European Journal of Pharmaceutical Sciences最新文献_第2页

Clinical efficacy and mechanistic insights of FDA-approved HDAC inhibitors in the treatment of lymphoma

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-03-03 DOI: 10.1016/j.ejps.2025.107057

Nasreddine El Omari , Saad Bakrim , Hamza Elhrech , Tarik Aanniz , Abdelaali Balahbib , Learn-Han Lee , Waleed Al Abdulmonem , Abdelhakim Bouyahya

Lymphomas are complex malignancies of blood cells, characterized by the malignant transformation of lymphocytes. This transformation is partially driven by disruptions in epigenetic regulation, particularly the acetylation of histones. Among the key players in this process are histone deacetylases (HDACs), whose aberrant activity contributes significantly to lymphoma development. Consequently, targeting HDACs represents a promising pharmacotherapeutic approach. Several HDAC inhibitors (HDACis) have demonstrated significant anticancer effects, with four FDA-approved molecules—vorinostat, romidepsin, belinostat, and panobinostat—forming critical components of chemotherapy regimens for lymphoma treatment. These HDAC inhibitors exhibit their therapeutic efficacy through mechanisms that indirectly impact cellular memory and induce cancer cell death via apoptosis and cell cycle arrest. Their clinical effectiveness is particularly notable in various types of lymphomas, underscoring their therapeutic potential.

The objective of this review is to provide a detailed analysis of FDA-approved HDACis, focusing on their molecular mechanisms of action and clinical applications in lymphoma treatment. Specifically, we aim to elucidate how these inhibitors modulate epigenetic regulation to achieve therapeutic efficacy, highlight their utility across different lymphoma subtypes, and examine their integration into combination therapies with other anticancer agents. Furthermore, this review seeks to identify gaps in current knowledge and propose directions for future research, including the development of next-generation HDAC inhibitors and strategies for optimizing their clinical use. By consolidating existing evidence, we strive to enhance the understanding of HDACis' role in lymphoma therapy and inspire advancements in their therapeutic potential.

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引用次数: 0

Dual centrifugation as fast and novel screening approach for optimal RNA loaded lipid-based nanoparticles 双离心法是筛选最佳 RNA 脂基纳米颗粒的快速而新颖的方法。

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-27 DOI: 10.1016/j.ejps.2025.107056

Valentin Bender , Christian Smolka , Franziska Pankratz , Monika Köll-Weber , Ulrich Massing , Regine Süss

The last decade has shown increased benefits for non-viral gene delivery. To overcome the challenges of nucleic acid administration, appropriate drug delivery systems (DDS) are required. The recently approved RNA formulations have demonstrated that lipid nanoparticles (LNPs) are suitable DDS for delivering RNAs. LNPs are commonly composed of cationic and/or ionizable lipids, helper lipids and PEGylated lipids. Conventional manufacturing procedures for LNPs are mixing systems, such as microfluidics, with drawbacks in terms of time and resource consumption. The LNPs produced also pose problems with storage stability. Based on a microRNA (miRNA) model, we present dual centrifugation (DC) as a novel and reproducible way for preparing RNA loaded LNP formulations via in-vial homogenization. Our formulations show promising results in size characteristics, as well as in their cell performance. Depending on the lipid composition of the LNPs, a remarkable knockdown efficiency is achieved. With a net formulation time of 7 min, an enormously fast approach can be presented. DC offers the capability for fast LNP screenings, with a loading capacity of up to 40 vials per run. The simplicity of the method could take advantage of bedside preparation, overcoming the hurdles of storage stability for LNP formulations.

