Han Wenzhao, Ke Junfeng, Guo Feng, Meng Fanwei, Li Hui, Wang Liping
Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, PR China.
Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, PR China.
Int J Pharm. 2021 Oct 25;608:121066. doi: 10.1016/j.ijpharm.2021.121066. Epub 2021 Sep 1.
Doxorubicin (DOX) is one of the most commonly used and effective chemotherapy drugs among anthracyclines. An inherent limitation of DOX is its nonspecificity, which can cause serious side effects, thereby preventing the therapeutic use of high drug doses. In this study, we designed and created a simple nano-drug delivery system (PEG-MAF = P) with low biological toxicity that was responsive to the tumor environment. PEG-MAF = P was designed to self-assemble into nanospheres via control of a phenylalanine dipeptide (FF). The N-terminus of the peptide was linked to aldehyde groups at both ends of oxidized Pluronic F127 (F127-CHO) via Schiff bonds. The acidic environment surrounding the tumors was suitable for triggering the Schiff bonds, causing the nanospheres to disintegrate. The C-terminus of FF was connected to a ligand peptide, ATN-161, which was able to recognize cells expressing high levels of integrin α5β1 antigens both in vivo and in vitro. To prevent the impediment in drug release, PEG was linked via a matrix metalloproteinase-9 response peptide. Therefore, in an acidic tumor microenvironment containing MMP-9, PEG-MAF = P disintegrated and rapidly released the drug. PEG-MAF = P exhibited low cytotoxicity, high drug-loading rate, and excellent antitumor properties both in vivo and in vitro. Compared with free DOX, PEG-MAF = P-DOX reduced injury to normal tissues.
阿霉素（DOX）是蒽环类药物中最常用且有效的化疗药物之一。DOX的一个固有局限性在于其非特异性，这可能导致严重的副作用，从而限制了高剂量药物的治疗应用。在本研究中，我们设计并创建了一种对肿瘤环境有响应、生物毒性低的简单纳米药物递送系统（PEG-MAF = P）。PEG-MAF = P被设计通过控制苯丙氨酸二肽（FF）自组装成纳米球。肽的N端通过席夫碱与氧化的普朗尼克F127（F127-CHO）两端的醛基相连。肿瘤周围的酸性环境适合触发席夫碱，导致纳米球解体。FF的C端连接到一种配体肽ATN-161，其在体内和体外都能够识别表达高水平整合素α5β1抗原的细胞。为防止药物释放受阻，PEG通过基质金属蛋白酶-9响应肽连接。因此，在含有MMP-9的酸性肿瘤微环境中，PEG-MAF = P解体并迅速释放药物。PEG-MAF = P在体内和体外均表现出低细胞毒性、高载药率和优异的抗肿瘤特性。与游离DOX相比，PEG-MAF = P-DOX对正常组织的损伤更小。
