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.
Acta Biomater. 2023 Oct 15;170:228-239. doi: 10.1016/j.actbio.2023.08.043. Epub 2023 Aug 25.
Actively targeted nanomedicines though conceptually attractive for tumor therapy are extremely hard to realize due to problems of premature drug leakage, excessive liver accretion, inadequate tumor uptake, and/or retarded drug release inside tumor cells. Here, we systemically studied the influence of disulfide crosslinking on the in vitro and in vivo performance of integrin-targeting micellar docetaxel (t-MDTX). Of note, t-M5DTX with a high disulfide content was clearly advantageous in terms of stability, intracellular drug release, anti-tumor activity toward αβ-overexpressing A549 cells, blood circulation and therapeutic efficacy in orthotopic A549-luc lung tumor-bearing mice. t-MDTX induced extraordinary tumor targetability with tumor-to-normal tissue ratios of 1.7-8.3. Further studies indicated that t-M5DTX could effectively eradicate αβ-overexpressing lung and prostate cancer patient-derived xenografts (PDX), in which ca. 80% mice became tumor-free. This integrin-targeting disulfide-crosslinked micellar docetaxel emerges as a promising actively targeted nanoformulation for tumor therapy. STATEMENT OF SIGNIFICANCE: Nanomedicines have a great potential in treating advanced tumor patients; however, their tumor-targeting ability and therapeutic efficacy remain unsatisfactory. In addition to PEGylation and ligand selection, particle size, stability and drug release behavior are also critical to their performance in vivo. In this paper, we find that small and cRGD-guided disulfide-crosslinked micellar docetaxel (t-MDTX) induces superior tumor uptake and retention but without increasing liver burden, leading to extraordinary selectivity and inhibition of αβ overexpressing lung tumors. t-MDTX is further shown to effectively treat αβ-positive patient-derived tumor models, lending it a high potential for clinical translation.
主动靶向纳米药物尽管在肿瘤治疗方面具有概念上的吸引力，但由于药物过早泄漏、肝脏蓄积过多、肿瘤摄取不足和/或肿瘤细胞内药物释放延迟等问题，实际上极难实现。在这里，我们系统地研究了二硫键交联对整合素靶向胶束多西紫杉醇（t-MDTX）的体外和体内性能的影响。值得注意的是，具有高二硫键含量的 t-M5DTX 在稳定性、细胞内药物释放、对过度表达αβ的 A549 细胞的抗肿瘤活性、血液循环和荷瘤原位 A549-luc 肺癌小鼠的治疗效果方面明显具有优势。t-MDTX 诱导了非凡的肿瘤靶向性，肿瘤与正常组织的比值为 1.7-8.3。进一步的研究表明，t-M5DTX 可以有效根除过度表达αβ的肺癌和前列腺癌患者来源异种移植（PDX），其中约 80%的小鼠肿瘤完全消除。这种主动靶向二硫键交联胶束多西紫杉醇有望成为一种有前途的肿瘤治疗主动靶向纳米制剂。
纳米药物在治疗晚期肿瘤患者方面具有很大的潜力；然而，它们的肿瘤靶向能力和治疗效果仍然不尽人意。除了聚乙二醇化和配体选择外，颗粒大小、稳定性和药物释放行为也是其体内性能的关键。在本文中，我们发现小且 cRGD 导向的二硫键交联胶束多西紫杉醇（t-MDTX）诱导了优异的肿瘤摄取和保留，但不会增加肝脏负担，从而导致对过度表达的αβ肺肿瘤具有非凡的选择性和抑制作用。t-MDTX 进一步被证明可以有效治疗αβ阳性患者来源的肿瘤模型，使其具有很高的临床转化潜力。