{"title":"Dual centrifugation as fast and novel screening approach for optimal RNA loaded lipid-based nanoparticles","authors":"Valentin Bender , Christian Smolka , Franziska Pankratz , Monika Köll-Weber , Ulrich Massing , Regine Süss","doi":"10.1016/j.ejps.2025.107056","DOIUrl":"10.1016/j.ejps.2025.107056","url":null,"abstract":"<div><div>The last decade has shown increased benefits for non-viral gene delivery. To overcome the challenges of nucleic acid administration, appropriate drug delivery systems (DDS) are required. The recently approved RNA formulations have demonstrated that lipid nanoparticles (LNPs) are suitable DDS for delivering RNAs. LNPs are commonly composed of cationic and/or ionizable lipids, helper lipids and PEGylated lipids. Conventional manufacturing procedures for LNPs are mixing systems, such as microfluidics, with drawbacks in terms of time and resource consumption. The LNPs produced also pose problems with storage stability. Based on a microRNA (miRNA) model, we present dual centrifugation (DC) as a novel and reproducible way for preparing RNA loaded LNP formulations via in-vial homogenization. Our formulations show promising results in size characteristics, as well as in their cell performance. Depending on the lipid composition of the LNPs, a remarkable knockdown efficiency is achieved. With a net formulation time of 7 min, an enormously fast approach can be presented. DC offers the capability for fast LNP screenings, with a loading capacity of up to 40 vials per run. The simplicity of the method could take advantage of bedside preparation, overcoming the hurdles of storage stability for LNP formulations.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"208 ","pages":"Article 107056"},"PeriodicalIF":4.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring the Novel Role and Mechanistic Insights of Skeletal Muscle Relaxant Cyclobenzaprine Hydrochloride in Esophageal Squamous Cell Carcinoma Treatment. 探索骨骼肌松弛剂盐酸环苯扎林在食管鳞状细胞癌治疗中的新作用和机理认识

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-26 DOI: 10.1016/j.ejps.2025.107051

Xiao Liu, Jibing Cheng, Maoju Tang, Chongbo Liao, Yong Yang, Man Luo, Lei Xu, Xiaowu Zhong, Qiang Ma, Xiaolan Guo

Objective: Cyclobenzaprine hydrochloride (Flexeril) is a muscle relaxant primarily used to relieve muscle pain and spasms. However, its potential anti-cancer role remains largely unexplored. This study aims to investigate the inhibitory effect of Flexeril on esophageal squamous cell carcinoma (ESCC) and to uncover the molecular mechanisms through which it affects the proliferation and metastasis of ESCC.

Methods: A compound library approved by the FDA was employed to screen drugs with inhibitory effects on ESCC. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay, and Plate colony formation was analyzed to evaluate the proliferative ability of ESCC cell lines (KYSE150 and Eca109) after treatment with Flexeril. Migratory ability was examined through Transwell and Scratch assays. Proteomics was performed to identify proteins regulated by Flexeril in KYSE150 and Eca109 cells. RT-PCR and Western blot were used to detect changes in related genes at the mRNA and protein levels after treatment with Flexeril. Drug affinity responsive target stability (DARTS) assay and cellular thermal shift assay (CETSA) were employed to identify the binding of Flexeril and JAK1 protein. Additionally, the comet assay was conducted to assess the DNA damage response in ESCC cells following WDHD1 knockdown or Flexeril exposure. Finally, tumor‑bearing nude mice model were constructed to evaluate the in vivo anticancer effects of Flexeril on ESCC.

Results: Flexeril significantly inhibited the proliferation and migration of ESCC cells in a time- and dose-dependent manner. Proteomics analysis identified WDHD1 as a downstream target of Flexeril exposure, and knockdown of WDHD1 mimicked the effects of Flexeril on proliferation and migration of ESCC. Conversely, overexpression of WDHD1 attenuated the inhibitory effects of Flexeril on ESCC. Mechanistically, the JAK1-STAT3 signaling pathway, but not the JAK2-STAT3 or PI3K-Akt-mTOR pathways, was involved in regulating WDHD1 expression in ESCC cells following Flexeril treatment. Overexpression of STAT3 or WDHD1 mitigated the inhibitory effects of Flexeril on ESCC proliferation and migration. Moreover, both Flexeril exposure and WDHD1 knockdown induced a DNA damage response (DDR) in ESCC cells. In addition, Flexeril significantly inhibited the growth of ESCC tumors in nude mice, downregulating the JAK1-STAT3-WDHD1 signaling pathway, with no significant damage observed in vital organs such as the heart, liver, spleen, lungs, or kidneys, as shown by histological examination.

Conclusion: Flexeril exhibits anti-cancer effects in ESCC by inhibiting the JAK1-STAT3-WDHD1 axis and inducing DDR. These findings suggest that Flexeril may serve as a potential novel therapeutic agent for the treatment of ESCC.

