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

Abstract 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.