected glucose–ZnPc (Glu-4-ZnPc-P) demonstrated superior phototoxicity (IC50 = 2.55 µM) compared to unprotected glucose conjugate (IC50 = 22.7 µM), protected galactose–ZnPc (IC50 = 7.13 µM), and free ZnPc in cytokine-stimulated HaCaT cells (IC50 = 5.84 µM). Cellular uptake analysis revealed that IL-17A, a cytokine that plays a central role in the pathogenesis of psoriasis, enhanced unprotected Glu-4-ZnPc uptake by 56.3%, while GLUT1 inhibitor BAY-876 reduced its accumulation by 23.8%. Intracellular ROS generation following Glu-4-ZnPc-P-PDT was significantly increased after stimulation with IL-17A, correlating with in vitro photocytotoxicity. In vivo PDT using Glu-4-ZnPc-P exhibited significant improvement in Psoriasis Area and Severity Index (PASI), inhibiting splenomegaly and restoring normal skin morphology. This study highlights sugar-conjugated zinc phthalocyanines as potential candidates for targeted PDT in psoriasis, providing a basis for further clinical investigations. Full article

(This article belongs to the Special Issue Photodynamic, Photothermal and Photoimmune Therapy and Other Antimicrobial Nanomedicine-Related Applications)

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16 pages, 3683 KiB

Open AccessArticle

Development of Graphene Oxide-Based Anticancer Drug Combination Functionalized with Folic Acid as Nanocarrier for Targeted Delivery of Methotrexate

by Reyhan Yanikoglu, Canan Yagmur Karakas, Fatih Ciftci, Mert Akın Insel, Zeynep Karavelioglu, Rahmetullah Varol, Abdurrahim Yilmaz, Rabia Cakir, Hüseyin Uvet and Cem Bulent Ustundag

Pharmaceutics 2024, 16(6), 837; https://doi.org/10.3390/pharmaceutics16060837 - 20 Jun 2024

Viewed by 747

Abstract

Graphene has become a prominent material in cancer research in recent years. Graphene and its derivatives also attract attention as carriers in drug delivery systems. In this study, we designed a graphene oxide (GO)-based methotrexate (MTX)-loaded and folic acid (FA)-linked drug delivery system. [...] Read more.

Graphene has become a prominent material in cancer research in recent years. Graphene and its derivatives also attract attention as carriers in drug delivery systems. In this study, we designed a graphene oxide (GO)-based methotrexate (MTX)-loaded and folic acid (FA)-linked drug delivery system. MTX and FA were bound to GO synthesized from graphite. MTX/FA/GO drug delivery system and system components were characterized using Fourier transform infrared spectroscopy (FTIR), differential calorimetric analysis (DSC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), zeta potential analysis, and dimension measurement (DLS) studies. SEM and TEM images confirmed the nanosheet structure of GO synthesized from graphite, and it was shown that MTX/FA binding to GO transformed the two-dimensional GO into a three-dimensional structure. FTIR and DSC graphs confirmed that oxygen atoms were bound to GO with the formation of carboxylic, hydroxyl, epoxide, and carbonyl groups as a result of the oxidation of graphite, and GO was successfully synthesized. Additionally, these analyses showed that MTX and FA bind physicochemically to the structure of GO. The in vitro Franz diffusion test was performed as a release kinetic test. The release kinetics mathematical model and correlation coefficient (R2) of MTX-loaded GO/FA nanomaterials were found to be the Higuchi model and 0.9785, respectively. Stiffness analyses showed that adding FA to this release system facilitated the entry of the drug into the cell by directing the system to target cells. As a result of the stiffness analyses, the stiffness values of the control cell group, free MTX, and MTX/FA/GO applied cells were measured as 2.34 kPa, 1.87 kPa, and 1.56 kPa, respectively. According to these results, it was seen that MTX/FA/GO weakened the cancer cells. Combined use of the MTX/FA/GO drug delivery system had a higher cytotoxic effect than free MTX on the MDA-MB-231 breast cancer cell line. The results showed that the synthesized MTX/FA/GO material has promising potential in cancer cell-specific targeted therapy for MTX as a drug delivery system. Full article

(This article belongs to the Special Issue Metal and Carbon Nanomaterials for Pharmaceutical Applications)

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13 pages, 3237 KiB

Open AccessArticle

Derivatization of Hyaluronan to Target Neuroblastoma and Neuroglioma Expressing CD44

by Giau Van Vo, Kummara Madhusudana Rao, Ildoo Chung, Chang-Sik Ha, Seong Soo A. An and Yang H. Yun

Pharmaceutics 2024, 16(6), 836; https://doi.org/10.3390/pharmaceutics16060836 - 20 Jun 2024

Viewed by 624

Abstract

Therapeutics for actively targeting over-expressed receptors are of great interest because the majority of diseased tissues originate from normal cells and do not possess a unique receptor from which they can be differentiated. One such receptor is CD44, which has been shown to [...] Read more.

Therapeutics for actively targeting over-expressed receptors are of great interest because the majority of diseased tissues originate from normal cells and do not possess a unique receptor from which they can be differentiated. One such receptor is CD44, which has been shown to be highly overexpressed in many breast cancers and other types of cancer cells. While CD44 has been documented to express low levels in normal adult neurons, astrocytes, and microglia, this receptor may be overexpressed by neuroblastoma and neuroglioma. If differential expression exists between normal and cancerous cells, hyaluronan (HA) could be a useful carrier that targets carcinomas. Thus, HA was conjugated with resveratrol (HA-R), and its efficacy was tested on cortical–neuroblastoma hybrid, neuroblastoma, and neuroglioma cells. Confocal and flow cytometry showed these cells express CD44 and are able to bind and uptake HA-R. The toxicity of HA-R correlated well with CD44 expression in this study. Therefore, conjugating resveratrol and other chemotherapeutics to HA could minimize the side effects for normal cells within the brain and nervous system and could be a viable strategy for developing targeted therapies. Full article

(This article belongs to the Special Issue Carbohydrate-Based Carriers for Drug Delivery)

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22 pages, 7523 KiB

Open AccessArticle

Single-Cell Transcriptomic and Targeted Genomic Profiling Adjusted for Inflammation and Therapy Bias Reveal CRTAM and PLCB1 as Novel Hub Genes for Anti-Tumor Necrosis Factor Alpha Therapy Response in Crohn’s Disease

by Mario Gorenjak, Boris Gole, Larisa Goričan, Gregor Jezernik, Uršula Prosenc Zmrzljak, Cvetka Pernat, Pavel Skok and Uroš Potočnik

Pharmaceutics 2024, 16(6), 835; https://doi.org/10.3390/pharmaceutics16060835 - 19 Jun 2024

Viewed by 571

Abstract

Background: The lack of reliable biomarkers in response to anti-TNFα biologicals hinders personalized therapy for Crohn’s disease (CD) patients. The motivation behind our study is to shift the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using single-cell RNA sequencing and [...] Read more.

