{"title":"Physiologically based in vitro – in vivo correlation of modified release oral formulations with non-linear intestinal absorption: A case study using mirabegron","authors":"Yoshinori Takahashi, Atsushi Kambayashi","doi":"10.1016/j.ejpb.2024.114479","DOIUrl":"10.1016/j.ejpb.2024.114479","url":null,"abstract":"<div><p>Establishing an <em>in vitro</em> – <em>in vivo</em> correlation (IVIVC) for oral modified release (MR) formulations would make it possible to substitute an <em>in vitro</em> dissolution test for human bioequivalence (BE) studies when changing the formulation or manufacturing methods. However, the number of IVIVC applications and approvals are reportedly low. One of the main reasons for failure to obtain IVIVCs using conventional methodologies may be the lack of consideration of the dissolution and absorption mechanisms of drugs in the physiological environment. In particular, it is difficult to obtain IVIVC using conventional methodologies for drugs with non-linear absorption processes. Therefore, the aim of the present study was to develop a physiologically based biopharmaceutics model (PBBM) that enables Level A IVIVCs for mirabegron MR formulations with non-linear absorption characteristics.</p><p>Using human pharmacokinetic (PK) data for immediate-release formulations of mirabegron, the luminal drug concentration-dependent membrane permeation coefficient was calculated through curve fitting. The membrane permeation coefficient data were then applied to the human PK data of the MR formulations to estimate the <em>in vivo</em> dissolution rate by curve fitting. It was assumed that <em>in vivo</em> dissolution could be described using a zero-order rate equation. Furthermore, a Levy plot was generated using the estimated <em>in vivo</em> dissolution rate and the <em>in vitro</em> dissolution rate obtained from the literature. Finally, the dissolution rate of the MR formulations from the Levy plot was applied to the PBBM to predict the oral PK of the mirabegron MR formulations.</p><p>This PB-IVIVC approach successfully generated linear Levy plots with slopes of almost 1.0 for MR formulations with different dose strengths and dissolution rates. The Cmax values of the MR formulations were accurately predicted using this approach, whereas the prediction errors for AUC exceeded the Level A IVIVC criteria. This can be attributed to the incomplete description of colonic absorption in the current PBBM.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114479"},"PeriodicalIF":4.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124003059/pdfft?md5=a5f2185c9c11d839d13a2add72eed60f&pid=1-s2.0-S0939641124003059-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sunil Kumar Sah , Kamare Alam , Mamta Kumari , R. Malootty , Subham Nath , Velayutham Ravichandiran , Subhadeep Roy , Santanu Kaity
{"title":"A 3D in-vitro biomimicking Caco-2 intestinal permeability model-based assessment of physically modified telmisartan towards an alkalizer-free formulation development","authors":"Sunil Kumar Sah , Kamare Alam , Mamta Kumari , R. Malootty , Subham Nath , Velayutham Ravichandiran , Subhadeep Roy , Santanu Kaity","doi":"10.1016/j.ejpb.2024.114480","DOIUrl":"10.1016/j.ejpb.2024.114480","url":null,"abstract":"<div><p>Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D <em>in-vitro</em> Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114480"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bjarke Strøm Larsen , Peter Meiland , Eidan Tzdaka , Ingunn Tho , Thomas Rades
{"title":"A unifying approach to drug-in-polymer solubility prediction: Streamlining experimental workflow and analysis","authors":"Bjarke Strøm Larsen , Peter Meiland , Eidan Tzdaka , Ingunn Tho , Thomas Rades","doi":"10.1016/j.ejpb.2024.114478","DOIUrl":"10.1016/j.ejpb.2024.114478","url":null,"abstract":"<div><p>This method paper describes currently used experimental methods to predict the drug-in-polymer solubility of amorphous solid dispersions and offers a combined approach for applying the <em>Melting-point-depression method</em>, the <em>Recrystallization method</em>, and the <em>Melting-and-mixing method</em>. It aims to describe and expand on the theoretical basis as well as the analytical methodology of the recently published <em>Melting-and-mixing method</em>. This solubility method relies on determining the relationship between drug loads and the enthalpy of melting and mixing of a crystalline drug in the