Development, characterization, and in vitro evaluation of poly(ethylene oxide)-block-poly(ε-caprolactone)-α-tocopheryl succinate micelles as a novel nanocarrier for rapamycin delivery
Ziyad Binkhathlan , Abdullah K. Alshememry , Ahmad M. Balkhair , Raisuddin Ali , Sulaiman S. Alhudaithi , Saad Alobid , Wajhul Qamar , Alhassan H. Aodah , Mohammad Reza Vakili , Afsaneh Lavasanifar
{"title":"Development, characterization, and in vitro evaluation of poly(ethylene oxide)-block-poly(ε-caprolactone)-α-tocopheryl succinate micelles as a novel nanocarrier for rapamycin delivery","authors":"Ziyad Binkhathlan , Abdullah K. Alshememry , Ahmad M. Balkhair , Raisuddin Ali , Sulaiman S. Alhudaithi , Saad Alobid , Wajhul Qamar , Alhassan H. Aodah , Mohammad Reza Vakili , Afsaneh Lavasanifar","doi":"10.1016/j.ijpx.2025.100341","DOIUrl":null,"url":null,"abstract":"<div><div>Rapamycin holds significant therapeutic potential for various diseases; however, its clinical application is limited by several formulation challenges, primarily its extremely low aqueous solubility (2.6 μg/mL). To address this, nanoparticle-based delivery systems have emerged as a promising strategy to enhance solubility and enable sustained drug release. Currently, Fyarro® (Aadi Bioscience, Inc.), an albumin-bound nanoparticle formulation, is the only FDA-approved injectable rapamycin product. In this study, we aimed to develop and evaluate novel poly(ethylene oxide)-<em>block</em>-poly(ε-caprolactone)-α-tocopheryl succinate (PEO-<em>b</em>-PCL-α-TS) micelles and assess their potential as a delivery system for rapamycin. PEO-<em>b</em>-PCL copolymers with varying PCL/PEO ratios were prepared <em>via</em> ring-opening polymerization and modified by α-TS conjugation, as confirmed by <sup>1</sup>H NMR, GPC, XRD, DSC analyses. The optimum rapamycin-loaded micelles (PEO<sub>2000</sub>-<em>b</em>-PCL<sub>4000</sub>-α-TS) exhibited nano-sized particles (< 22 nm) with a narrow polydispersity index (<0.29), high drug encapsulation efficiency (≥92 %), and enhanced solubility (>1.3 mg/mL). Stability studies demonstrated that encapsulation protected rapamycin from degradation, maintaining over 90 % drug retention for three months at 4 °C, while <em>in vitro</em> release studies showed sustained release, with 50 % of rapamycin released from PEO<sub>2000</sub>-<em>b</em>-PCL<sub>4000</sub>-α-TS micelles over 72 h. <em>In vitro</em> cytotoxicity assays revealed anticancer activity against lung carcinoma epithelial cells (A549), and the human colon adenocarcinoma cell line (HCT116). Minimal toxicity (≥70 % viability) was observed in normal human fibroblast cells (HFF1). These results point to the potential of PEO-<em>b</em>-PCL-α-TS micelles as a promising nanocarrier system, offering improved rapamycin solubility, enhanced stability, sustained release, and effective anticancer activity.</div></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":"9 ","pages":"Article 100341"},"PeriodicalIF":5.2000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Pharmaceutics: X","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S259015672500026X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Rapamycin holds significant therapeutic potential for various diseases; however, its clinical application is limited by several formulation challenges, primarily its extremely low aqueous solubility (2.6 μg/mL). To address this, nanoparticle-based delivery systems have emerged as a promising strategy to enhance solubility and enable sustained drug release. Currently, Fyarro® (Aadi Bioscience, Inc.), an albumin-bound nanoparticle formulation, is the only FDA-approved injectable rapamycin product. In this study, we aimed to develop and evaluate novel poly(ethylene oxide)-block-poly(ε-caprolactone)-α-tocopheryl succinate (PEO-b-PCL-α-TS) micelles and assess their potential as a delivery system for rapamycin. PEO-b-PCL copolymers with varying PCL/PEO ratios were prepared via ring-opening polymerization and modified by α-TS conjugation, as confirmed by 1H NMR, GPC, XRD, DSC analyses. The optimum rapamycin-loaded micelles (PEO2000-b-PCL4000-α-TS) exhibited nano-sized particles (< 22 nm) with a narrow polydispersity index (<0.29), high drug encapsulation efficiency (≥92 %), and enhanced solubility (>1.3 mg/mL). Stability studies demonstrated that encapsulation protected rapamycin from degradation, maintaining over 90 % drug retention for three months at 4 °C, while in vitro release studies showed sustained release, with 50 % of rapamycin released from PEO2000-b-PCL4000-α-TS micelles over 72 h. In vitro cytotoxicity assays revealed anticancer activity against lung carcinoma epithelial cells (A549), and the human colon adenocarcinoma cell line (HCT116). Minimal toxicity (≥70 % viability) was observed in normal human fibroblast cells (HFF1). These results point to the potential of PEO-b-PCL-α-TS micelles as a promising nanocarrier system, offering improved rapamycin solubility, enhanced stability, sustained release, and effective anticancer activity.
期刊介绍:
International Journal of Pharmaceutics: X offers authors with high-quality research who want to publish in a gold open access journal the opportunity to make their work immediately, permanently, and freely accessible.
International Journal of Pharmaceutics: X authors will pay an article publishing charge (APC), have a choice of license options, and retain copyright. Please check the APC here. The journal is indexed in SCOPUS, PUBMED, PMC and DOAJ.
The International Journal of Pharmaceutics is the second most cited journal in the "Pharmacy & Pharmacology" category out of 358 journals, being the true home for pharmaceutical scientists concerned with the physical, chemical and biological properties of devices and delivery systems for drugs, vaccines and biologicals, including their design, manufacture and evaluation. This includes evaluation of the properties of drugs, excipients such as surfactants and polymers and novel materials. The journal has special sections on pharmaceutical nanotechnology and personalized medicines, and publishes research papers, reviews, commentaries and letters to the editor as well as special issues.