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使用靶向紫杉醇前药开发谷胱甘肽刺激响应性胶束以增强抗癌效果。

Development of GSH-Stimuli-Responsive Micelles Using a Targeted Paclitaxel Prodrug for Enhanced Anticancer Effect.

作者信息

Ning Qian, Yu Guangping, Yi Wenkai, Gu Minhui, Xu Qianqian, Ye Zhiting, Zhang Mengxia, Tang Shengsong

机构信息

College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410127, China.

Hunan Province Key Laboratory for Antibody-Based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua 418000, China.

出版信息

Pharmaceutics. 2025 Apr 21;17(4):538. doi: 10.3390/pharmaceutics17040538.

DOI:10.3390/pharmaceutics17040538
PMID:40284532
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12030733/
Abstract

Cancer ranks as a leading cause of death worldwide. It is urgent to develop intelligent co-delivery systems for cancer chemotherapy to achieve reduced side-effects and enhanced therapeutic efficacy. We chose oligo-hyaluronic acid (oHA, a low molecular weight of HA) as the carrier, and adriamycin (ADM) and paclitaxel (PTX) as the co-delivered drugs. The oHA-ss-PTX macromolecular prodrug was synthesized by introducing glutathione-stimuli-responsive disulfide bonds through chemical reactions. Then, we constructed ADM-loading micelles (ADM/oHA-ss-PTX) in one step by microfluidic preparation. The delivery efficacy was evaluated comprehensively in vitro and in vivo. The biocompatibility of ADM/oHA-ss-PTX was assessed by hemolysis activity analysis, BSA adsorption testing, and cell viability assay in endothelial cells. The resulting ADM/oHA-ss-PTX micelles possessed a dynamic size (127 ± 1.4 nm, zeta potential -9.0 mV), a high drug loading content of approximately 21.2% (PTX) and 7.6% (ADM). Compared with free ADM+PTX, ADM/oHA-ss-PTX showed enhanced blood stability and more efficiently inhibited cancer cell proliferation. Moreover, due to the CD44-mediated endocytosis pathway, a greater number of ADM/oHA-ss-PTX micelles were absorbed by A549 cells than by oHA-saturated A549 cells. In vivo experiments also showed that ADM/oHA-ss-PTX micelles had excellent therapeutic effects and targeting ability. These results show that ADM/oHA-ss-PTX micelles were a promising platform for co-delivery sequential therapy in CD44-positive cancer. In conclusion, these results convincingly demonstrate that ADM/oHA-ss-PTX micelles hold great promise as a novel platform for co-delivering multiple drugs. Their enhanced properties not only validate the potential of this approach for sequential cancer therapy in CD44-positive cancers but also pave the way for future clinical translation and further optimization in cancer treatment.

摘要

癌症是全球主要的死亡原因之一。开发用于癌症化疗的智能共递送系统以减少副作用并提高治疗效果迫在眉睫。我们选择低分子量透明质酸（oHA）作为载体，并选择阿霉素（ADM）和紫杉醇（PTX）作为共递送药物。通过化学反应引入谷胱甘肽刺激响应性二硫键，合成了oHA-ss-PTX大分子前药。然后，我们通过微流体制备一步构建了载ADM的胶束（ADM/oHA-ss-PTX）。在体外和体内对递送效果进行了综合评估。通过溶血活性分析、牛血清白蛋白吸附测试和内皮细胞活力测定评估了ADM/oHA-ss-PTX的生物相容性。所得的ADM/oHA-ss-PTX胶束具有动态尺寸（127±1.4nm，zeta电位-9.0mV），较高的载药量，PTX约为21.2%，ADM约为7.6%。与游离ADM+PTX相比，ADM/oHA-ss-PTX显示出血液稳定性增强，更有效地抑制癌细胞增殖。此外，由于CD44介导的内吞途径，A549细胞比oHA饱和的A549细胞吸收更多的ADM/oHA-ss-PTX胶束。体内实验还表明，ADM/oHA-ss-PTX胶束具有优异的治疗效果和靶向能力。这些结果表明，ADM/oHA-ss-PTX胶束是CD44阳性癌症共递送序贯治疗的有前景的平台。总之，这些结果令人信服地证明，ADM/oHA-ss-PTX胶束作为一种新型的多种药物共递送平台具有巨大的潜力。它们增强的特性不仅验证了这种方法在CD44阳性癌症序贯治疗中的潜力，也为未来的临床转化和癌症治疗的进一步优化铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/e0013e2549b8/pharmaceutics-17-00538-g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/2e3e6efb5fdf/pharmaceutics-17-00538-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/d308a20bf9d4/pharmaceutics-17-00538-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/228b2d980fe7/pharmaceutics-17-00538-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/fc259e281f7c/pharmaceutics-17-00538-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/6edc23ff517e/pharmaceutics-17-00538-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/04ab92472186/pharmaceutics-17-00538-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/e0013e2549b8/pharmaceutics-17-00538-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/77791cbb64a9/pharmaceutics-17-00538-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/70f05331a245/pharmaceutics-17-00538-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/a8ec0445b932/pharmaceutics-17-00538-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/3c5fed25499e/pharmaceutics-17-00538-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/3a0ef16381c7/pharmaceutics-17-00538-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/4c8be3cb5fdf/pharmaceutics-17-00538-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/2e3e6efb5fdf/pharmaceutics-17-00538-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/d308a20bf9d4/pharmaceutics-17-00538-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/228b2d980fe7/pharmaceutics-17-00538-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/fc259e281f7c/pharmaceutics-17-00538-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/6edc23ff517e/pharmaceutics-17-00538-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/04ab92472186/pharmaceutics-17-00538-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5759/12030733/e0013e2549b8/pharmaceutics-17-00538-g012.jpg

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