presence of an amorphous polymer. This relationship is used to determine the soluble drug load of an amorphous solid dispersion from the recorded enthalpy of melting and mixing of the crystalline drug portion in a drug-polymer sample at equilibrium solubility. Due to the complex analytical methodology of the <em>Melting-and-mixing method</em>, a software solution called the <em>Glass Solution Companion app</em> was developed. Using this new tool, it is possible to calculate the predicted drug-in-polymer solubility and Flory-Huggins interaction parameter from experimental samples, as well as to generate the resulting solubility-temperature curve. This software can be used for calculations for all three experimental methods, which would be useful for comparing the applicability of the methods on a given drug-polymer system. Since it is difficult to predict the suitability of these drug-in-polymer solubility methods for a specific drug-polymer system <em>in silico</em>, some experimental investigation is necessary. By optimizing the experimental protocol, it is possible to collect data for the three experimental methods simultaneously for a specific drug-polymer system. These results can then be readily analyzed using the <em>Glass Solution Companion app</em> to find the most appropriate method for the drug-polymer system, and therefore, the most reliable drug-in-polymer solubility prediction.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114478"},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124003047/pdfft?md5=0dc41c456466d07409605e53503dbc86&pid=1-s2.0-S0939641124003047-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leonor Cunha Silva , Francisco Branco , Joana Cunha , Carla Vitorino , Célia Gomes , Mylène A. Carrascal , Amílcar Falcão , Bruno Miguel Neves , Maria Teresa Cruz
{"title":"The potential of exosomes as a new therapeutic strategy for glioblastoma","authors":"Leonor Cunha Silva , Francisco Branco , Joana Cunha , Carla Vitorino , Célia Gomes , Mylène A. Carrascal , Amílcar Falcão , Bruno Miguel Neves , Maria Teresa Cruz","doi":"10.1016/j.ejpb.2024.114460","DOIUrl":"10.1016/j.ejpb.2024.114460","url":null,"abstract":"<div><p>Glioblastoma (GBM) stands for the most common and aggressive type of brain tumour in adults. It is highly invasive, which explains its short rate of survival. Little is known about its risk factors, and current therapy is still ineffective. Hence, efforts are underway to develop novel and effective treatment approaches against this type of cancer.</p><p>Exosomes are being explored as a promising strategy for conveying and delivering therapeutic cargo to GBM cells. They can fuse with the GBM cell membrane and, consequently, serve as delivery systems in this context. Due to their nanoscale size, exosomes can cross the blood–brain barrier (BBB), which constitutes a significant hurdle to most chemotherapeutic drugs used against GBM. They can subsequently inhibit oncogenes, activate tumour suppressor genes, induce immune responses, and control cell growth.</p><p>However, despite representing a promising tool for the treatment of GBM, further research and clinical studies regarding exosome biology, engineering, and clinical applications still need to be completed.</p><p>Here, we sought to review the application of exosomes in the treatment of GBM through an in-depth analysis of the scientific and clinical studies on the entire process, from the isolation and purification of exosomes to their design and transformation into anti-oncogenic drug delivery systems. Surface modification of exosomes to enhance BBB penetration and GBM-cell targeting is also a topic of discussion.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114460"},"PeriodicalIF":4.4,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002868/pdfft?md5=f552ae56077815d7d8c8af4dac354329&pid=1-s2.0-S0939641124002868-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lan-Chi Hsieh , Thai-Khuong Le , Fang-Ci Hu , Ya-Ting Chen , Shuchen Hsieh , Chih-Chung Wu , Shu-Ling Hsieh
