Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China.
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China; College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, PR China.
J Control Release. 2023 Aug;360:304-315. doi: 10.1016/j.jconrel.2023.06.032. Epub 2023 Jul 4.
Nanomedicines while showing a great potential in improving the performance of chemotherapeutics like docetaxel (DTX) are distressed by a high liver deposition and poor tumor penetration, which might not only cause liver toxicity but also moderate therapeutic effect. Herein, we report that cRGD-directed 24 nm disulfide-crosslinked micellar docetaxel (cRGD-MDTX) presents low liver accumulation, high tumor uptake, and deep tumor penetration, leading to the potent suppression of different solid tumors. cRGD-MDTX was optimized with a cRGD density of 4% and DTX loading of 10 wt%. Interestingly, cRGD-MDTX enabled an extraordinary tumor-liver ratio of 2.8/1 with a DTX uptake of 8.3 %ID/g in αβ over-expressing PC3 prostate tumor. The therapeutic studies demonstrated striking antitumor effects of cRGD-MDTX toward PC3 prostate tumor, prostate cancer patient-derived xenografts (PDX), orthotopic A549-Luc lung cancer and orthotopic SKOV3-Luc ovarian tumor models, in which tumor growth was effectually inhibited and 6-8 times better improvement of median survival time over free DTX was observed. This small disulfide-crosslinked micellar drug capable of relegating liver deposition opens a new avenue to nanomedicines for targeted therapy.
纳米药物在提高多西紫杉醇（DTX）等化疗药物的疗效方面具有很大的潜力，但存在肝沉积高和肿瘤穿透性差的问题，这不仅可能导致肝毒性，还会影响治疗效果。本文报道了一种 cRGD 导向的 24nm 二硫键交联胶束多西紫杉醇（cRGD-MDTX），具有低肝蓄积、高肿瘤摄取和深肿瘤穿透性，能有效抑制多种实体瘤。cRGD-MDTX 的 cRGD 密度为 4%，DTX 载药量为 10wt%。有趣的是，cRGD-MDTX 使肿瘤-肝脏的比率达到 2.8/1，αβ 过表达的 PC3 前列腺肿瘤中 DTX 的摄取量达到 8.3%ID/g。治疗研究表明，cRGD-MDTX 对 PC3 前列腺肿瘤、前列腺癌患者来源异种移植瘤（PDX）、原位 A549-Luc 肺癌和原位 SKOV3-Luc 卵巢肿瘤模型具有显著的抗肿瘤作用，能有效抑制肿瘤生长，中位生存期延长 6-8 倍。这种能够减轻肝沉积的小二硫键交联胶束药物为靶向治疗的纳米药物开辟了新途径。
