Self-Assembled ROS-Sensitive Polymer–Peptide Therapeutics Incorporating Built-in Reporters for Evaluation of Treatment Efficacy

Abstract

One of the major challenges in current cancer therapy is to maximize therapeutic effect and evaluate tumor progression under the scheduled treatment protocol. To address these challenges, we synthesized the cytotoxic peptide (KLAKLAK)2 (named KLAK) conjugated amphiphilic poly(β-thioester)s copolymers (H-P-K) composed of reactive oxygen species (ROS) sensitive backbones and hydrophilic polyethylene glycol (PEG) side chains. H-P-K could self-assemble into micelle-like nanoparticles by hydrophobic interaction with copolymer backbones as cores and PEG and KLAK as shells. The assembled polymer-peptide nanoparticles remarkably improved cellular internalization and accumulation of therapeutic KLAK in cells. Compared to free KLAK peptide, the antitumor activity of H-P-K was significantly enhanced up to ∼400 times, suggesting the effectiveness of the nanoscaled polymer-peptide conjugation as biopharmaceuticals. The higher antitumor activity of nanoparticles was attributed to the efficient disruption of mitochondrial membranes and subsequent excessive ROS production in cells. To realize the ROS monitoring and treatment evaluation, we encapsulated squaraine (SQ) dyes as built-in reporters in ROS-sensitive H-P-K micelles. The overgenerated ROS around mitochondria stimulated the swelling of nanoparticles and subsequent release of SQ, which formed H-aggregates and significantly increased the photoacoustic (PA) signal. We believed that this self-assembled polymer-peptide nanotherapeutics incorporating built-in reporters has great potential for high antitumor performance and in situ treatment evaluation.

Molecular Photoacoustic Contrast Agents: Design Principles & Applications

“…used a micelle encapsulated squaraine dye to monitor in vitro reactive oxygen species (ROS) generation in U87 glioblastoma cells by PAI. Micelle encapsulated nile red dye was also investigated by the authors in parallel experiments as a fluorescent ROS sensor . Key to this study was the tailored ROS‐sensitive micelle that was derived from the cytotoxic KLAK peptide conjugated with a ROS‐sensitive amphiphilic poly( β ‐thioester) copolymer (H‐P‐K) and a hydrophillic PEG2000‐SH side chain.…”

Oxidation‐Responsive Materials: Biological Rationale, State of the Art, Multiple Responsiveness, and Open Issues

“…Upon oxidation and therefore with increasing water content, the ester cleavage accelerates; it is worth mentioning that the electron‐withdrawing character of oxidized groups such as sulfoxides/sulfones can also help labializing proximal esters . The influence of the high water content and that of electronegative substituents cannot be easily separated and therefore it is only possible to ascribe the more rapid release of chemically bound drugs to a combination of the two effects.…”

Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

“…The development of the nanotechnology‐based drug delivery systems (NDDSs) elevates the tumor accumulation and reduces the distribution in normal tissue . However, one practical problem lies in the irresponsiveness of NDDSs towards the tumor microenvironment, which results in insufficient intratumoral drug release and more off‐target exposure . Thus, bilirubin, an endogenous hydrophobic antioxidant, can react with overproduced reactive oxygen species (ROS) inside tumors, turn into hydrophilic biliverdin and lead to on‐demand drug release .…”