{"title":"Targeted colorectal cancer treatment: In vitro anti-cancer effects of carnosine nanoparticles supported by agar and magnetic iron oxide","authors":"Lan-Chi Hsieh , Thai-Khuong Le , Fang-Ci Hu , Ya-Ting Chen , Shuchen Hsieh , Chih-Chung Wu , Shu-Ling Hsieh","doi":"10.1016/j.ejpb.2024.114477","DOIUrl":"10.1016/j.ejpb.2024.114477","url":null,"abstract":"<div><p>The usage of peptides in the colorectal cancer (CRC) treatment promises to be a new anti-cancer therapy with improved treatment efficacy. Carnosine, a natural dipeptide molecule, has been demonstrated to be a potential anti-cancer drug. Nonetheless, it shows an exhibition of high-water solubility and is quickly degraded by carnosinase. Meanwhile, agar and magnetic iron oxide are the most used materials for drug delivery due to some of their advantages such as the low cost and the larger biocompatibility feature. The purpose of this study was to investigate the anti-cancer ability of agar-encapsulated carnosine nanoparticles (AgCa-NPs) and agar-encapsulated carnosine nanoparticles-coated magnetic iron oxide nanoparticles (AgCaN-MNPs) in human CRC cells, HCT-116. We evaluated the effects of AgCa-NPs and AgCaN-MNPs with a variety of concentrations (0, 5, 10, 15, 30, 40, or 50 mM) on HCT-116 cells after 72 h and 96 h by using MTT assay and observation cell morphology. We then analyzed the cell cycle progression and assessed the expression changes of genes related to apoptosis, autophagy, necroptosis, and angiogenesis after treatment for 96 h. The results showed that AgCa-NPs and AgCaN-MNPs <em>in vitro</em> study decreased HCT-116 cells viability. This effect was attributed to arrest of cell cycle, induction of programmed cell death, and suppression of angiogenesis by AgCa-NPs and AgCaN-MNPs. These findings revealed the antitumor efficacy of AgCa-NPs or AgCaN-MNPs for CRC treatment.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114477"},"PeriodicalIF":4.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142097990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xin Chen , Yirui Qin , Lijun Wang , Yujing Zhu , Hailu Zhang , Wenhu Liu , Mei Zeng , Qian Dai
{"title":"Co-amorphous systems of sulfasalazine with matrine-type alkaloids: Enhanced solubility behaviors and synergistic therapeutic potential","authors":"Xin Chen , Yirui Qin , Lijun Wang , Yujing Zhu , Hailu Zhang , Wenhu Liu , Mei Zeng , Qian Dai","doi":"10.1016/j.ejpb.2024.114475","DOIUrl":"10.1016/j.ejpb.2024.114475","url":null,"abstract":"<div><p>Sulfasalazine (SULF), a sulfonamide antibiotic, has been utilized in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) since its discovery. However, its poor water solubility causes the high daily doses (1–––3 g) for patients, which may lead to the intolerable toxic and side effects for their lifelong treatment for RA and IBD. In this work, two water-soluble natural anti-inflammatory alkaloids, matrine (MAR) and sophoridine (SPD), were employed to construct the co-amorphous systems of SULF for addressing its solubility issue. These newly obtained co-amorphous forms of SULF were comprehensively characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). We also investigated their dissolution behavior, including powder dissolution, in vitro release, and intrinsic dissolution rate. Both co-amorphous systems exhibited superior dissolution performance compared to crystalline SULF. The underlying mechanism responsible for the enhanced dissolution behaviors in co-amorphous systems were also elucidated. These mechanisms include the inhibition of nucleation, complexation, increased hydrophilicity, and robust intermolecular interactions in aqueous solutions. Importantly, these co-amorphous systems demonstrated satisfactory physical stability under various storage conditions. Network pharmacological analysis was utilized to investigate the potential therapeutic targets of both co-amorphous systems against RA, revealing similar yet distinct multi-target synergistic therapeutic mechanisms in the treatment of this condition. Our study suggests these drug-drug co-amorphous systems hold promise for optimizing SULF dosage in the future and providing a potential drug combination strategy.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114475"},"PeriodicalIF":4.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142097991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Manuel R. Pouso , Bruna L. Melo , Joaquim J. Gonçalves , António G. Mendonça , Ilídio J. Correia , Duarte de Melo-Diogo
