Guo Yuanyuan, Niu Boning, Song Qingle, Zhao Yongdan, Bao Yuling, Tan Songwei, Si Luqin, Zhang Zhiping
Department of Pharmacy, Liyuan Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.
J Mater Chem B. 2016 Apr 7;4(13):2338-2350. doi: 10.1039/c6tb00055j. Epub 2016 Mar 15.
Developing multifunctional nanoparticles (NPs) to improve therapeutic efficacy is highly desirable in cancer therapy. In an attempt to respond to such a challenge, a novel copolymer, d-α-tocopherol polyethylene glycol succinate-SS-poly(lactide) (TPGS-SS-PLA) with a disulfide linkage between the TPGS and PLA units, was synthesized for paclitaxel (PTX) delivery. PTX-loaded NPs were fabricated using a nanoprecipitation method to form a particle size of ∼130 nm with good in vitro stability, which can be disassociated under intracellular reductive conditions to release PTX rapidly. The detached TPGS can further promote the drug retention and cytotoxicity through its P-glycoprotein inhibiting property. Integrin-specific targeting peptide, cyclic RGD (cRGD), was further conjugated to the surface of the NPs for targeting the drug delivery. The RGD-decorated NPs exhibited enhanced cellular uptake, PTX accumulation and cell cytotoxicity as compared to non-targeted NPs on murine melanoma B16F10 cells, PTX-sensitive human ovarian A2780 cells and PTX-resistant A2780/T cells. In vivo evaluation of the targeted NPs further showed an extended half-life, increased AUC (area under the concentration-time curve), and significant tumor growth inhibition in mouse sarcoma S180- and B16F10-tumor bearing mice, with reduced side effects as compared to Taxol® and non-targeted NPs. These results indicate that the RGD decorated redox-sensitive NPs could deliver chemotherapies specifically inside the cell via receptor-mediated endocytosis with enhanced efficacy, especially in integrin αβ/αβ-rich tumor cells. Such a targeted nanocarrier against receptor clustering prepared from a non-cytotoxic and biodegradable copolymer might have great potential in cancer treatment.
在癌症治疗中，开发多功能纳米颗粒（NPs）以提高治疗效果是非常必要的。为应对这一挑战，合成了一种新型共聚物，即二-α-生育酚聚乙二醇琥珀酸酯-SS-聚丙交酯（TPGS-SS-PLA），其TPGS和PLA单元之间存在二硫键，用于紫杉醇（PTX）递送。采用纳米沉淀法制备了负载PTX的NPs，形成粒径约为130 nm且具有良好体外稳定性的颗粒，该颗粒可在细胞内还原条件下解离以快速释放PTX。游离的TPGS可通过其抑制P-糖蛋白的特性进一步促进药物滞留和细胞毒性。将整合素特异性靶向肽环RGD（cRGD）进一步偶联到NPs表面以实现药物靶向递送。与非靶向NPs相比，RGD修饰的NPs在小鼠黑色素瘤B16F10细胞、PTX敏感的人卵巢A2780细胞和PTX耐药的A2780/T细胞上表现出增强的细胞摄取、PTX积累和细胞毒性。对靶向NPs的体内评估进一步显示，在携带小鼠肉瘤S180和B16F10肿瘤的小鼠中，其半衰期延长、曲线下面积（AUC）增加且肿瘤生长受到显著抑制，与紫杉醇和非靶向NPs相比副作用减少。这些结果表明，RGD修饰的氧化还原敏感NPs可通过受体介导的内吞作用将化疗药物特异性递送至细胞内，疗效增强，尤其是在富含整合素αβ/αβ的肿瘤细胞中。这种由无细胞毒性且可生物降解的共聚物制备的针对受体聚集的靶向纳米载体在癌症治疗中可能具有巨大潜力。
