Self-Amplifying Nanotherapeutic Drugs Homing to Tumors in a Manner of Chain Reaction.

Abstract

Active tumor-targeting drug delivery has great potency in cancer therapy. However, the targeting efficiency of traditional active tumor-targeting nanotherapeutic drugs is limited by the scarcity of their accessible targets/receptors in tumors. Here, a novel self-amplifying tumor-targeting strategy with a chain reaction mechanism is developed. A coagulation targeting peptide (GNQEQVSPLTLLKXC, termed A15)-decorated poly(L-glutamic acid)-graft-maleimide poly(ethylene glycol)/combretastatin A4 conjugate (A15-PLG-CA4) is prepared to obtain a self-amplifying nanotherapeutic platform homing to tumors. After administration to tumor-bearing mice, A15-PLG-CA4 starts a chain reaction cycle consisting of intratumoral hemorrhage, target FXIIIa amplification, blood clot binding, and CA4 release in tumors. In this way, A15-PLG-CA4 increases the level of its accessible targets (FXIIIa) in a manner of chain reaction. The FXIIIa activity at 8 h is 4.1-fold more than the one at 0 h in the C26 tumors treated with A15-PLG-CA4. The total CA4 concentration at 24 h is 2.9-fold more than the control. A15-PLG-CA4 shows a significantly higher antitumor effect against large C26 tumors (≈500 mm³ ) thanks to the remarkable tumor-targeting ability compared with the control. Therefore, this report highlights the potential of the self-amplifying tumor-targeting strategy in the development of next generation active tumor-targeting nanotherapeutic drugs for tumor therapy.