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引用次数: 0

NGF regulates survival and differentiation of umbilical mesenchymal stem/stromal cells into GABAergic, dopaminergic and cholinergic lineages

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-24 DOI: 10.1016/j.ejps.2025.107053

Paulina Borkowska , Małgorzata Kowalczyk , Aleksandra Zielińska , Karol Poskrobko , Magdalena B Rother , Monika Paul-Samojedny , Jan Kowalski

Mesenchymal stem cells advantageous properties have led scientists to conduct trials on a range of medical conditions, including incurable neurodegenerative diseases. Wharton-Jelly derived mesenchymal stem cells, given their ease of collection, are frequently selected for these studies. This research aimed to investigate the effects of nerve growth factor (NGF) gene overexpression on the neural differentiation, survivability, and gene and protein expression of these cells. The level of gene expression was tested using the ddPCR method.

Six umbilical cords from donors were collected, and three randomly chosen primary cultures of Wharton-Jelly derived mesenchymal stem cells were used in experiment. Cells were transduced with lentiviral vectors and underwent a 12-day differentiation process.

The results revealed neuron-like cells with significantly high expression of CHAT, GAD2 and TH genes. A corresponding increase in protein expression was also observed. Immunostaining demonstrated notable differences in neuron-like phenotypes, contingent on the environmental conditions of the research groups. Throughout the experiment, samples with transduced mesenchymal stem cells overexpressing the NGF gene showed the highest expression levels from almost all of studied genes and proteins, and were also the most phenotypically similar to neuron-like cells.

The study concluded that sustained overexpression of NGF:

guides mesenchymal stem cells towards the neural pathway,

facilitates the differentiation of modified mesenchymal stem cells into GABAergic, dopaminergic, and cholinergic neuron-like cells,

suggests that GABAergic neurons’ marker predominantly co-expresses with other neurons’ markers, such as cholinergic or dopaminergic ones,

increases survivability of modified mesenchymal stem cells in toxic conditions;

The limitations of the study is that we merely know that cells have begun to express neurogenic markers, but in the absence of standards for mature neuronal markers, we do not yet know how far they have progressed as differentiating cells.

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引用次数: 0

Prediction of surfactant-mediated dissolution of poorly soluble drugs from drug powder

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-24 DOI: 10.1016/j.ejps.2025.107052

Roshni P. Patel, Erik B. Nordquist, James E. Polli

Beyond rough “what if” estimation, in vitro dissolution is infrequently predicted. The objective was to assess the predictability of a powder dissolution model with a single diffusion layer thickness model, where dissolution of various drugs was facilitated by several surfactant micelles. Powder dissolution of three poorly water soluble drugs (i.e., posaconazole, ritonavir, and griseofulvin) was measured into buffer, as well as four surfactant solutions [i.e., sodium lauryl sulfate (SLS), polysorbate 80 (PS80), polyoxyethylene (10) lauryl ether (POE10), and cetyltrimethylammonium bromide (CTAB)]. Drug solubility, micelle sizing, and powder sizing were also performed. Prediction of drug dissolution employed the film dissolution model, applied to spherical drug particle fractions of the percent weight particle size distribution, and with a surfactant-mediated dissolution component. There were two competing models for diffusion layer thickness: fixed thickness (i.e., h_fixed) and radius-dependent thickness (i.e., h_max) models. SLS, PS80, POE10, and CTAB increased the dissolution of posaconazole, ritonavir, and griseofulvin, compared to no-surfactant buffer. Results show that in vitro drug dissolution from various polydisperse powders into several surfactant solutions was successfully predicted using a surfactant-mediated dissolution model. The best diffusion layer thickness for the fixed thickness model and the radius-dependent model were separately found to be h_fixed = 12 µm and h_max = 12 µm, respectively, with h_fixed = 12 µm being the more preferred. Also, the powder dissolution model where powder was parameterized in terms of its entire particle size distribution was successful in predicting observed dissolution profiles using each h_fixed = 12 µm and h_max = 12 µm; model use of a mean particle size was also successful in prediction using h_fixed = 12 µm. Credibility assessment of the in vitro dissolution model was performed, including model verification and validation considerations in light of the question of interest, the context of use, and model risk.

