肿瘤微环境响应聚合物胶束在肿瘤诊疗中的应用

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

肿瘤微环境(tumor microenvironment,TME)是一种在肿瘤发生发展过程中,由肿瘤细胞与浸润的免疫细胞、基质细胞、血管、细胞外基质和分泌因子等共同构成的特殊生理环境,表现出乏氧、弱酸性、高内源性过氧化氢(H2O2)浓度、高谷胱甘肽(glutathione,GSH)含量,以及部分酶过度表达等特征.目前,基于TME响应聚合物胶束(polymeric micelles,PMs)体系为药物的精准递送提供了新思路,在纳米医学领域引起了越来越多的关注.TME响应PMs,在正常生理环境(如血液)中保持结构稳定,而到达肿瘤组织后,可通过质子化、界面电性翻转、化学键水解等物理化学变化来响应TME的生理特性,提高对肿瘤组织的靶向能力,实现在肿瘤组织中的有效富集.本文回顾了近年来TME响应PMs的研究进展,重点介绍了TME响应PMs的设计思路、响应机制和靶向策略.在对各响应策略进行归纳整理之后,总结比较了各响应策略的优势及其不足.并在此基础上,探讨了TME响应PMs在肿瘤精准诊疗中更多的应用前景.

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(H2O2),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.TMEresponsive 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.