pH敏感型靶向纳米载体/吡啶类双光子化合物在光动力治疗癌症方面的应用探索

Photodynamic therapy (PDT) is one of the new approaches for cancer therapy. However, the applications of most photosensitizers (Ps) are restricted on skin and superficial tumor on account of their poor active targeting ability while distributing in the body, poor water solubility and excitement by light with a comparatively short wavelength (600-700nm), which leads to poor penetration. Therefore, this project is designed to overcome these shortages. A tumor targeting cRGD decorated pH sensitive diblock polymer is employed as nano delivery system to co-encapsulate pyridine two-photon compound (L2pa) and Ps, which is synthesized based on the Atom Transfer Radical Polymerization (ATRP) theory and designed to target tumor cells and release fast. And then, near infrared light with an approximately 1000nm wavelength is able to indirectly excite Ps through fluorescence resonance energy transfer which can upconvert the energy of near infrared light to Ps molecules. Tumor cells and neovascular in tumor tissue are damaged by the generated singlet oxygen. Therefore, this delivery system is supposed to treat deeper tumors through the application of ‘triple targeting’ (pH, cRGD and light) two-photon PDT. Generation of singlet oxygen, cellular uptake, cell toxicity, targeting ability, pharmacodynamics and pharmacokinetics are studied in this project. According to this project, the theory of PDT is expected to be developed and the new approach of cancer therapy to be provided. Furthermore, efforts are being made to expand the application of current Ps.

光动力疗法（PDT）是近期发展的利用光和光敏剂（Ps）高效治疗肿瘤疾病的新型疗法之一。但Ps在体内分布的主动靶向性差、难溶于水以及受限于穿透力较弱的较短波长光源激发（600-700nm），仅能治疗皮肤和浅表肿瘤，是该领域亟待解决的科学问题。本项目依据原子转移自由基聚合原理合成pH敏感型两嵌段共聚物并修饰靶向性cRGD环肽，同时装载新型吡啶类双光子化合物（L2pa）和Ps，以构建纳米给药系统，靶向肿瘤组织，释出装载物，采用1000nm左右穿透力较强的近红外光源激发富集在肿瘤内的L2pa，通过荧光共振能量转移效应间接激发Ps产生单线态氧，杀伤肿瘤细胞和新生微血管，实现双光子光动力疗法对深部肿瘤及大块肿瘤的pH、cRGD和激发光三重靶向治疗。系统研究单线态氧产生、细胞摄取、细胞毒性、靶向性、药效学和药动力学等，旨在发展PDT理论，拓宽Ps治疗范围并提高疗效，为肿瘤疾病的治疗提供新思路和新方法。

光动力疗法对癌症的诊疗由于光敏剂的疏水性以及较浅的组织激发深度而受到限制，本项目利用合成的pH敏感聚合物，聚2-（二异丙基氨基）乙基甲基丙烯酸酯---聚2-甲基丙烯酸羟丙酯（PSPMA-PDPA），构建纳米递药系统，同时装载强双光子吸收化合物和光敏剂，利用近红外激光（808 nm）实现双光子光动力疗法（TP-PDT）抗小鼠乳腺癌。通过胶束的包埋，减少了供体和受体之间距离，且胶束中的双光子化合物具有较大的双光子截面积，保证了FRET效率；聚合物的pH敏感特性，让光敏剂在正常pH下于胶束内部聚集，使得单线态氧产率较低，避免对正常组织的光毒性；在肿瘤的弱酸性pH环境下，聚合物两嵌段均离子化且相互吸引、缠绕，形成具有较强疏水性能的内核，提高光敏剂的单线态氧产率，杀伤肿瘤细胞。该胶束可将药物递送至肿瘤细胞，且光敏剂和聚合物材料具有较低的细胞毒性，对给药细胞加以近红外激光光照时，TP-PDT对其产生有效的杀伤作用，且诱导细胞凋亡坏死。体内有效性实验表明，基于该载药胶束的TP-PDT对肿瘤生长有明显抑制作用。通过本项目的尝试，有助于推动TP-PDT的理论进一步发展，也证明TP-PDT在抗肿瘤应用上拥有巨大潜力。