Department of Biomaterials, College of Materials, Research Center of Biomedical Engineering of Xiamen & Key Laboratory of Biomedical Engineering of Fujian Province & Fujian Provincial Key Laboratory for Soft Functional Materials Research, Xiamen University, Xiamen 361005, China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China.
J Mater Chem B. 2021 Jul 14;9(27):5547-5559. doi: 10.1039/d1tb01025e.
Sonodynamic therapy has attracted wide attention as a noninvasive therapy due to deep tissue penetration. However, majority sonosensitizers often suffer from poor physiological stability, rapid blood clearance and nonspecific targeting, which seriously hinders their further practical applications. Inspired by the concept of active targeting drug delivery, both dual-functional chemo-drug pemetrexed (PEM, emerges an innate affinity toward the folate receptor) and amphiphilic d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected to be covalently linked by an esterase-responsive ester linkage. The synthesized self-targeting TPGS-PEM prodrug and indocyanine green (ICG) as functional motifs can be self-assembled into a TPGS-PEM-ICG nanoplatform within an aqueous medium. The TPGS-PEM-ICG nanoplatform with outstanding structural and physiological stability not only protects the sonosensitizer from reticular endothelial system clearance but also achieves active targeting drug delivery and efficient tumor enrichment. Moreover, TPGS-PEM-ICG nanoplatform can selectively recognize tumor cells and then realize on-demand drug burst release by multiple stimuli of internal lysosomal acidity, esterase and external ultrasound, which guarantee low side effects toward normal tissues and organs. It is also worth noting that our nanoplatform exhibits protruding tumor enrichment under the precise guidance of photoacoustic/fluorescence imaging. Further in vitro and in vivo experimental results well confirmed that the TPGS-PEM-ICG nanoplatform possesses enhanced chemo-sonodynamic effects. Interestingly, the highly toxic reactive oxygen species can remarkably reduce the blood oxygen saturation signal of the tumor microenvironment via precise, multifunctional and high-resolution photoacoustic imaging. Taken together, the TPGS-PEM-ICG nanoplatform can be expected to hold enormous potential for diagnosis, prognosis and targeted therapy for tumor.
超声动力治疗因其具有良好的组织穿透性而受到广泛关注，是一种非侵入性治疗方法。然而，大多数声敏剂往往存在较差的生理稳定性、快速的血液清除率和非特异性靶向性，这严重阻碍了它们的进一步实际应用。受主动靶向药物传递概念的启发，选择双功能化疗药物培美曲塞（PEM，对叶酸受体具有天然亲和力）和两亲性 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）通过酯酶响应酯键共价连接。合成的自靶向 TPGS-PEM 前药和吲哚菁绿（ICG）作为功能基元可以在水介质中自组装成 TPGS-PEM-ICG 纳米平台。TPGS-PEM-ICG 纳米平台具有出色的结构和生理稳定性，不仅可以保护声敏剂免受网状内皮系统清除，还可以实现主动靶向药物传递和高效肿瘤富集。此外，TPGS-PEM-ICG 纳米平台可以通过内部溶酶体酸度、酯酶和外部超声的多种刺激选择性识别肿瘤细胞，然后实现按需药物爆发释放，从而保证对正常组织和器官的低副作用。值得注意的是，我们的纳米平台在光声/荧光成像的精确指导下表现出突出的肿瘤富集。进一步的体外和体内实验结果充分证实了 TPGS-PEM-ICG 纳米平台具有增强的化疗-超声动力效应。有趣的是，高毒性的活性氧物质可以通过精确的、多功能的和高分辨率的光声成像显著降低肿瘤微环境的血氧饱和度信号。综上所述，TPGS-PEM-ICG 纳米平台有望在肿瘤的诊断、预后和靶向治疗方面具有巨大潜力。
