神经肽Y1受体介导的高选择性乳腺癌靶向治疗药物研究

Proper targeting is one of the key issues in anticancer drug discovery and development warranting that the developed drug reaches the targeted tissue and efficiently induces its pharmacological action. This project aims to develop a novel targeted nanomedicine for breast cancer therapy, including preparation of sub-200 nm biodegradable albumin nanoparticles, encapsulation of doxorubicin inside the nanoparticles, conjunction of novel targeted molecules PNBL-NPY on the surface of the nanoparticles. Once arriving at the breast tumor site, the PNBL-NPY will actively recognize and bind to the neuropeptide Y1 receptors that significantly over-expressed on the surface of the breast cancer cells, and the nanoparticles will be delivered directly into the cancer cells through internalization. This system is high selective and able to distinguish the breast cancer cells from the normal cells, due to normal breast cells only express Y2 receptors. This project also aims to investigate the surface binding process between targeted molecules and nanoparticles with chemical and cell biological methodology, and optimize the density of the targeted molecules to improve the targetability and the effective cell toxicity of the nanoparticles on MCF-7 human breast cancer cells. The expected results of this project will be that the breast cancer could be highly specifically targeted and cured by the developed composite nanoparticles, providing a more secure, efficient and lower toxicity therapy for breast cancer.

靶向性药物是目前抗癌药物研发的重点和难点。本项目拟开发一种用于乳腺癌治疗的新型主动靶向型纳米药物，研究思路如下：利用化学方法构建和制备出尺寸小于200nm、内部包埋有抗癌药物阿霉素、表面偶联有新型活性靶分子PNBL-NPY的可生物降解白蛋白纳米粒子，通过纳米粒子表面的PNBL-NPY主动识别乳腺癌细胞上高表达的Y1受体，有效区分仅在正常乳腺细胞上表达的Y2受体，主动递送抗癌药物至癌细胞内，达到降低抗癌药物对正常细胞的毒副作用的目的；利用化学及细胞生物学的相关技术，研究活性靶分子与纳米材料表面结合的作用过程，通过优化活性靶分子的结合密度，有效提高复合纳米粒子对人乳腺癌MCF-7细胞的靶向效果和有效毒性作用。通过本项目的研究，有望制备出一种新型主动靶向治疗乳腺癌的复合纳米粒子，为将来临床上更安全、高效和低毒副作用地治疗乳腺癌奠定坚实基础。

针对目前抗癌药物靶向性差、毒副作用较大的缺点，本研究开发了一种用于乳腺癌治疗的新型主动靶向型纳米药物。.利用化学方法构建和制备出尺寸小于 200nm、内部包埋有抗癌药物阿霉素、表面偶联有新型活性靶分子 PNBL-NPY或AP-NPY 的可生物降解白蛋白纳米粒子。所制备出的PNBL-NPY-DOX-ANP复合纳米粒子的粒径在140 nm左右，形貌均一且分散性较好。白蛋白纳米粒子对DOX的搭载率和包封率分别在2.57 % 和 86.5 %。实验结果表明，PNBL-NPY配体可以显著提高DOX-ANP对人乳腺癌MCF-7细胞的靶向作用（65.8 %），且该过程主要是由MCF-7细胞上表达的Y1受体内吞调控。经过PNBL-NPY修饰后的纳米粒子较正常的乳腺细胞MCF-10A，更容易进入MCF-7细胞（70.4 %）。PNBL-NPY-DOX-ANP对癌细胞生长的抑制作用明显强于DOX-ANP。除此之外，研究还发现PNBL-NPY配体自身对MCF-7 细胞存活率也有显著抑制作用，但是对MCF-10A细胞的生长却没有影响。因此，PNBL-NPY-DOX-ANP对乳腺癌细胞MCF-7生长的抑制作用，不仅来自于纳米粒子内部的DOX，而且和PNBL-NPY配体的协同作用有关。.进一步研究发现，AP-NPY-DOX-ANP复合纳米粒子的粒径在244 nm左右，形貌均一且分散性较好。实验结果表明，AP-NPY配体的修饰可以显著提高DOX-ANP对人乳腺癌MCF-7细胞的靶向作用，经过AP-NPY修饰的载药纳米粒子更容易进入到癌细胞内。AP-NPY-DOX-ANP对MCF-7细胞的有效毒性作用明显强于PNBL-NPY-DOX-ANP。因此，AP-NPY配体是较PNBL-NPY更优异的活性靶分子。.综上所述，本研究所制备出的复合纳米粒子，可以通过其表面的 PNBL-NPY或AP-NPY主动识别乳腺癌细胞上高表达的 Y1 受体，有效区分仅在正常乳腺细胞上表达的 Y2 受体，主动递送抗癌药物至癌细胞内，达到降低抗癌药物对正常细胞的毒副作用的目的，为将来临床上更安全、高效、低毒的治疗乳腺癌提供了新的依据。

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