Background: The lack of reliable biomarkers in response to anti-TNFα biologicals hinders personalized therapy for Crohn’s disease (CD) patients. The motivation behind our study is to shift the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using single-cell RNA sequencing and an innovative approach designed to uncover PBMCs gene expression signals, which may be masked due to the treatment or ongoing inflammation; Methods: The single-cell RNA sequencing was performed on PBMC samples from CD patients either naïve to biological therapy, in remission while on adalimumab, or while on ustekinumab but previously non-responsive to adalimumab. Sieves for stringent downstream gene selection consisted of gene ontology and independent cohort genomic profiling. Replication and meta-analyses were performed using publicly available raw RNA sequencing files of sorted immune cells and an association analysis summary. Machine learning, Mendelian randomization, and oligogenic risk score methods were deployed to validate DEGs highly relevant to anti-TNFα therapy response; Results: This study found PLCB1 in CD4⁺ T cells and CRTAM in double-negative T cells, which met the stringent statistical thresholds throughout the analyses. An additional assessment proved causal inference of both genes in response to anti-TNFα therapy; Conclusions: This study, jointly with an innovative design, uncovered novel candidate genes in the anti-TNFα response landscape of CD, potentially obscured by therapy or inflammation. Full article

(This article belongs to the Section Biologics and Biosimilars)

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14 pages, 432 KiB

Open AccessArticle

Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients

by Heriberto Bruzzoni-Giovanelli, Habib Zouali, Mourad Sahbatou, Benjamin Maneglier, Jean-Michel Cayuela, Angelita Rebollo, Gustavo H. Marin, Daniela Geromin, Carole Tomczak, Antonio Alberdi, Jean-Francois Deleuze and Philippe Rousselot

Pharmaceutics 2024, 16(6), 834; https://doi.org/10.3390/pharmaceutics16060834 - 19 Jun 2024

Viewed by 495

Abstract

The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the importance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In the OPTIM-imatinib trial, we demonstrated that therapeutic [...] Read more.

The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the importance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In the OPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improve the molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitutional exomes and RNAseq data of these patients. We performed an association analysis between the constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks of treatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5′/3′ (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition)

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14 pages, 6040 KiB

Open AccessArticle

Personalized SO₂ Prodrug for pH-Triggered Gas Enhancement in Anti-Tumor Radio-Immunotherapy

by Zhiran Chen, Xiaoxiang Zhou, Bo Wu, Han Tang, Wei Wei, Daoming Zhu, Yi Ding and Longyun Chen

Pharmaceutics 2024, 16(6), 833; https://doi.org/10.3390/pharmaceutics16060833 - 19 Jun 2024

Viewed by 472

Abstract

The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis. As a non-invasive therapeutic method, radiotherapy is utilized for tumor ablation. In this study, we aimed to improve the [...] Read more.

The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis. As a non-invasive therapeutic method, radiotherapy is utilized for tumor ablation. In this study, we aimed to improve the therapeutic impact of radiotherapy and trigger an immune response by formulating a benzothiazole sulfinate (BTS)-loaded fusion liposome (BFL) nanoplatform, which was then combined with radiotherapy for anti-cancer treatment. The platelet cell membrane, equipped with distinctive surface receptors, enables BFL to effectively target tumors while evading the immune system and adhering to tumor cells. This facilitates BFL’s engulfment by cancer cells, subsequently releasing BTS within them. Following the release, the BTS produces sulfur dioxide (SO₂) for gas therapy, initiating the oxidation of intracellular glutathione (GSH). This process demonstrates efficacy in repairing damage post-radiotherapy, thereby achieving effective radiosensitization. It was revealed that an immune response was triggered following the enhanced radiosensitization facilitated by BFL. This approach facilitated the maturation of dendritic cell (DC) within lymph nodes, leading to an increase in the proportion of T cells in distant tumors. This resulted in significant eradication of primary tumors and inhibition of growth in distant tumors. In summary, the integration of personalized BFL with radiotherapy shows potential in enhancing both tumor immune response and the elimination of tumors, including metastasis. Full article

(This article belongs to the Special Issue Lipid-Based Nanoparticles for Drug Delivery in Cancer)

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3 pages, 176 KiB

Open AccessEditorial

Aspects and Implementation of Pharmaceutical Quality by Design

by Tamás Sovány, Katalin Kristó and Ildikó Csóka

Pharmaceutics 2024, 16(6), 832; https://doi.org/10.3390/pharmaceutics16060832 - 19 Jun 2024

Viewed by 402

Abstract

The introduction of the Quality by Design concept in 2004 has brought a paradigm shift in the pharmaceutical industry as well as a new era in pharmaceutical research and development [...] Full article

(This article belongs to the Special Issue Aspects and Implementation of Pharmaceutical Quality by Design)

10 pages, 1763 KiB

Open AccessArticle

The Distinctive Role of Gluconic Acid in Retarding Percutaneous Drug Permeation: Formulation of Lidocaine-Loaded Chitosan Nanoparticles

by Amnon C. Sintov

Pharmaceutics 2024, 16(6), 831; https://doi.org/10.3390/pharmaceutics16060831 - 19 Jun 2024

Viewed by 384

Abstract

The objective of the present investigation was to evidence the skin retardation phenomenon of lidocaine by gluconic acid as an inactive ingredient involved in citrate-crosslinking chitosan nanoparticles. Lidocaine hydrochloride was loaded in nanoparticles based on chitosan, fabricated by using a water-in-oil microemulsion as [...] Read more.

The objective of the present investigation was to evidence the skin retardation phenomenon of lidocaine by gluconic acid as an inactive ingredient involved in citrate-crosslinking chitosan nanoparticles. Lidocaine hydrochloride was loaded in nanoparticles based on chitosan, fabricated by using a water-in-oil microemulsion as a template and citric acid as an ionic cross-linker. Gluconic acid (pentahydroxy hexanoic acid) was added during the fabrication and compared with caproic acid, a non-hydroxy hexanoic acid. The chitosan nanoparticulate systems were characterized for mean particle size, particle size distribution, and zeta potential. The pentahydroxy hexanoic acid decreased the zeta potential to a significantly lower value than those obtained from both plain citrate and citrate–hexanoic acid formulations. The relatively lower value implies that gluconate ions are partly attached to the nanoparticle’s surface and mask its positively charged groups. It was also noted that the in vitro percutaneous permeation flux of lidocaine significantly decreased when gluconate-containing chitosan nanoparticles were applied, i.e., 6.1 ± 1.5 μg‧cm⁻²‧h⁻¹ without gluconic acid to 3.4 ± 2.3 μg‧cm⁻²‧h⁻¹ with gluconic acid. According to this result, it is suggested that gluconate ions played a role in retarding drug permeation through the skin, probably by calcium chelation in the stratum granulosum, which in turn stimulated lamellar body secretion, lipid synthesis, and intracellular release of Ca²⁺ from the endoplasmic reticulum. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications, 2nd Edition)

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15 pages, 3379 KiB

Open AccessArticle

The Assessment of Physicochemical and Antimicrobial Properties of Hydrophilic Gels Containing Tetracycline Hydrochloride and Various Concentrations of Ethanol

by Agnieszka Kostrzębska, Adam Junka, Malwina Brożyna and Witold Musiał

Pharmaceutics 2024, 16(6), 830; https://doi.org/10.3390/pharmaceutics16060830 - 19 Jun 2024

Viewed by 404

Abstract

The high prevalence of acne, which affects nearly 85% of adolescents and young adults, underscores the importance of exploring new therapeutic solutions. The aim of the present study was to design a stable hydrogel formulation containing tetracycline hydrochloride (TC) in the presence of [...] Read more.

