Application of TME-responsive polymeric micelles in tumor diagnosis and treatment

The tumor microenvironment (TME) constitutes a unique biological environment comprising tumor cells, infiltrating immune cells, stromal cells, blood vessels, extracellular matrix, and secreted factors during tumor growth and development. Various essential physiological characteristics are present in the TME, such as hypoxia, slight acidity, a high concentration of endogenous hydrogen peroxide (HO), excess levels of glutathione (GSH), and overexpression of certain enzymes. TME-responsive nanomedicine delivery systems offer promising methods for precise drug delivery, gaining increasing attention in nanomedicine research. Among these nanomedicine systems, TME-responsive polymeric micelles (PMs) have emerged as a potential successful option for cancer diagnosis and therapy. These micelles exhibit remarkable biocompatibility, improved permeability, minimal toxicity to healthy cells, and the ability to dissolve various drugs in their micellar core. Due to their nano-size, they can accumulate in the TME and passively target tumor cells via the enhanced permeability and retention (EPR) effect. Consequently, TME-responsive PMs loaded with drugs hold significant potential for tumor diagnosis and treatment. Currently, TME-responsive strategies for drug delivery systems include pH responsiveness, reactive oxygen species (ROS) responsiveness, enzyme responsiveness, GSH responsiveness, hypoxia responsiveness, and dual/multiple responsiveness, which combine different responsiveness modes. This section introduces several examples of PMs in each TME-responsive strategy, analyzing their design ideas, responsive mechanisms, and targeting strategies. TME-responsive polymeric micelles remain stable in the normal physiological environment, such as blood. However, upon reaching the tumor tissue, they undergo physicochemical changes like protonation, surface electrical transformation, and/or chemical bond hydrolysis, thus enhancing their targeting ability to tumor cells and achieving high enrichment in tumor tissues or drug release. Design ideas for TME-responsive PMs encompass the type of TME responsiveness, the corresponding TME-sensitive chemical structure, and further categorize responsive mechanisms into six approaches: Size change, surface electrical transformation, break of micelle main structurees, switch between hydrophilicity and hydrophobicity, electrical inversion of micelles, and ligand exposure. TME-responsive PMs undergo specific physicochemical changes in tumor tissue (e.g., size, morphology, surface charge, aggregation state) to improve drug targeting and enhance therapeutic effects. Besides carrying antitumor drugs, these PMs can accommodate various functional molecules like optical probes, imaging contrast agents, immune stimulators, or DNA/ siRNA, enabling high-performance tumor imaging, targeted therapy, immunotherapy, gene therapy, photothermal therapy, or efficacy monitoring. With advancements in tumor diagnosis technology and research on various new tumor-targeting probes, TME-responsive PMs can achieve multi-module integration and multiple responsiveness. This enables loading diagnostic probes and therapeutic drugs together, constructing an integrated platform for tumor diagnosis and treatment, facilitating image-guided therapy, and significantly advancing related tertiary prevention for tumors. Presently, most TME-responsive PMs are still in the research stage. pH-responsive PMs NC-6300, which have undergone clinical trials, demonstrated satisfactory experimental results. For further clinical application, researchers will explore more targeted structural designs to address the trade-off between the protective barrier of hydrophilic layers and tumor-targeted recognition, as well as between passive enrichment and deep infiltration. Additionally, further research efforts will focus on improving the internal circulation stability and tumor enrichment efficiency of PMs while reducing the toxicity of dissociated products.