Advances of Stimuli-Responsive Amphiphilic Copolymer Micelles in Tumor Therapy

Abstract

Amphiphilic copolymers are composed of both hydrophilic and hydrophobic chains, which can self-assemble into polymeric micelles in aqueous solution via the hydrophilic/hydrophobic interactions. Due to their unique properties, polymeric micelles have been widely used as drug carriers. Poorly soluble drugs can be covalently attached to polymer chains or non-covalently incorporated in the micelles, with improved pharmacokinetic profiles and enhanced efficacy. In recent years, stimuli-responsive amphiphilic copolymer micelles have attracted significant attention. These micelles can respond to specific stimuli, including physical triggers (light, temperature, etc). chemical stimuli (pH, redox, etc). and physiological factors (enzymes, ATP, etc). Under these stimuli, the structures or properties of the micelles can change, enabling targeted therapy and controlled drug release in tumors. These stimuli-responsive strategies offer new avenues and approaches to enhance the tumor efficacy and reduce drug side effects. We will review the applications of different types of stimuli-responsive amphiphilic copolymer micelles in tumor therapy, aiming to provide valuable guidance for future research directions and clinical translation.

Keywords: delivery system; polymer micelles; stimuli-responsive; tumor therapy.

Figure 1

Overview of the stimuli-responsive polymer micelles in cancer treatment.

Figure 2

Schematic Illustration of the Core Concept of the Study (A) Processes of siRNA delivery and gene silencing, in which cellular entry, endosomal escape, and duration pattern of silencing activity are of importance for siRNA therapeutic development. Most people paid their attention to cellular entry in past decades. Increasing evidence proves that efficient endosomal escape of siRNA constitutes a determining factor of success or failure. (B) Chemical structure of proposed triblock polymer of PDDT and the preparing process of PDDT-Ms/siRNA polyplexes. (C) Cellular uptake and intracellular trafficking of PDDT-Ms/siRNA polyplexes. pH-responsive disassembling of the polyplexes will happen once they stay in the acidic endosomal environment. Two siRNAs targeting PLK1 and PD-L1 were employed in this study to achieve successful cancer treatment. Reprinted with permission from Li C, Zhou J, Wu Y, et al. Core role of hydrophobic core of polymeric nanomicelle in endosomal escape of siRNA. Nano Lett. 2021;21(8):3680–3689. Copyright (2021). American Chemical Society.

Figure 3

(A) Schematic illustration for the preparation of TF@CNM + DOX polyprodrug nanoparticles via self-assembly of a mixture of TPP-POEGMA-b-P(CNM-co-DOX) and FA-POEGMA-b-P(CNM-co-DOX) and their application to reverse multi-drug resistance; the proposed mechanism for TF@CNM + DOX nanoparticles; (1) cellular internalization of TF@CNM + DOX micelles via folate receptor-mediated endocytosis and CNM release at the endosomal pH 5.0; (2) excessive production of ROS in turn triggers the release of DOX mainly in the mitochondria through the cleavage of TK linkers. (B) pH and ROS-Responsive Release of CNM and DOX from the Polyprodrugs, Respectively. Reprinted with permission from Mukerabigwi JF, Tang R, Cao Y, et al. Mitochondria-targeting polyprodrugs to overcome the drug resistance of cancer cells by self-amplified oxidation-triggered drug release. Bioconjug Chem. 2023;34(2):377–391. Copyright (2023). American Chemical Society.

Figure 4

(A) Schematic illustration for the formation of polyprodrug micelles and the combination of PDT and light-boosted hypoxia aggravation for hypoxia-responsive self-immolative drug release inside tumor tissues. (B) The mechanism of PDT and hypoxia-responsive drug release from the polyprodrug. Reprinted with permission from Zhou Q, Mohammed F, Wang Y, et al. Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy. J Control Release. 2021;339:130–142. Copyright (2021). Elsevier.

Figure 5

Schematic representation of NQO1-Responsive drug delivery system and their enzyme-triggered disassembly and drug release facilitated by NQO1 depolymerization and disassembly of the micellar structure. Reprinted with permission from Park J, Jo S, Lee YM, et al. Enzyme-triggered disassembly of polymeric micelles by controlled depolymerization via cascade cyclization for anticancer drug delivery. ACS Appl Mater Interfaces. 2021;13(7):8060–8070. Copyright (2021). American Chemical Society.

Figure 6

Self-assembly of UCNPs-CW/NG/DOX@P-DASA Reprinted with permission from Zhang Y, Zhang X, Chen W, et al. Self-assembled micelle responsive to quick NIR light irradiation for fast drug release and highly efficient cancer therapy. J Control Release. 2021;336:469-479. Copyright (2021). Elsevier.