基于磷脂酶D催化合成和触发释放的磷脂酰纳米前药用于肿瘤靶向传递的研究

Targeting nanoparticle drugs, as an efficient solution in relieving the severe side effects of chemotherapeutics, have become increasingly interesting in cancer therapy. However, most of the nanoparticle drugs are still in the preclinical stage, even with the rapid development of the nanoparticle engineering and integration of multiple functions. In order to improve the efficiency of treatment, the major problem is how to keep nanoparticle drugs stable during transportation, and make them efficiently released in the target tumor. In this study, a new phosphatidy-prodrug based on the Phospholipases D catalysis and triggered release will be developed, exploiting the characterestics of PLD (over expression in tumor tissues , transphosphatidylation and hydrolysis). First, the self-assembled prodrug is planned to be efficiently catalyzed and synthetized with PLD. Then, targeted multifunctional modification and optimization of formulation and preparation process in the nanoparticle will be performed to improve the hydrolysis activity of the prodrug in tumor tissue . After that, the drug release rate, the anticancer activity and toxicity related of the phosphatidy-prodrug can be measured with different cancer models vitro and vivo, to evaluate the triggered release performance of the prodrug. All these research will be a significant improvement in solving the conflicting targets of both keeping the nanoparticle drug stable and simultaneously guarantee the efficient release of the drug in the tumor target. They will also provide new strategies and application methods in tumor targeting drug delivery.

化疗药物杀灭肿瘤细胞的同时也作用于正常细胞，靶向纳米药物是降低化疗毒副作用的有效途径。尽管纳米药物的制备与多功能化技术的快速发展推动了它们在肿瘤治疗方面的应用，但大多数纳米药物还处在临床前研究阶段。纳米药物在转运时安全稳定，在肿瘤内有效释放活性药物是提高治疗靶向效率，降低毒副作用的关键因素。为此，本课题拟利用PLD肿瘤组织过表达和转脂与水解催化的特点，催化转脂合成肿瘤内PLD触发释放的磷脂酰前药。研究将通过PLD高效催化合成自组装纳米前药；质膜表面靶向多功能修饰；优化纳米粒处方和制备工艺，提高纳米前药对PLD水解敏感性；建立体内体外肿瘤生物模型，测定前药在不同模型中的释放率及相关活性和毒性，评价前药响应释放效应。解决靶向药物安全稳定性和靶位有效释放同时共存的矛盾，为肿瘤靶向药物治疗提供的了新的策略和应用手段。

利用磷脂酶D（PLD）在肿瘤组织内过表达和水解/转脂双向反应特性，设计了一种安全、有效的两亲性前体药物输送系统，即在体外合适的催化反应条件下，PLD催化磷脂分子中的磷脂酰基(供体)转移到多种含羟基化合物(受体)上，形成新的磷脂类化合物，靶向积累到肿瘤组织经活性特异性升高的PLD水解释放药物，释放出原药，特异性原位杀灭肿瘤细胞。.采用模式药物阿霉素和米托蒽醌分别与磷脂经PLD催化，共价键合“包装“成稳定无活性的纳米前药形式，前药在水溶液中可以自组装形成纳米粒，具备一般纳米载药系统的特性。纳米前药在生理无PLD存在的环境下性质稳定，在PLD存在时酶促释放原药；在不同PLD表达的肿瘤细胞内，原药释放量和细胞毒性与PLD的表达呈正相关，表明磷脂酰纳米前药具有PLD酶促特异性响应释放能力。采用共聚焦显微镜和流式细胞仪观察前药在肿瘤细胞内的吸收、定位和分布情况，结果显示前药通过内吞途径进入细胞，能够躲避MCF-7/ADR耐药株高表达P-gp的泵出而明显提高细胞内的载药量，进一步研究发现前药主要是通过小窝蛋白介导内吞途径进入细胞，其在胞内运输过程与内质网和高尔基体有关，可能更加有利于前药在肿瘤细胞内的酶促释放。采用MCF-7/ADR耐药乳腺癌荷瘤小鼠和SKOV-3人卵巢癌荷瘤小鼠对前药的抗肿瘤活性进行评价，结果显示化疗药物阿霉素和米托蒽醌经PLD转脂催化修饰后，既保留了其抗肿瘤活性，同时显著地改善了其对心、肾的毒副作用，具有良好的临床应用前景。.课题建立一种磷脂酶D催化合成和触发释放的肿瘤靶向磷脂酰纳米前药策略，改善了传统前药释放的非特异性或不确定性，为纳米前药响应性释放提供了一种新的策略。.

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