The high prevalence of acne, which affects nearly 85% of adolescents and young adults, underscores the importance of exploring new therapeutic solutions. The aim of the present study was to design a stable hydrogel formulation containing tetracycline hydrochloride (TC) in the presence of ethanol at various concentration levels. The antibiotic stability was assessed over a period of 84 days using the HPLC method. The rheological properties of the formulations and their microbiological activity were also evaluated. Hydrogels without ethanol and those containing 5% and 25% alcohol showed similar rheological properties and high stability of the antibiotic throughout the observation period. The formulation with the highest ethanol content of 50% differed significantly from the others in terms of rheological properties. Although the flow and viscosity curves were like those of the other formulations, the viscosity values were significantly lower. The stability of tetracycline in this formulation was also significantly lower, and by the 84th day of observation, the concentration of the drug had decreased to almost 45% of its initial content. The formulations containing the highest concentration of ethanol displayed the highest activity against the biofilm of the acne-causing agent, Cutibacterium acnes. The study demonstrated the possibility of developing stable and antimicrobial effective hydrogel formulations with tetracycline and ethanol as a substance enhancing drug penetration into the hair follicles. Full article

(This article belongs to the Special Issue Pharmaceutical Formulations with Antimicrobial Properties, 2nd Edition)

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21 pages, 1867 KiB

Open AccessArticle

Targeting Intracranial Tumours with a Combination of RNA and Chemotherapy

by Abdulhamid S. Fatani, Andreas G. Schätzlein and Ijeoma F. Uchegbu

Pharmaceutics 2024, 16(6), 829; https://doi.org/10.3390/pharmaceutics16060829 - 18 Jun 2024

Viewed by 505

Abstract

Glioblastoma multiforme (GBM) is a fast-growing and aggressive brain tumour, which remains largely resistant to treatment; the prognosis for patients is poor, with a median survival time of about 12–18 months, post diagnosis. In an effort to bring more efficacious treatments to patients, [...] Read more.

Glioblastoma multiforme (GBM) is a fast-growing and aggressive brain tumour, which remains largely resistant to treatment; the prognosis for patients is poor, with a median survival time of about 12–18 months, post diagnosis. In an effort to bring more efficacious treatments to patients, we targeted the down regulation of ITCH, an E3 ligase that is overexpressed in a variety of cancers, and which inhibits P73, a tumour suppressor gene. 6-O-glycolchitosan (GC) was used to deliver siRNA ITCH (GC60-siRNA-ITCH) and gemcitabine via the nose to brain route in CD-1 nude mice which had previously been implanted intracranially with U87-MG-luc2 cells. Prior to this in vivo study, an in vitro study established the synergistic effect of siRNA-ITCH in combination with a chemotherapy drug—gemcitabine. A downregulation of ITCH, an upregulation of p73 and enhanced apoptosis were observed in vitro in U87-MG cells, using qPCR, Western blot analysis, confocal laser scanning microscopy, flow cytometry and cytotoxicity assays. When GC60-siRNA-ITCH was combined with gemcitabine, there was a resultant decrease in cell proliferation in vitro. In CD1 mice, the administration of siRNA-ITCH (7 doses of 0.081 mg/kg) alone did not significantly affect animal survival (increasing mean survival from 29 to 33 days when compared to untreated animals), whereas intranasal gemcitabine had a significant effect on survival (increasing survival from 29 to 45 days when compared to untreated animals, p < 0.01). The most significant effect was seen with combination therapy (GC60-siRNA-ITCH plus gemcitabine), where survival increased by 89%, increasing from 29 to 54 days (p < 0.01). Our data demonstrate that siRNA chemosensitises brain tumours to gemcitabine and that the nose-to-brain delivery route may be a viable route for the treatment of intracranial tumours. Full article

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16 pages, 6554 KiB

Open AccessArticle

Immunomodulatory and Anticancer Effects of Fridericia chica Extract-Loaded Nanocapsules in Myeloid Leukemia

by Alice de Freitas Gomes, Adriane Dâmares de Souza Jorge Batalha, Carlos Eduardo de Castro Alves, Renata Galvão de Azevedo, Jesus Rafael Rodriguez Amado, Tatiane Pereira de Souza, Hector Henrique Ferreira Koolen, Felipe Moura Araújo da Silva, Francisco Celio Maia Chaves, Serafim Florentino Neto, Antônio Luiz Boechat and Gemilson Soares Pontes

Pharmaceutics 2024, 16(6), 828; https://doi.org/10.3390/pharmaceutics16060828 - 18 Jun 2024

Viewed by 414

Abstract

Nanocapsules provide selective delivery and increase the bioavailability of bioactive compounds. In this study, we examined the anticancer and immunomodulatory potential of Fridericia chica (crajiru) extract encapsulated in nanocapsules targeting myeloid leukemias. Nanocapsules containing crajiru (nanocapsules-CRJ) were prepared via interfacial polymer deposition and [...] Read more.

Nanocapsules provide selective delivery and increase the bioavailability of bioactive compounds. In this study, we examined the anticancer and immunomodulatory potential of Fridericia chica (crajiru) extract encapsulated in nanocapsules targeting myeloid leukemias. Nanocapsules containing crajiru (nanocapsules-CRJ) were prepared via interfacial polymer deposition and solvent displacement. Size and polydispersity were measured by dynamic light scattering. Biological assays were performed on leukemia cell lines HL60 and K562 and on non-cancerous Vero cells and human PBMC. The anticancer activity was evaluated using cytotoxicity and clonogenic assays, while the immunomodulatory activity was evaluated by measuring the levels of pro- and anti-inflammatory cytokines in PBMC supernatants treated with concentrations of nanocapsules-CRJ. Nanocapsules-CRJ exhibited significant cytotoxic activity against HL60 and K562 cells at concentrations ranging from 0.75 to 50 μg/mL, with the greatest reductions in cell viability observed at 50 μg/mL (p < 0.001 for HL60; p < 0.01 for K562), while not affecting non-cancerous Vero cells and human PBMCs. At concentrations of 25 μg/mL and 50 μg/mL, nanocapsules-CRJ reduced the formation of HL60 and K562 colonies by more than 90% (p < 0.0001). Additionally, at a concentration of 12 μg/mL, nanocapsules-CRJ induced the production of the cytokines IL-6 (p = 0.0002), IL-10 (p = 0.0005), IL-12 (p = 0.001), and TNF-α (p = 0.005), indicating their immunomodulatory potential. These findings suggest that nanocapsules-CRJ hold promise as a potential therapeutic agent with both cytotoxic and immunomodulatory properties. Full article

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

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23 pages, 7648 KiB

Open AccessArticle

Multistage Nanocarrier Based on an Oil Core–Graphene Oxide Shell

by Immacolata Tufano, Raffaele Vecchione, Valeria Panzetta, Edmondo Battista, Costantino Casale, Giorgia Imparato and Paolo Antonio Netti

Pharmaceutics 2024, 16(6), 827; https://doi.org/10.3390/pharmaceutics16060827 - 18 Jun 2024

Viewed by 433

Abstract

Potent synthetic drugs, as well as biomolecules extracted from plants, have been investigated for their selectivity toward cancer cells. The main limitation in cancer treatment is the ability to bring such molecules within each single cancer cell, which requires accumulation in the peritumoral [...] Read more.

