MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou 310027, China.
ACS Appl Mater Interfaces. 2017 May 3;9(17):14596-14605. doi: 10.1021/acsami.6b15853. Epub 2017 Apr 18.
5-Aminolevulinic acid (ALA), the precursor of photosensitizer protoporphyrin IX (PpIX), is a U.S. FDA-approved photodynamic therapeutic agent. However, realizing efficient delivery of ALA is still a big challenge as it is hydrophilic and cannot be recognized and selectively accumulated in tumor cells. In this study, matrix metalloproteinase-2 (MMP-2) and pH dual-sensitive ALA prodrug nanocarriers were constructed as a programmed delivery strategy for the targeted delivery of ALA. The nanocarriers were prepared by the co-modification of gold nanoparticles (AuNPs) with hydrazone-linked ALA and MMP-2-activatable cell-penetrating peptides (CPPs). Cationic CPP RRRRRRRR (R8) was shielded by zwitterionic stealth peptide EKEKEKEKEKEKEKEKEKEK (EK10) via MMP-2 substrate peptide PLGLAG. The zwitterionic stealth peptide EK10 is designed to endow ALA prodrug nanocarriers with strong antifouling ability and prolonged circulation time. Upon arriving at the tumor tissue, the shielded cationic CPP R8 can be activated by tumor-microenvironment-overexpressed MMP-2, which enabled enhanced cellular uptake of ALA. The results of drug loading and release, cellular uptake, PpIX generation and accumulation, photodynamic cytotoxicity, and photodynamic tumor inhibition demonstrated that such tumor-microenvironment-sensitive ALA prodrug nanocarriers could be considered as potential candidates for targeted photodynamic cancer therapy.
5-氨基酮戊酸（ALA）是卟啉 IX（PpIX）的前体，是美国食品和药物管理局批准的光动力治疗药物。然而，由于 ALA 具有亲水性，不能被识别并选择性地在肿瘤细胞中积累，因此实现其高效传递仍然是一个巨大的挑战。在本研究中，构建了基质金属蛋白酶-2（MMP-2）和 pH 双重敏感的 ALA 前药纳米载体，作为一种靶向递药的编程策略。纳米载体通过腙键连接的 ALA 和 MMP-2 激活型细胞穿透肽（CPP）对金纳米粒子（AuNPs）进行共修饰制备而成。阳离子 CPP RRRRRRRR（R8）通过 MMP-2 底物肽 PLGLAG 被两性离子隐形肽 EKEKEKEKEKEKEKEKEK（EK10）屏蔽。两性离子隐形肽 EK10 的设计赋予了 ALA 前药纳米载体强大的抗污能力和延长的循环时间。到达肿瘤组织后，肿瘤微环境过表达的 MMP-2 可以激活屏蔽的阳离子 CPP R8，从而增强 ALA 的细胞摄取。载药和释放、细胞摄取、PpIX 的生成和积累、光动力细胞毒性以及光动力肿瘤抑制的结果表明，这种肿瘤微环境敏感的 ALA 前药纳米载体可被视为用于靶向光动力癌症治疗的潜在候选药物。
