Construction and antitumor properties of a targeted nano-drug carrier system responsive to the tumor microenvironment

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.