Potent synthetic drugs, as well as biomolecules extracted from plants, have been investigated for their selectivity toward cancer cells. The main limitation in cancer treatment is the ability to bring such molecules within each single cancer cell, which requires accumulation in the peritumoral region followed by homogeneous spreading within the entire tissue. In the last decades, nanotechnology has emerged as a powerful tool due to its ability to protect the drug during blood circulation and allow enhanced accumulation around the leaky regions of the tumor vasculature. However, the ideal size for accumulation of around 100 nm is too large for effective penetration into the dense collagen matrix. Therefore, we propose a multistage system based on graphene oxide nanosheet-based quantum dots (GOQDs) with dimensions that are 12 nm, functionalized with hyaluronic acid (GOQDs-HA), and deposited using the layer-by-layer technique onto an oil-in-water nanoemulsion (O/W NE) template that is around 100 nm in size, previously stabilized by a biodegradable polymer, chitosan. The choice of a biodegradable core for the nanocarrier is to degrade once inside the tumor, thus promoting the release of smaller compounds, GOQDs-HA, carrying the adsorbed anticancer compound, which in this work is represented by curcumin as a model bioactive anticancer molecule. Additionally, modification with HA aims to promote active targeting of stromal and cancer cells. Cell uptake experiments and preliminary penetration experiments in three-dimensional microtissues were performed to assess the proposed multistage nanocarrier. Full article

(This article belongs to the Special Issue Smart Nanocarriers for Drug Delivery in Cancer Therapy)

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13 pages, 1320 KiB

Open AccessArticle

Unveiling Anticancer Potential of COX-2 and 5-LOX Inhibitors: Cytotoxicity, Radiosensitization Potential and Antimigratory Activity against Colorectal and Pancreatic Carcinoma

by Jelena Bošković, Vladimir Dobričić, Otilija Keta, Lela Korićanac, Jelena Žakula, Jelena Dinić, Sofija Jovanović Stojanov, Aleksandar Pavić and Olivera Čudina

Pharmaceutics 2024, 16(6), 826; https://doi.org/10.3390/pharmaceutics16060826 - 18 Jun 2024

Viewed by 411

Abstract

Apart from cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells and cell antimigratory effects); however, the relationship between the inhibition of other inflammation-related enzyme 5-LOX inhibitors and anticancer activity is still [...] Read more.

Apart from cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells and cell antimigratory effects); however, the relationship between the inhibition of other inflammation-related enzyme 5-LOX inhibitors and anticancer activity is still not well understood. In our study, the cytotoxicity of thirteen COX-2 and 5-LOX inhibitors previously presented by our group (1–13) was tested on three cancer cell lines (HCT 116, HT-29 and BxPC-3) and one healthy cell line (MRC-5). Compounds 3, 5, 6 and 7 showed moderate cytotoxicity, but good selectivity towards cancer cell lines. IC₅₀ values were in the range of 22.99–51.66 µM (HCT 116 cell line), 8.63–41.20 µM (BxPC-3 cell line) and 24.78–81.60 µM (HT-29 cell line; compound 7 > 100 µM). In comparison to tested, commercially available COX-2 and 5-LOX inhibitors, both cytotoxicity and selectivity were increased. The addition of compounds 6 and 7 to irradiation treatment showed the most significant decrease in cell proliferation of the HT-29 cell line (p < 0.001). The antimigratory potential of the best dual COX-2 and 5-LOX inhibitors (compounds 1, 2, 3 and 5) was tested by a wound-healing assay using the SW620 cell line. Compounds 1 and 3 were singled out as compounds with the most potent effect (relative wound closure was 3.20% (24 h), 5,08% (48 h) for compound 1 and 3.86% (24 h), 7.68% (48 h) for compound 3). Considering all these results, compound 3 stood out as the compound with the most optimal biological activity, with the best dual COX-2 and 5-LOX inhibitory activity, good selectivity towards tested cancer cell lines, significant cell antimigratory potential and a lack of toxic effects at therapeutic doses. Full article

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

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20 pages, 889 KiB

Open AccessReview

The Effect of Photodynamic Therapy on Enterococcus spp. and Its Application in Dentistry: A Scoping Review

by Mariaignacia Rubilar-Huenchuman, Camilo Ortega-Villanueva, Iván A. González and Christian Erick Palavecino

Pharmaceutics 2024, 16(6), 825; https://doi.org/10.3390/pharmaceutics16060825 - 18 Jun 2024

Viewed by 502

Abstract

Enterococci spp. are Gram-positive bacteria that cause mild to severe infections, many associated with the oral cavity, such as periapical infections and healthcare-associated infections (HAIs). Many of these infections become serious diseases that are difficult to resolve, specifically when multidrug-resistant (MDR) strains cause [...] Read more.

Enterococci spp. are Gram-positive bacteria that cause mild to severe infections, many associated with the oral cavity, such as periapical infections and healthcare-associated infections (HAIs). Many of these infections become serious diseases that are difficult to resolve, specifically when multidrug-resistant (MDR) strains cause them. In recent years, the number of MDR strains of Enterococcus spp. has increased significantly. This increased prevalence of MDR strains produces significant pressure to generate more antimicrobial therapies, but there is a decline in the production of new antibiotics, driving the development of complementary therapies, such as photodynamic therapy (PDT). PDT combines a photosensitizer agent (PS), light, and oxygen to cause photooxidative stress in bacterial cells. PDT can eradicate Enterococcus spp. contaminations, improve the classic cleaning processes, and eradicate the bacteria in dental pieces. PDT’s effectiveness can be improved with nanoparticles that function as carriers. Our work aims to describe the advances in PDT against Enterococcus spp. as a complement to antibiotic therapy, focusing on infections by Enterococcus faecium and Enterococcus faecalis, dental hygiene, and using nanoparticles to improve the antimicrobial effect. A systematic bibliographic search without a meta-analysis was conducted on various databases, using inclusion and exclusion criteria to identify the most relevant research. Of the 193 non-redundant articles found, 65 were selected for a systematic review, from which a summary table was created and a manual description was made. Photodynamic therapy for treating E. faecium and E. faecalis is a widely studied area, with promising results concerning bactericidal effectiveness and reductions in biofilm formation, particularly in regard to dental hygiene. Because most of the studies were conducted in vitro or ex vivo, the results indicated that there were not sufficient data to initiate clinical trials for safety and efficacy studies on humans. Full article

(This article belongs to the Special Issue Research on the Design and Development of Infectious, Inflammatory and Cancer Therapeutics)

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15 pages, 2485 KiB

Open AccessArticle

Dual-Omics Approach Unveils Novel Perspective on the Quality Control of Genetically Engineered Exosomes

by Christopher Olson, Konstantin Ivanov, Darin Boyes, David Bengford, Joy Ku, Renceh Flojo, Pengyang Zhang and Biao Lu

Pharmaceutics 2024, 16(6), 824; https://doi.org/10.3390/pharmaceutics16060824 - 18 Jun 2024

Viewed by 490

Abstract

Exosomes, nanoscale vesicles derived from human cells, offer great promise for targeted drug delivery. However, their inherent diversity and genetic modifications present challenges in terms of ensuring quality in clinical use. To explore solutions, we employed advanced gene fusion and transfection techniques in [...] Read more.