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引用次数: 0

GDNF reduces fibril-induced early-stage alpha-synuclein pathology after delivery of 20S proteasome inhibitor lactacystin

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-21 DOI: 10.1016/j.ejps.2025.107048

Safak Er , Ilmari Parkkinen , Karolina Trepczyk , Anna Seelbach , Maria Samuela Pasculli , Francesca De Lorenzo , Kelvin Luk , Elzbieta Jankowska , Piotr Chmielarz , Andrii Domanskyi , Mikko Airavaara

Failures in protein homeostasis are linked to Parkinson's disease (PD) and other neurodegenerative diseases. Lewy bodies, proteinaceous inclusions rich in phosphorylated alpha-synuclein are a hallmark of PD. Glial cell line-derived neurotrophic factor (GDNF) can eliminate Lewy body-like inclusions in mouse dopamine neurons. This study explores whether GDNF has protective effects against alpha-synuclein protofibril toxicity under proteasome inhibition by lactacystin, both in vitro and in vivo. GDNF did not shield midbrain dopamine neurons from lactacystin-induced neurodegeneration, but still prevented phosphorylated alpha-synuclein accumulation. In vivo experiment with control or GDNF-expressing viral vectors assessed alpha-synuclein pathology spread in the nigrostriatal pathway and lactacystin-caused damage in the midbrain. GDNF overexpression reduced phosphorylated alpha-synuclein inclusions. Lactacystin-treated mice showed motor asymmetry and decreased spontaneous activity, exacerbated without AAV-GDNF pre-treatment. However, GDNF's neuroprotective effect could not be confirmed in vivo, due to side-effects from overexpression in the midbrain. Importantly, these findings show that GDNF continues to eliminate alpha-synuclein aggregation despite lactacystin-induced proteasome inhibition. Activating neurotrophic signaling pathways may protect against alpha-synuclein pathology in PD, even with impaired protein degradation mechanisms.

{"title":"GDNF reduces fibril-induced early-stage alpha-synuclein pathology after delivery of 20S proteasome inhibitor lactacystin","authors":"Safak Er , Ilmari Parkkinen , Karolina Trepczyk , Anna Seelbach , Maria Samuela Pasculli , Francesca De Lorenzo , Kelvin Luk , Elzbieta Jankowska , Piotr Chmielarz , Andrii Domanskyi , Mikko Airavaara","doi":"10.1016/j.ejps.2025.107048","DOIUrl":"10.1016/j.ejps.2025.107048","url":null,"abstract":"<div><div>Failures in protein homeostasis are linked to Parkinson's disease (PD) and other neurodegenerative diseases. Lewy bodies, proteinaceous inclusions rich in phosphorylated alpha-synuclein are a hallmark of PD. Glial cell line-derived neurotrophic factor (GDNF) can eliminate Lewy body-like inclusions in mouse dopamine neurons. This study explores whether GDNF has protective effects against alpha-synuclein protofibril toxicity under proteasome inhibition by lactacystin, both <em>in vitro</em> and <em>in vivo.</em> GDNF did not shield midbrain dopamine neurons from lactacystin-induced neurodegeneration, but still prevented phosphorylated alpha-synuclein accumulation. <em>In vivo</em> experiment with control or GDNF-expressing viral vectors assessed alpha-synuclein pathology spread in the nigrostriatal pathway and lactacystin-caused damage in the midbrain. GDNF overexpression reduced phosphorylated alpha-synuclein inclusions. Lactacystin-treated mice showed motor asymmetry and decreased spontaneous activity, exacerbated without AAV-GDNF pre-treatment. However, GDNF's neuroprotective effect could not be confirmed <em>in vivo</em>, due to side-effects from overexpression in the midbrain. Importantly, these findings show that GDNF continues to eliminate alpha-synuclein aggregation despite lactacystin-induced proteasome inhibition. Activating neurotrophic signaling pathways may protect against alpha-synuclein pathology in PD, even with impaired protein degradation mechanisms.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"208 ","pages":"Article 107048"},"PeriodicalIF":4.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Local delivery of lipid-based nanoparticles containing microbial nucleic acid for osteoimmunomodulation

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-21 DOI: 10.1016/j.ejps.2025.107050

N.R. Rahmani , F. Jahanmard , A. Hassani Najafabadi , J. Flapper , O. Dogan , A. Khodaei , G. Storm , M. Croes , M.C. Kruyt , D. Gawlitta , H. Weinans , E. Mastrobattista , S. Amin Yavari

