Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Biotherapy Research Center, and Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Sci Rep. 2017 Apr 20;7(1):975. doi: 10.1038/s41598-017-01168-7.
Paclitaxel (PTX), especially albumin-bound PTX in clinical, has displayed significant inhibition of tumor growth in patients. But the systemic distribution and poor water solubility of PTX often lead to severe side effects, consequently limiting the anti-tumor efficacy. In this study, we developed a novel PTX-loaded polymeric micelle drug delivery system. These self-assembled polymeric micelles from core to outside consisted of poly L-phenylalanine (pPhe), DTSSP linked poly L-lysine (pLys), poly ethylene glycol (PEG) and dehydroascorbic acids (DHA). pPhe formed the hydrophobic core to encapsulate PTX; DTSSPs on pLys covalently cross-linked and formed disulfide bond to stabilize PTX from loss in blood circulation; PEG improved solubility to lower toxicity of PTX for its high hydrophilicity; DHA targeted tumors by specifically recognizing GLUT1 mainly expressed on tumor cells. Thus, PTX would be precisely released into tumor cells with high dose of glutathione to break disulfide bond. Moreover, these PTX-loaded polymer micelles significantly suppressed tumor cell viability, proliferation, and migration in vitro, and also greatly inhibited tumor growth and prolonged survival in tumor-bearing mice without detectable side effects. Therefore, the new drug delivery system could reduce severe side effects and enhance anti-tumor efficacy of PTX via peripheral stabilization, low toxicity and tumor targeting.
紫杉醇（PTX），特别是临床中的白蛋白结合型 PTX，已显示出对患者肿瘤生长的显著抑制作用。但 PTX 的全身分布和较差的水溶性常常导致严重的副作用，从而限制了其抗肿瘤疗效。在本研究中，我们开发了一种新型的载紫杉醇聚合物胶束药物递送系统。这些自组装的聚合物胶束从内到外依次由聚 L-苯丙氨酸（pPhe）、DTSSP 连接的聚 L-赖氨酸（pLys）、聚乙二醇（PEG）和脱氢抗坏血酸（DHA）组成。pPhe 形成疏水性内核以包载 PTX；pLys 上的 DTSSP 共价交联并形成二硫键，以稳定 PTX 在血液循环中的损失；PEG 提高了 PTX 的溶解度，降低了其毒性，因为其具有很高的亲水性；DHA 通过特异性识别主要在肿瘤细胞上表达的 GLUT1 靶向肿瘤。因此，PTX 将在具有高谷胱甘肽浓度的肿瘤细胞中被精确释放，以打破二硫键。此外，这些载 PTX 的聚合物胶束在体外显著抑制了肿瘤细胞的活力、增殖和迁移，并且在荷瘤小鼠中也极大地抑制了肿瘤生长并延长了生存期，而没有可检测到的副作用。因此，通过外周稳定化、低毒性和肿瘤靶向作用，新的药物递送系统可以降低 PTX 的严重副作用并增强其抗肿瘤疗效。