Exosomes, nanoscale vesicles derived from human cells, offer great promise for targeted drug delivery. However, their inherent diversity and genetic modifications present challenges in terms of ensuring quality in clinical use. To explore solutions, we employed advanced gene fusion and transfection techniques in human 293T cells to generate two distinct sets of genetically engineered samples. We used dual-omics analysis, combining transcriptomics and proteomics, to comprehensively assess exosome quality by comparing with controls. Transcriptomic profiling showed increased levels of engineering scaffolds in the modified groups, confirming the success of genetic manipulation. Through transcriptomic analysis, we identified 15 RNA species, including 2008 miRNAs and 13,897 mRNAs, loaded onto exosomes, with no significant differences in miRNA or mRNA levels between the control and engineered exosomes. Proteomics analysis identified changes introduced through genetic engineering and over 1330 endogenous exosome-associated proteins, indicating the complex nature of the samples. Further pathway analysis showed enrichment in a small subset of cellular signaling pathways, aiding in our understanding of the potential biological impacts on recipient cells. Detection of over 100 cow proteins highlighted the effectiveness of LC-MS for identifying potential contaminants. Our findings establish a dual-omics framework for the quality control of engineered exosome products, facilitating their clinical translation and therapeutic applications in nanomedicine. Full article

(This article belongs to the Special Issue Advances in Nanocarriers for Drug Delivery and Targeting, 2nd Edition)

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20 pages, 2999 KiB

Open AccessArticle

Acid-Responsive Decomposable Nanomedicine Based on Zeolitic Imidazolate Frameworks for Near-Infrared Fluorescence Imaging/Chemotherapy Combined Tumor Theranostics

by Heze Guo, Vincent Mukwaya, Daikun Wu, Shuhan Xiong and Hongjing Dou

Pharmaceutics 2024, 16(6), 823; https://doi.org/10.3390/pharmaceutics16060823 - 18 Jun 2024

Viewed by 575

Abstract

Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) are gaining traction in tumor theranostics for their effectiveness in encapsulating both imaging agents and therapeutic drugs. While typically, similar hydrophilic molecules are encapsulated in either pure aqueous or organic environments, few studies have explored co-encapsulation of [...] Read more.

Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) are gaining traction in tumor theranostics for their effectiveness in encapsulating both imaging agents and therapeutic drugs. While typically, similar hydrophilic molecules are encapsulated in either pure aqueous or organic environments, few studies have explored co-encapsulation of chemotherapeutic drugs and imaging agents with varying hydrophilicity and, consequently, constructed multifunctional ZIF-8 composite NPs for acid-responsive, near-infrared fluorescence imaging/chemotherapy combined tumor theranostics. Here, we present a one-pot method for the synthesis of uniform Cy5.5&DOX@ZIF-8 nanoparticles in mixed solvents, efficiently achieving simultaneous encapsulation of hydrophilic doxorubicin (DOX) and hydrophobic Cyanine-5.5 (Cy5.5). Surface decoration with dextran (Dex) enhanced colloidal stability and biocompatibility. The method significantly facilitated co-loading of Cy5.5 dyes and DOX drugs, endowing the composite NPs with notable fluorescent imaging capabilities and pH-responsive chemotherapy capacities. In vivo near-infrared fluorescence (NIRF) imaging in A549 tumor-bearing mice demonstrated significant accumulation of Cy5.5 at tumor sites due to enhanced permeability and retention (EPR) effects, with fluorescence intensities approximately 48-fold higher than free Cy5.5. Enhanced therapeutic efficiency was observed in composite NPs compared to free DOX, validating tumor-targeted capability. These findings suggest ZIF-8-based nanomedicines as promising platforms for multifunctional tumor theranostics. Full article

(This article belongs to the Topic Application of Nanomaterials and Nanobiotechnology in Cancer)

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17 pages, 6445 KiB

Open AccessArticle

Self-Assembled Nanocomposite DOX/TPOR₄@CB[7]₄ for Enhanced Synergistic Photodynamic Therapy and Chemotherapy in Neuroblastoma

by Zhouxia Lu, Xu Chen, Conghui Wang, Xuelian Luo, Xiaohan Wu, Xing Zhao and Song Xiao

Pharmaceutics 2024, 16(6), 822; https://doi.org/10.3390/pharmaceutics16060822 - 18 Jun 2024

Viewed by 398

Abstract

DOX/TPOR₄@CB[7]₄ was synthesized via self-assembly, and its physicochemical properties and ability to generate reactive oxygen species (ROS) were evaluated. The impact of photodynamic therapy on SH-SY5Y cells was assessed using the MTT assay, while flow cytometry analysis was employed to [...] Read more.

DOX/TPOR₄@CB[7]₄ was synthesized via self-assembly, and its physicochemical properties and ability to generate reactive oxygen species (ROS) were evaluated. The impact of photodynamic therapy on SH-SY5Y cells was assessed using the MTT assay, while flow cytometry analysis was employed to detect cell apoptosis. Confocal laser scanning microscopy was utilized to observe the intracellular distribution of DOX/TPOR₄@CB[7]₄ in SH-SY5Y cells. Additionally, fluorescence imaging of DOX/TPOR₄@CB[7]₄ in nude mice bearing SH-SY5Y tumors and examination of the combined effects of photodynamic and chemical therapies were conducted. The incorporation of CB[7] significantly enhanced the optical properties of DOX/TPOR₄@CB[7]₄, resulting in increased ROS production and pronounced toxicity towards SH-SY5Y cells. Moreover, both the apoptotic and mortality rates exhibited significant elevation. In vivo experiments demonstrated that tumor growth inhibition was most prominent in the DOX/TPOR₄@CB[7]₄ group. π–π interactions facilitated the binding between DOX and photosensitizer TPOR, with TPOR’s naphthalene hydrophilic groups encapsulated within CB[7]’s cavity through host–guest interactions with CB[7]. Therefore, CB[7] can serve as a nanocarrier to enhance the combined application of chemical therapy and photodynamic therapy, thereby significantly improving treatment efficacy against neuroblastoma tumors. Full article

(This article belongs to the Special Issue Multicomponent Nanomedicines for Photodynamic Diagnosis and Photodynamic Therapy)

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9 pages, 201 KiB

Open AccessCorrection

Correction: Shrewsbury, S.B. The Upper Nasal Space: Option for Systemic Drug Delivery, Mucosal Vaccines and “Nose-to-Brain”. Pharmaceutics 2023, 15, 1720

by Stephen B. Shrewsbury

Pharmaceutics 2024, 16(6), 821; https://doi.org/10.3390/pharmaceutics16060821 - 18 Jun 2024

Viewed by 286

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

14 pages, 8407 KiB

Open AccessArticle

Stability of Multicomponent Antidote Parenteral Formulations for Autoinjectors against Chemical War Agents (Neurotoxics)

by María José Rodríguez Fernández, Daniel Hernández, Brayan Javier Anaya, Dolores R. Serrano and Juan José Torrado

Pharmaceutics 2024, 16(6), 820; https://doi.org/10.3390/pharmaceutics16060820 - 17 Jun 2024

Viewed by 396

Abstract

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, [...] Read more.