Osteoimmunomodulation is a strategy to promote bone regeneration in implants by modifying the immune environment. CpG-containing oligonucleotides type C (CpG ODN C) and Polyinosinic:polycytidylic acid (Poly[I:C]) are analogs of microbial nucleic acids that have been studied for various immunotherapeutic applications. This research investigates the potential of CpG ODN C and Poly(I:C) as an osteoimmunomodulatory agent for bone regenerative purposes. We encapsulated each nucleic acid in a lipid-based nanoparticle to facilitate the delivery into intracellular pathogen recognition receptors in immune cells. The lipid-based nanoparticles were ±250 nm in size with a negative charge (−36 to −40 mV) and an encapsulation efficiency of ±60 %. Lipid-based nanoparticles containing nucleic acids, Lip/CpG ODN C and Lip/Poly(I:C), increased the production of TNF, IL-6, and IL-10 by primary human macrophages compared to free-form nucleic acids. Conditioned medium from macrophages treated with CpG ODN C (10 µg/ml) and Lip/CpG ODN C (0.1, 1, and 10 µg/ml) promoted osteoblast differentiation of human mesenchymal stromal cells by 2.6-fold and 3-fold, respectively; no effect was seen for Lip/Poly(I:C). Bone implants were prepared, consisting of a biphasic calcium phosphate scaffold, bone morphogenetic protein (BMP) 2, and lipid-based nanoparticles suspended in gelatin methacryloyl (GelMA) hydrogel. Implants were evaluated for de novo bone formation in an extra-skeletal implantation model in rabbits for 5 weeks. Based on the particles suspended in GelMA, six groups of implants were prepared: Lip/CpG ODN C, Lip/Poly(I:C), Lip (empty), CpG ODN C, Poly(I:C), and a control group consisting of empty GelMA. After 5 weeks, healthy bone tissue formed in all of the implants with active osteoblast and osteoclast activity, however, the amount of new bone volume and scaffold degradation were similar for all implants. We suggest that the working concentrations of the nucleic acids employed were inadequate to induce a relevant inflammatory response. Additionally, the dosage of BMP-2 used may potentially mask the immune-stimulatory effect. Lip/CpG ODN C holds potential as a bioactive agent for osteoimmunomodulation, although further in vivo demonstration should corroborate the current in vitro findings.

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引用次数: 0

Enhancing the photothermal properties of indocyanine green in melanoma spheroids via encapsulation in Span 80-containing lipid nanocapsules

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-21 DOI: 10.1016/j.ejps.2025.107049

Siyang Wu , Taher Hatahet , Wafa' T. Al-Jamal

Indocyanine green (ICG), a well-known photosensitiser, has shown potential in photothermal therapy (PTT) for cancer treatment, but its effectiveness is limited by poor skin penetration and rapid clearance. To address this, lipid nanocapsules (LNCs) were used as nanocarriers to enhance ICG's cellular uptake and photothermal (PT) performance in melanoma cells. Utilising our recently developed Span 80-modified LNCs (LNC100-S8) with high biocompatibility and enhanced cellular uptake in B16F10 melanoma cells, ICG was loaded into LNC100-S8 using the phase inversion temperature method. The results showed that ICG encapsulation at 4.5 mg/mL maintained small LNC sizes (95–105 nm). Moreover, the heating capacity of ICG in LNCs was approximately 1.5 times higher than free ICG, achieving temperature increases over 10 °C post-irradiation. In cell cancer monolayers, LNC100-S8 enhanced ICG uptake by 1.5 times compared to free ICG and reduced cell viability to 50 % following 808 nm laser irradiation. More promisingly, ICG-LNC100-S8 combined with laser irradiation significantly reduced three-dimensional B16F10 spheroids size up to 11 days post-treatment compared to free ICG. Overall, our findings validate LNC100-S8, as promising nanocarriers for enhancing ICG-based PTT, supporting their potential applications in vivo to treat melanoma and other skin cancers.

吲哚菁绿（ICG）是一种著名的光敏剂，在癌症治疗的光热疗法（PTT）中已显示出潜力，但其有效性受到皮肤渗透性差和清除速度快的限制。为了解决这个问题，我们使用脂质纳米胶囊（LNCs）作为纳米载体来提高ICG在黑色素瘤细胞中的细胞吸收和光热（PT）性能。我们最近开发的Span 80改性LNC（LNC100-S8）具有很高的生物相容性，能增强B16F10黑色素瘤细胞对ICG的吸收。结果表明，4.5 毫克/毫升的 ICG 封装可保持 LNC 的尺寸（95-105 纳米）。此外，LNCs 中 ICG 的加热能力约为游离 ICG 的 1.5 倍，辐照后温度可升高 10°C 以上。在细胞癌单层中，与游离 ICG 相比，LNC100-S8 对 ICG 的吸收能力提高了 1.5 倍，在 808 纳米激光照射后，细胞存活率降低了 50%。更有希望的是，与游离 ICG 相比，ICG-LNC100-S8 与激光照射相结合可显著减少三维 B16F10 球形体的大小，处理后可维持 11 天。总之，我们的研究结果验证了 LNC100-S8 是增强基于 ICG 的 PTT 的有前途的纳米载体，支持其在体内治疗黑色素瘤和其他皮肤癌的潜在应用。

