光促/酶促双控释透明质酸纳米靶向联合治疗药物的制备及其疗效的PET评估

Although cancer is a devastating fetal disease, the effective prevention and controlling of cancer development remains challenges. According to the clinical data, in time therapy will be one of the best way to prolong the patients’ survival rate and improve the quality of life. In this respect, more and more researchers are focusing on enhancing the drug curative effect by using controlled drug release mechanisms or combined therapy strategy. Based on the theory and our published work, we proposed that modifications of hyaluronic acid (HA) by a photosensitizer via a kind of reactive oxygen species (ROS) sensitive bond to construct a self-assembled nanoparticle. The self-assembled hyaluronic nanoparticles will be further used as cargos for chemotherapeutics, for example paclitaxel (PTX). The final nanodrug will simultaneously provide PDT and chemotherapy for tumor ablations. After intravenous injection, the particles will accumulate in tumor by both passive targeting (EPR effect) and active targeting (HA targeting of CD44 overexpressed on tumor cells) abilities and release PTX by hyaluronidase degradations of HA particles. Moreover, the formed nanocomplex will further be broke down when photodynamic therapy (PDT) started with generating of large amount of ROS. Compared to the traditional nanodrug, our proposed nanodrug holds 1) both passive and active targeting abilities for enhanced tumor targeting potential; 2) the two steps controlled release of drug offers an improved tumor ablation effect with low side effects in vivo. To further evaluate and confirm the therapeutic effects, we further plan to apply PET imaging to monitor the therapeutic effects of this new type of ROS/enzyme sensitive nanodrug. Specifically, 18F-FDG and 18F-RGD2 will be applied for monitoring the metabolic and protein expression changes in tumors after drug treatments..Overall, our proposed project will be helpful for developing of a new type of HA based nanodrug for combined therapeutics as well as using PET imaging technology for new drug evaluations.

恶性肿瘤是危害人类健康的严重疾病之一。临床研究表明，及时的治疗干预是控制和治愈肿瘤的最有效手段，而如何提高现有药物治疗效果，已成为了基础研究的一个热门领域。靶向释放药物和联合治疗策略已经被证明是提高药物疗效的两个关键因素。在此理论基础和本课题组前期工作基础上，申请人提出以肿瘤靶向性透明质酸为基础，设计合成一类由活性氧分子（ROS）和透明质酸酶共同控制释放的光动力治疗（PDT）/化疗联合治疗的纳米药物，并在细胞水平和动物模型中验证此双因子控释的新型纳米药物的强靶向性和高疗效性。为阐明纳米药物的作用机制和疗效，申请人同时提出利用高灵敏的PET/CT技术，以18F-FDG和18F-RGD2为分子探针，从肿瘤组织代谢和特异蛋白表达两个层面监测和评估新型纳米药物的疗效。.本项目的实施，将有助于新型可控释透明质酸纳米药物的开发，推动联合治疗药物的发展以及促进分子影像技术在新药疗效评估方面的广阔应用。

恶性肿瘤是危害人类健康的严重疾病之一。及时有效的治疗干预是控制和治愈肿瘤的最佳选择，但现有药物疗效常不尽如人意，如何提高现有药物疗效已成为基础研究的一个热门领域。靶向释放药物和联合治疗策略已被证明是提高药效的两个关键因素。为此，我们设计制备了具有良好的生物相容性及肿瘤靶向性的透明质酸纳米颗粒，并合成一类由活性氧分子（ROS）和透明质酸酶共同控制释放的光动力治疗（PDT）/化疗联合治疗的纳米药物，并在细胞水平和动物模型中验证此双因子控释的新型纳米药物的强靶向性和高疗效性。同时利用高灵敏的18F-FDG PET技术，从肿瘤组织代谢层面监测和评估新型纳米药物的疗效。本研究中，我们从以下多个层面对改善PDT、化疗疗效及疗效监测层面进行了探索。我们在光促/酶促双控释透明质酸纳米靶向联合化疗药物方面进行了深入研究。我们合成了HA-TK-CA（HT），而TK可在ROS作用下发生断裂，而后通过物理包埋的方式装载了光敏剂Ce6和化疗药物HCPT，形成了联合光动力治疗及化疗的透明质酸纳米靶向联合药物HTCC，该靶向纳米药物利用光动力治疗过程中释放大量ROS，可使TK断裂、HA-TK-CA核壳结构破坏而释放出化疗药物的特性，同时肿瘤内透明质酸酶活性较高，从而实现了光促/酶促双控释透明质酸纳米靶向联合治疗药物的肿瘤靶向药物释放，降低对正常器官的毒副作用，并从体内外多方面证实了该纳米联合治疗药物光促/酶促双控释药物的特性并取得了良好的疗效。.综上，本研究设计构建了双靶向的光促/酶促双控释纳米药物，用于肿瘤的化疗/光疗联合治疗，提高了药物在肿瘤部位释放率，增强了肿瘤治疗效果。并借助PET成像技术早期监测新型纳米药物疗效，扩大分子影像在新药研发、药效评估方面的应用，促进分子影像学的发展，为新型纳米药物向临床转化提供实验依据。