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, and midazolam); (ii) pH (3 versus 4); and (iii) type of elastomeric sealing material (PH 701/50 C BLACK versus 4023/50 GRAY). Syringes were stored at three different temperatures: 4, 25, and 40 °C. Samples were assayed at different time points to study the physical appearance, drug sorption on the sealing elastomeric materials, and drug content in solution. Midazolam was unstable in all tested experimental conditions. Drug adsorption was observed in both types of sealing elastomeric materials and was significantly (p < 0.01) dependent on the lipophilicity of the drug. The most stable formulation was the combination of pralidoxime and atropine at pH 4 with the elastomeric sealing material 4023/50 GRAY. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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23 pages, 5172 KiB

Open AccessArticle

Development and Quality Control of a Population Pharmacokinetic Model Library for Caspofungin

by Nuo Xu, Yufei Shi, Yixue Wang, Wenyao Mak, Wenyu Yang, Kar Weng Ng, Yue Wu, Zhijia Tang, Qingfeng He, Gangfeng Yan, Xiaoqiang Xiang and Xiao Zhu

Pharmaceutics 2024, 16(6), 819; https://doi.org/10.3390/pharmaceutics16060819 - 17 Jun 2024

Viewed by 371

Abstract

Background: Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of [...] Read more.

Background: Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy. Objective: This work aimed to develop a caspofungin population pharmacokinetic (popPK) library and demonstrate its utility by assessing the probability of target attainment across diverse settings. Methods: We established a caspofungin popPK model library following a rigorous literature review, re-implementing selected models in R with rxode2. Quality control procedures included a comparison of different studies and assessing covariate impacts. Model libraries were primarily used to perform Monte Carlo simulations to estimate target attainment and guide personalized dosing in Candida infections. Results: A total of 13 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area), liver function, and albumin level. The results show that children and adults showed considerable differences in pharmacokinetics. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥90% at their respective susceptible MIC values. In contrast, for C. glabrata, 70% of the adult studies reached a PTA of ≥90%, while all pediatric studies achieved the same PTA level. Conclusion: At the recommended dosage, adult patients showed notably lower exposure to caspofungin compared to pediatric patients. Considering body size, liver function, and serum albumin is crucial when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatric patients. Full article

(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)

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27 pages, 1353 KiB

Open AccessReview

New Oxazolidinones for Tuberculosis: Are Novel Treatments on the Horizon?

by Ricky Hao Chen, Andrew Burke, Jin-Gun Cho, Jan-Willem Alffenaar and Lina Davies Forsman

Pharmaceutics 2024, 16(6), 818; https://doi.org/10.3390/pharmaceutics16060818 - 17 Jun 2024

Viewed by 482

Abstract

Multidrug-resistant tuberculosis (MDR-TB) is a global health concern. Standard treatment involves the use of linezolid, a repurposed oxazolidinone. It is associated with severe adverse effects, including myelosuppression and mitochondrial toxicity. As such, it is imperative to identify novel alternatives that are better tolerated [...] Read more.

Multidrug-resistant tuberculosis (MDR-TB) is a global health concern. Standard treatment involves the use of linezolid, a repurposed oxazolidinone. It is associated with severe adverse effects, including myelosuppression and mitochondrial toxicity. As such, it is imperative to identify novel alternatives that are better tolerated but equally or more effective. Therefore, this review aims to identify and explore the novel alternative oxazolidinones to potentially replace linezolid in the management of TB. The keywords tuberculosis and oxazolidinones were searched in PubMed to identify eligible compounds. The individual drug compounds were then searched with the term tuberculosis to identify the relevant in vitro, in vivo and clinical studies. The search identified sutezolid, tedizolid, delpazolid, eperezolid, radezolid, contezolid, posizolid and TBI-223, in addition to linezolid. An additional search resulted in 32 preclinical and 21 clinical studies. All novel oxazolidinones except posizolid and eperezolid resulted in positive preclinical outcomes. Sutezolid and delpazolid completed early phase 2 clinical studies with better safety and equal or superior efficacy. Linezolid is expected to continue as the mainstay therapy, with renewed interest in drug monitoring. Sutezolid, tedizolid, delpazolid and TBI-223 displayed promising preliminary results. Further clinical studies would be required to assess the safety profiles and optimize the dosing regimens. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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47 pages, 3150 KiB

Open AccessReview

Progress in Topical and Transdermal Drug Delivery Research—Focus on Nanoformulations

by Dominique Lunter, Victoria Klang, Adina Eichner, Sanela M. Savic, Snezana Savic, Guoping Lian and Franciska Erdő

Pharmaceutics 2024, 16(6), 817; https://doi.org/10.3390/pharmaceutics16060817 - 16 Jun 2024

Viewed by 826

Abstract

Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The [...] Read more.

Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The skin is involved in body temperature regulation by the storage of fat and water. It is an interesting tissue in regard to the local and transdermal application of active ingredients for prevention or treatment of pathological conditions. Topical and transdermal delivery is an emerging route of drug and cosmetic administration. It is beneficial for avoiding side effects and rapid metabolism. Many pharmaceutical, technological and cosmetic innovations have been described and patented recently in the field. In this review, the main features of skin morphology and physiology are presented and are being followed by the description of classical and novel nanoparticulate dermal and transdermal drug formulations. The biophysical aspects of the penetration of drugs and cosmetics into or across the dermal barrier and their investigation in diffusion chambers, skin-on-a-chip devices, high-throughput measuring systems or with advanced analytical techniques are also shown. The current knowledge about mathematical modeling of skin penetration and the future perspectives are briefly discussed in the end, all also involving nanoparticulated systems. Full article

(This article belongs to the Special Issue Nanoparticles for Local Drug Delivery)

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15 pages, 3446 KiB

Open AccessArticle

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

by Jing Xiong, Dezhong Xu, Hui Zhang, Yan Shi, Xiangxiang Wu and Sicen Wang

Pharmaceutics 2024, 16(6), 816; https://doi.org/10.3390/pharmaceutics16060816 - 16 Jun 2024

Viewed by 497

Abstract

Progesterone (PROG) is a natural steroid hormone with low solubility and high permeability that belongs to biopharmaceutics classification system class II. In this study, novel pharmaceutical cocrystals of PROG were successfully prepared by solvent evaporation or a liquid-assisted grinding process aimed at enhancing [...] Read more.

