Hydrogen peroxide-responsive anticancer hyperbranched polymer micelles for enhanced cell apoptosis

Abstract

Chemotherapeutic drugs that induce apoptosis in tumor cells via regulating intracellular reactive oxygen species (ROS) levels represent a promising strategy against cancer. Here we report an effective anticancer nanomicelle system based on hydrogen peroxide (H₂O₂)-responsive hyperbranched polymers through enhanced cell apoptosis for efficient cancer therapy. Firstly, the hydrophobic anticancer drug 7-ethyl-10-hydroxy-camptothecin (SN38) was conjugated onto a hydrophilic and biocompatible hyperbranched polyglycerol (HPG) via a H₂O₂-responsive thioether linkage, forming the SN38-conjugated HPG (HPG-2S-SN38). The amphiphilic HPG-2S-SN38 self-assembled into stable nanomicelles which could encapsulate cinnamaldehyde (CA) that induces apoptotic cell death via ROS production in a large number of cancer cells. The release of SN38 and CA from the CA-loaded HPG-2S-SN38 micelles was dependent on H₂O₂ concentration, whereas CA was released remarkably faster than SN38 under an oxidative condition. The in vitro study suggested that the CA-loaded HPG-2S-SN38 nanomicelles entered cancer cells rapidly and subsequently were activated by the intracellular oxidative environment to release CA and SN38. The preferentially released CA could effectively induce intracellular ROS production, which in turn accelerated the degradation of micelles and the release of SN38. Compared to the HPG-2S-SN38 micelles and the mixture of CA and SN38, the CA-encapsulated HPG-2S-SN38 micelles resulted in more intracellular ROS generation, which efficiently enhanced the proliferation inhibition of tumor cells via inducing cell apoptosis, exerting a synergistic anticancer effect of CA and SN38. The H₂O₂-sensitive CA-loaded HPG-2S-SN38 micelles that amplified the antitumor effect by enhancing the cell apoptosis have enormous potential as novel anticancer therapeutics.