{"title":"Development of dual-crosslinked Pluronic F127/Chitosan injectable hydrogels incorporating graphene nanosystems for breast cancer photothermal therapy and antibacterial applications","authors":"Manuel R. Pouso , Bruna L. Melo , Joaquim J. Gonçalves , António G. Mendonça , Ilídio J. Correia , Duarte de Melo-Diogo","doi":"10.1016/j.ejpb.2024.114476","DOIUrl":"10.1016/j.ejpb.2024.114476","url":null,"abstract":"<div><p>Nanomaterials with responsiveness to near-infrared light can mediate the photoablation of cancer cells with an exceptional spatio-temporal resolution. However, the therapeutic outcome of this modality is limited by the nanostructures’ poor tumor uptake. To address this bottleneck, it is appealing to develop injectable <em>in situ</em> forming hydrogels due to their capacity to perform a tumor-confined delivery of the nanomaterials with minimal off-target leakage. In particular, injectable <em>in situ</em> forming hydrogels based on Pluronic F127 have been emerging due to their FDA-approval status, biocompatibility, and thermosensitive sol–gel transition. Nevertheless, the application of Pluronic F127 hydrogels has been limited due to their fast dissociation in aqueous media. Such limitation may be addressed by combining the thermoresponsive sol–gel transition of Pluronic F127 with other polymers with crosslinking capabilities. In this work, a novel dual-crosslinked injectable <em>in situ</em> forming hydrogel based on Pluronic F127 (thermosensitive gelation) and Chitosan (ionotropic gelation in the presence of NaHCO<sub>3</sub>), loaded with Dopamine-reduced graphene oxide (DOPA-rGO; photothermal nanoagent), was developed for application in breast cancer photothermal therapy. The dual-crosslinked hydrogel incorporating DOPA-rGO showed a good injectability (through 21 G needles), <em>in situ</em> gelation capacity and cytocompatibility (viability > 73 %). As importantly, the dual-crosslinking improved the hydrogel’s porosity and prevented its premature degradation. After irradiation with near-infrared light, the dual-crosslinked hydrogel incorporating DOPA-rGO produced a photothermal heating (ΔT ≈ 22 °C) that reduced the breast cancer cells’ viability to just 32 %. In addition, this formulation also demonstrated a good antibacterial activity by reducing the viability of <em>S. aureus</em> and <em>E. coli</em> to 24 and 33 %, respectively. Overall, the dual-crosslinked hydrogel incorporating DOPA-rGO is a promising macroscale technology for breast cancer photothermal therapy and antimicrobial applications.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114476"},"PeriodicalIF":4.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124003023/pdfft?md5=3c7ef09ecce1b31c9422cd4539e90de7&pid=1-s2.0-S0939641124003023-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gabriel Teixeira , Paula Brandão , Ana I.M.C. Lobo Ferreira , Dinis O. Abranches , Luís M.N.B.F. Santos , Olga Ferreira , João A.P. Coutinho
{"title":"Designing type V deep eutectic solvents with antimalarial pharmaceutical ingredients","authors":"Gabriel Teixeira , Paula Brandão , Ana I.M.C. Lobo Ferreira , Dinis O. Abranches , Luís M.N.B.F. Santos , Olga Ferreira , João A.P. Coutinho","doi":"10.1016/j.ejpb.2024.114463","DOIUrl":"10.1016/j.ejpb.2024.114463","url":null,"abstract":"<div><p>This work studies the formation of deep eutectic solvents formed by one active pharmaceutical ingredient (quinine, pyrimethamine, or 2-phenylimidazopyridine) and a second component potentially acting as an excipient (betaine, choline chloride, tetramethylammonium chloride, thymol, menthol, gallic acid, vanillin, acetovanillone, 4-hydroxybenzaldehyde, syringaldehyde, propyl gallate, propylparaben, or butylated hydroxyanisole), aiming to address challenges regarding drug solubility, bioavailability, and permeability. A preliminary screening was carried out using the thermodynamic model COSMO-RS, narrowing down the search to three promising excipients (thymol, propyl gallate, and butylated hydroxyanisole). Nine solid–liquid equilibrium (SLE) phase diagrams were experimentally measured combining the three model drugs with the screened excipients, and using a combination of a visual melting method and differential scanning calorimetry. Negative deviations from thermodynamic ideality were observed in all nine systems. Furthermore, a total of four new cocrystals were found, with powder and single crystal X-ray diffraction techniques being employed to verify their unique diffraction patterns. In the thermodynamic modelling of the SLE diagrams, two COSMO-RS parametrizations (TZVP and TZVPD-FINE) were also applied, though neither consistently delivered a better description over the other.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114463"},"PeriodicalIF":4.4,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002893/pdfft?md5=28089df7203b8cfb55029c414e4254e0&pid=1-s2.0-S0939641124002893-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prisca Hamm , Denise Beckmann , Rafael Worschech , Alexandra Braun , Marcus Gutmann , Adelheid Korb-Pap , Tessa Lühmann , Thomas Pap , Lorenz Meinel