Progesterone (PROG) is a natural steroid hormone with low solubility and high permeability that belongs to biopharmaceutics classification system class II. In this study, novel pharmaceutical cocrystals of PROG were successfully prepared by solvent evaporation or a liquid-assisted grinding process aimed at enhancing its solubility and bioavailability. The cocrystal formers selected based on crystal engineering principles were carboxylic acids, namely, 4-formylbenzeneboronic acid (BBA), isophthalic acid (IPA), and 3-nitrophthalic acid (NPA). The cocrystal structures were characterized using multiple techniques. Single-crystal X-ray diffraction results showed that the carbonyl group, acting as a hydrogen bond acceptor, was pivotal in the cocrystal network formation, with C–H···O interactions further stabilizing the crystals. The cocrystals exhibited improved solubility and dissolution profiles in vitro, with no significant changes in hygroscopicity. The parallel artificial membrane permeability assay (PAMPA) models indicated that the cocrystals retained PROG’s high permeability. Pharmacokinetic studies in Sprague–Dawley rats revealed that all cocrystals increased PROG exposure, with AUC_(0~∞) values for PROG–BBA, PROG–IPA, and PROG–NPA being 742.59, 1201.72 and 442.67 h·ng·mL⁻¹, respectively. These values are substantially higher compared to free PROG, which had an AUC_(0~∞) of 301.48 h·ng·mL⁻¹. Notably, PROG–IPA provided the highest AUC improvement, indicating a significant enhancement in bioavailability. Collectively, the study concludes that the cocrystal approach is a valuable strategy for optimizing the physicochemical properties and oral bioavailability of PROG, with potential implications for the development of other poor water-soluble drugs. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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12 pages, 1837 KiB

Open AccessArticle

Application of Photodynamic Therapy with 5-Aminolevulinic Acid to Extracorporeal Photopheresis in the Treatment of Cutaneous T-Cell Lymphoma: A First-in-Human Phase I/II Study

by Eidi Christensen, Olav Andreas Foss, Toril Holien, Petras Juzenas and Qian Peng

Pharmaceutics 2024, 16(6), 815; https://doi.org/10.3390/pharmaceutics16060815 - 16 Jun 2024

Viewed by 592

Abstract

Extracorporeal photopheresis (ECP) is a therapeutic modality used for T-cell-mediated disorders. This approach involves exposing isolated white blood cells to photoactivatable 8-methoxypsoralen (8-MOP) and UVA light, aiming to induce apoptosis in T-cells and thereby modulate immune responses. However, conventional 8-MOP-ECP lacks cell selectivity, [...] Read more.

Extracorporeal photopheresis (ECP) is a therapeutic modality used for T-cell-mediated disorders. This approach involves exposing isolated white blood cells to photoactivatable 8-methoxypsoralen (8-MOP) and UVA light, aiming to induce apoptosis in T-cells and thereby modulate immune responses. However, conventional 8-MOP-ECP lacks cell selectivity, killing both healthy and diseased cells, and has shown limited treatment efficacy. An alternative approach under investigation involves the use of 5-aminolevulinic acid (ALA) in conjunction with light, referred to as ALA-based photodynamic therapy. Our previous ex vivo studies suggest that ALA-ECP exhibits greater selectivity and efficiency in killing T-cells derived from patients with T-cell-mediated disorders compared to those treated with 8-MOP-ECP. We have conducted a clinical phase I–(II) study evaluating ALA-ECP safety and tolerability in cutaneous T-cell lymphoma (CTCL). Here, 20 ALA-ECP treatments were administered to one CTCL patient, revealing no significant changes in vital signs. Two adverse events were reported; both evaluated by the Internal Safety Review Committee as non-serious. In addition, five conceivable events with mainly mild symptoms took place. During the study period, a 53% reduction in skin involvement and a 50% reduction in pruritus was observed. In conclusion, the results indicate that ALA-ECP treatment is safe and well tolerated. Full article

(This article belongs to the Special Issue Photodynamic Therapy: Rising Star in Pharmaceutical Applications)

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15 pages, 3425 KiB

Open AccessArticle

In Vivo Evaluation of ⁶⁸Ga-Labeled NOTA-EGFRvIII Aptamer in EGFRvIII-Positive Glioblastoma Xenografted Model

by Jun Young Park, Ye Lim Cho, Tae Sup Lee, Daekyun Lee, Ju-Hyung Kang, Soryong Lim, Yujin Lee, Jae Hyun Lim and Won Jun Kang

Pharmaceutics 2024, 16(6), 814; https://doi.org/10.3390/pharmaceutics16060814 - 16 Jun 2024

Viewed by 546

Abstract

EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the [...] Read more.

EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the potential of the ⁶⁸Ga-NOTA-EGFRvIII aptamer as a nuclear imaging probe for visualizing EGFRvIII-expressing glioblastoma by positron emission tomography (PET). EGFRvIII aptamer was selected using the SELEX technology, and flow cytometry and fluorescence microscopy verified the high binding affinity to EGFRvIII positive U87MG vIII 4.12 glioma cells but not to EGFRvIII negative U87MG cells. The EGFRvIII aptamer was conjugated with a chelator (1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA) for ⁶⁸Ga-labeling. The ⁶⁸Ga-NOTA-EGFRvIII aptamer was prepared using the preconcentration-based labeling method with a high radiolabeling yield at room temperature. Ex vivo biodistribution analyses confirmed the significantly higher tumor uptake of the ⁶⁸Ga-NOTA-EGFRvIII aptamer in EGFRvIII-expressing xenograft tumors than that in EGFRvIII negative tumors, confirming the specific tumor uptake of the ⁶⁸Ga-NOTA-EGFRvIII aptamer in vivo. PET imaging studies revealed a high retention rate of the ⁶⁸Ga-NOTA-EGFRvIII aptamer in U87MG vIII 4.12 tumors but only low uptake levels in U87-MG tumors, suggesting that the ⁶⁸Ga-NOTA-EGFRvIII aptamer may be used as a PET imaging agent for EGFRvIII-expressing glioblastoma. Full article

(This article belongs to the Special Issue Advances in Radiopharmaceuticals for Disease Diagnoses and Therapy)

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17 pages, 9236 KiB

Open AccessArticle

Alimentary Treatment with Trehalose in a Pharmacological Model of Alzheimer’s Disease in Mice: Effects of Different Dosages and Treatment Regimens

by Alexander B. Pupyshev, Anna A. Akopyan, Michael V. Tenditnik, Marina V. Ovsyukova, Nina I. Dubrovina, Victor M. Belichenko, Tatiana A. Korolenko, Svetlana A. Zozulya, Tatiana P. Klyushnik and Maria A. Tikhonova

Pharmaceutics 2024, 16(6), 813; https://doi.org/10.3390/pharmaceutics16060813 - 16 Jun 2024

Viewed by 460

Abstract

In the treatment of experimental neurodegeneration with disaccharide trehalose, various regimens are used, predominantly a 2% solution, drunk for several weeks. We studied the effects of different regimens of dietary trehalose treatment in an amyloid-β (Aβ) 25–35-induced murine model of Alzheimer’s disease (AD). [...] Read more.