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引用次数: 0

Cancer-type OATP1B3-V1 is a functional plasma membrane transporter mediating increased uptake of chemotherapeutics in vitro and in vivo.

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.ejps.2025.107046

Éva Bakos, Virág Bujdosó-Székely, Izabel Patik, Laura Király, Tamás Langó, Eszter Kozák, Mihály Cserepes, József Tóvári, Csilla Özvegy-Laczka

Cancer-type Organic anion transporting polypeptide 1B3, ct-OATP1B3-V1 is a tumor-specific isoform of liver-type OATP1B3 (Lt-OATP1B3). Ct-OATP1B3-V1 is identical with liver-specific Lt-OATP1B3 except it lacks the first 28 amino acids. Although there is a growing interest in using this isoform as a biomarker for colorectal cancer, available data regarding cellular localization and function of ct-OATP1B3-V1 remains controversial. The main objective of our study was to clarify the localization and function of ct-OATP1B3-V1 in vitro and in vivo, and to investigate its role in chemotherapy sensitivity. For this aim, A431 and HCT-8 carcinoma cell lines overexpressing ct-OATP1B3-V1 were generated. With the help of these cell lines, localization and activity of ct-OATP1B3-V1 as well as its effect on chemotherapy sensitivity was examined both in vitro and in vivo. We found that ct-OATP1B3-V1 is a functional plasma membrane transporter that sensitizes the cells toward various chemotherapeutics, including docetaxel, oxaliplatin and capecitabine metabolites in vitro. Increased sensitivity to docetaxel and capecitabine of ct-OATP1B3-V1 expressing cells was also confirmed in in vivo experiments performed on A431-V1 derived xenografts. However, due to the apparent proliferative advantage of V1-expressing xenografts over the mock-transfected control, they could not be completely eradicated by either docetaxel or capecitabine treatment. Our results demonstrate that while ct-OATP1B3-V1 can be exploited to inhibit tumor growth, this strategy alone is likely insufficient for complete tumor elimination, possibly due to the more complex in vivo functions of ct-OATP1B3-V1.

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引用次数: 0

A physiologically based biopharmaceutics modeling (PBBM) framework for characterizing formulation-dependent food effects: paving the road towards fed virtual BE studies for itraconazole amorphous solid dispersions.

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.ejps.2025.107047

Niklas Rudolph, Nitin Charbe, David Plano, Abdullah Al Shoyaib, Arindom Pal, Heather Boyce, Liang Zhao, Fang Wu, James Polli, Jennifer Dressman, Rodrigo Cristofoletti

This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected to extensive in vitro biopharmaceutical testing, including solubility studies and dissolution tests under fasted and fed state conditions, revealing significant differences in dissolution behaviors between Sempera® and Tolsura®. The impact of food and hypochlorhydria on drug absorption was evaluated using a stepwise mechanistic deconvolution-reconvolution PBBM approach, integrating fundamental parameters based on the in vitro data into the final model. Our model not only successfully predicted the effects of acid reducing agents (ARA) and food on the oral absorption of ITRA, but also captured the between-subject variability, demonstrating the utility of this approach in understanding the complex interplay between drug, formulation, and gastrointestinal environment. Most importantly, the PBBM was able to accurately predict the positive impact of food on the absorption of Sempera® and the negative food effect of Tolsura®. The findings highlight the importance of considering formulation characteristics and gastrointestinal physiology, underscoring the potential of PBBM in bioequivalence (BE) assessment of generic formulations under varying physiological conditions, including in the fed state and in hypochlorhydric patients. The successful application of this stepwise and mechanistic PBBM approach suggests a potential pathway for streamlining drug development and may contribute to more informed decision-making for BE assessment.

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引用次数: 0