Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, PR China.
J Control Release. 2017 Jun 10;255:120-131. doi: 10.1016/j.jconrel.2017.03.037. Epub 2017 Mar 23.
GRP78, a specific cancer cell-surface marker, is implicated in cancer cells proliferation, apoptosis resistance, metastasis and drug resistance. l-VAP (SNTRVAP) is a tumor homing peptide exhibiting high binding affinity in vitro to GRP78 protein overexpressed on glioma, glioma stem cells, vasculogenic mimicry and neovasculature. Even though short peptides are often non-immunogenic and demonstrate high affinity to tumor cells, their targeting efficacy is always undermined by rapid blood clearance and enzymatic degradation. In the present study, two d peptides RI-VAP (retro inverso isomer of l-VAP) and d-VAP (retro isomer of l-VAP) were developed by structure-guided peptide design and retro-inverso isomerization technique for glioma targeting. RI-VAP and d-VAP were predicted to bind their receptor GRP78 protein with similar binding affinity, which was experimentally confirmed. The results of in vivo imaging demonstrated that RI-VAP and d-VAP had remarkably advantage over l-VAP for tumor accumulation. In addition, RI-VAP and d-VAP modified paclitaxel-loaded polymeric micelle had better anti-tumor efficacy in comparison to taxol, paclitaxel-loaded plain micelles and l-VAP modified micelles. Overall, the VAP modified micelles suggested in the present study could effectively achieve glioma-targeted drug delivery, validating the potential of the stable VAP peptides in improving the therapeutic efficacy of paclitaxel for glioma.
GRP78 是一种特定的癌细胞表面标志物，与癌细胞增殖、凋亡抵抗、转移和耐药有关。l-VAP（SNTRVAP）是一种肿瘤归巢肽，在体外对胶质瘤、胶质瘤干细胞、血管生成拟态和新生血管中过度表达的 GRP78 蛋白具有高结合亲和力。尽管短肽通常是非免疫原性的，并表现出对肿瘤细胞的高亲和力，但由于快速的血液清除和酶降解，其靶向效果总是受到影响。在本研究中，通过结构导向的肽设计和反相异构化技术，开发了两种 d 肽 RI-VAP（l-VAP 的反向异构体）和 d-VAP（l-VAP 的反向异构体）用于Glioma 靶向。RI-VAP 和 d-VAP 被预测与它们的受体 GRP78 蛋白具有相似的结合亲和力，这一预测得到了实验的证实。体内成像结果表明，RI-VAP 和 d-VAP 比 l-VAP 更有利于肿瘤积累。此外，与紫杉醇负载的普通胶束和 l-VAP 修饰的胶束相比，RI-VAP 和 d-VAP 修饰的紫杉醇负载聚合物胶束具有更好的抗肿瘤疗效。总之，本研究中提出的 VAP 修饰的胶束可以有效地实现Glioma 靶向药物传递，验证了稳定的 VAP 肽在提高紫杉醇治疗Glioma 的疗效方面的潜力。