In the treatment of experimental neurodegeneration with disaccharide trehalose, various regimens are used, predominantly a 2% solution, drunk for several weeks. We studied the effects of different regimens of dietary trehalose treatment in an amyloid-β (Aβ) 25–35-induced murine model of Alzheimer’s disease (AD). Aβ-treated mice received 2% trehalose solution daily, 4% trehalose solution daily (continuous mode) or every other day (intermittent mode), to drink for two weeks. We revealed the dose-dependent effects on autophagy activation in the frontal cortex and hippocampus, and the restoration of behavioral disturbances. A continuous intake of 4% trehalose solution caused the greatest activation of autophagy and the complete recovery of step-through latency in the passive avoidance test that corresponds to associative long-term memory and learning. This regimen also produced an anxiolytic effect in the open field. The effects of all the regimens studied were similar in Aβ load, neuroinflammatory response, and neuronal density in the frontal cortex and hippocampus. Trehalose successfully restored these parameters to the levels of the control group. Thus, high doses of trehalose had increased efficacy towards cognitive impairment in a model of early AD-like pathology. These findings could be taken into account for translational studies and the development of clinical approaches for AD therapy using trehalose. Full article

(This article belongs to the Special Issue Novel Therapies Based on Autophagy Modulation: Targets, Mechanisms, and Delivery Approaches)

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13 pages, 4962 KiB

Open AccessArticle

Novel Hydrogels Based on the Nano-Emulsion Formulation Process: Development, Rheological Characterization, and Study as a Drug Delivery System

by Usama Jamshaid, Nicolas Anton, Mohamed Elhassan, Guillaume Conzatti and Thierry F. Vandamme

Pharmaceutics 2024, 16(6), 812; https://doi.org/10.3390/pharmaceutics16060812 - 14 Jun 2024

Viewed by 402

Abstract

In this study, we present a new type of polymer-free hydrogel made only from nonionic surfactants, oil, and water. Such a system is produced by taking advantage of the physicochemical behavior and interactions between nonionic surfactants and oil and water phases, according to [...] Read more.

In this study, we present a new type of polymer-free hydrogel made only from nonionic surfactants, oil, and water. Such a system is produced by taking advantage of the physicochemical behavior and interactions between nonionic surfactants and oil and water phases, according to a process close to spontaneous emulsification used in the production of nano-emulsions. Contrary to the classical process of emulsion-based gel formulation, we propose a simple one-step approach. Beyond the originality of the concept, these nanoemulgels appear as very promising systems able to encapsulate and deliver various molecules with different solubilities. In the first section, we propose a comprehensive investigation of the gel formation process and its limits through oscillatory rheological characterization, characterization of the sol/gel transitions, and gel strength. The second section is focused on the follow-up of the release of an encapsulated model hydrophilic molecule and on the impact of the rheological gel properties on the release profiles. Full article

(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Improvement of Drug Bioavailability)

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17 pages, 6751 KiB

Open AccessReview

Development of neffy, an Epinephrine Nasal Spray, for Severe Allergic Reactions

by Anne K. Ellis, Thomas B. Casale, Michael Kaliner, John Oppenheimer, Jonathan M. Spergel, David M. Fleischer, David Bernstein, Carlos A. Camargo, Jr., Richard Lowenthal and Sarina Tanimoto

Pharmaceutics 2024, 16(6), 811; https://doi.org/10.3390/pharmaceutics16060811 - 14 Jun 2024

Viewed by 617

Abstract

Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription fulfillment rates, failure to carry, and failure to use due to fear of needles. Given that delayed administration of [...] Read more.

Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription fulfillment rates, failure to carry, and failure to use due to fear of needles. Given that delayed administration of epinephrine is associated with increased morbidity/mortality, there has been a growing interest in developing needle-free, easy-to-use delivery devices. neffy (epinephrine nasal spray) consists of three Food and Drug Administration (FDA)-approved components: epinephrine, Intravail A3 (absorption enhancer), and a Unit Dose Spray (UDS). neffy’s development pathway was established in conjunction with the FDA and the European Medicines Agency and included multiple clinical trials to evaluate pharmacokinetic and pharmacodynamic responses under a variety of conditions, such as self-administration and allergic and infectious rhinitis, as well as an animal anaphylaxis model of severe hypotension, where neffy demonstrated a pharmacokinetic profile that is within the range of approved injection products and a pharmacodynamic response that is as good or better than injections. The increased pulse rate (PR) and blood pressure (BP) observed even one minute following the administration of neffy confirm the activation of α and β adrenergic receptors, which are the key components of epinephrine’s mechanism of action. The results suggest that neffy will provide a safe and effective needle-free option for the treatment of severe allergic reactions, including anaphylaxis. Full article

(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments, 2nd Edition)

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16 pages, 4622 KiB

Open AccessArticle

The Potential of Dutasteride for Treating Multidrug-Resistant Candida auris Infection

by J. Francis Borgio, Noor B. Almandil, Prathas Selvaraj, J. Sherlin John, Rahaf Alquwaie, Eman AlHasani, Norah F. Alhur, Razan Aldahhan, Reem AlJindan, Dana Almohazey, Sarah Almofty, T. Stalin Dhas and Sayed AbdulAzeez

Pharmaceutics 2024, 16(6), 810; https://doi.org/10.3390/pharmaceutics16060810 - 14 Jun 2024

Viewed by 578

Abstract

Novel antifungal drugs are urgently needed to treat candidiasis caused by the emerging fungal multidrug-resistant pathogen Candida auris. In this study, the most cost-effective drug repurposing technology was adopted to identify an appropriate option among the 1615 clinically approved drugs with anti- [...] Read more.

Novel antifungal drugs are urgently needed to treat candidiasis caused by the emerging fungal multidrug-resistant pathogen Candida auris. In this study, the most cost-effective drug repurposing technology was adopted to identify an appropriate option among the 1615 clinically approved drugs with anti-C. auris activity. High-throughput virtual screening of 1,3-beta-glucanosyltransferase inhibitors was conducted, followed by an analysis of the stability of 1,3-beta-glucanosyltransferase drug complexes and 1,3-beta-glucanosyltransferase–dutasteride metabolite interactions and the confirmation of their activity in biofilm formation and planktonic growth. The analysis identified dutasteride, a drug with no prior antifungal indications, as a potential medication for anti-auris activity in seven clinical C. auris isolates from Saudi Arabian patients. Dutasteride was effective at inhibiting biofilm formation by C. auris while also causing a significant reduction in planktonic growth. Dutasteride treatment resulted in disruption of the cell membrane, the lysis of cells, and crushed surfaces on C. auris, and significant (p-value = 0.0057) shrinkage in the length of C. auris was noted at 100,000×. In conclusion, the use of repurposed dutasteride with anti-C. auris potential can enable rapid recovery in patients with difficult-to-treat candidiasis caused by C. auris and reduce the transmission of nosocomial infection. Full article

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

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Pharmaceutics, Volume 16, Issue 6 (June 2024) – 149 articles

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