{"title":"Transglutaminase-catalyzed covalent","authors":"Prisca Hamm , Denise Beckmann , Rafael Worschech , Alexandra Braun , Marcus Gutmann , Adelheid Korb-Pap , Tessa Lühmann , Thomas Pap , Lorenz Meinel","doi":"10.1016/j.ejpb.2024.114462","DOIUrl":"10.1016/j.ejpb.2024.114462","url":null,"abstract":"<div><p>Nature realizes protein and peptide depots by catalyzing covalent bonds with the <strong>e</strong>xtra<strong>c</strong>ellular <strong>m</strong>atrix (ECM) of tissues. We are translating this natural blueprint for the sustained delivery of a myostatin-inhibiting peptide (Anti-Myo), resulting in an enzyme depot established from injectable solutions. For that, we fused Anti-Myo to the D-domain of insulin-like growth factor I, a <strong>t</strong>rans<strong>g</strong>lutaminase (TG) substrate. TG catalyzed the covalent binding of the D-domain to ECM proteins, such as laminin and fibronectin, on bioengineered ECM and in mice. ECM decorated with Anti-Myo suppressed myostatin activity and pathway activation and reduced the differentiation of preconditioned bone marrow-derived macrophages into osteoclasts in vitro.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114462"},"PeriodicalIF":4.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002881/pdfft?md5=2d348b334f8e48d4c0bb55a457cbc3b5&pid=1-s2.0-S0939641124002881-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Homeyra Seydi , Kosar Nouri , Bahare Shokouhian , Abbas Piryaei , Moustapha Hassan , Marco Cordani , Ali Zarrabi , Faezeh Shekari , Massoud Vosough
{"title":"MiR-29a-laden extracellular vesicles efficiently induced apoptosis through autophagy blockage in HCC cells","authors":"Homeyra Seydi , Kosar Nouri , Bahare Shokouhian , Abbas Piryaei , Moustapha Hassan , Marco Cordani , Ali Zarrabi , Faezeh Shekari , Massoud Vosough","doi":"10.1016/j.ejpb.2024.114470","DOIUrl":"10.1016/j.ejpb.2024.114470","url":null,"abstract":"<div><h3>Background</h3><p>In spite of significant advancements in theraputic modalities for hepatocellular carcinoma (HCC), there is still a high annual mortality rate with a rising incidence. Major challenges in the HCC clinical managment are related to the development of therapy resistance, and evasion of tumor cells apoptosis which leading unsatisfactory outcomes in HCC patients. Previous investigations have shown that autophagy plays crucial role in contributing to drug resistance development in HCC. Although, miR-29a is known to counteract authophagy, increasing evidence revealed a down-regulation of miR-29a in HCC patients which correlates with poor prognosis. Beside, evidences showed that miR-29a serves as a negative regulator of autophagy in other cancers. In the current study, we aim to investigate the impact of miR-29a on the autophagy and apoptosis in HCC cells using extracellular vesicles (EVs) as a natural delivery system given their potential in the miRNA delivery both <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Method</h3><p>Human Wharton’s Jelly mesenchymal stromal cell-derived extracellular vesicles were lately isolated through 20,000 or 110,000 × g centrifugation (EV20K or EV110K, respectively), characterized by western blot (WB), scanning electron microscopy (SEM), and dynamic light scattering (DLS). miR-29a was subsequently loaded into these EVs and its loading efficiency was evaluated <em>via</em> RT-qPCR. Comprehensive <em>in vitro</em> and <em>in vivo</em> assessments were then performed on Huh-7 and HepG2 cell lines.</p></div><div><h3>Results</h3><p>EV20K-miR-29a treatment significantly induces cell apoptosis and reduces both cell proliferation and colony formation in Huh-7 and HepG2 cell lines. In addition, LC3-II/LC3-I ratio was increased while the expression of key autophagy regulators <em>TFEB</em> and <em>ATG9A</em> were downregulated by this treatment. These findings suggest an effective blockade of autophagy by EV20K-miR-29a leading to apoptosis in the HCC cell lines through concomitant targeting of critical mediators within each pathway.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"203 ","pages":"Article 114470"},"PeriodicalIF":4.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}