可穿透胰腺癌双重屏障的肿瘤微环境响应型多级HSA/lipid纳米递药系统研究

The dual drug barriers of low blood supply and high fibrotic matrix restrict nanomedicine delivery to pancreatic cancer cells. Abraxane can penetrate tumor fibrotic matrix and is the only nanomedicine approved by FDA for first-line treatment of pancreatic cancer. But Abraxane delivery is still restricted by low blood supply of pancreatic cancer and its own weak blood retention. Therefore, we design tumor microenvironment-responsive multistage HSA/lipid nano-sized drug delivery system (CT/HP). CT/HP forms nano-sized prodrug of cilengitide and can continuously release low concentration of cilengitide under the trigger of tumor vascular enzyme to improve tumor blood supply. Thermo-sensitive lipid package not only can improve blood retention of HP, but also can rapidly release high concentration of HP with the tumor heat treatment, thus conductive to their tumor absorption and stromal penetration. Improvement of blood supply, drug blood retention, fibrotic matrix penetration, and pharmacodynamics behaviors of CT/HP will be investigated by building tumor spheroids, tumor-burdened nude mice models, etc. CT/HP will improve the blood supply and drug blood retention, and contribute to HP’s penetration, thus penetrating dual barriers. CT/HP will further enhance Abraxane delivery, improve nanomedicine chemotherapy of pancreatic cancer, and has a good potential for clinical use which will provide novel strategies for pancreatic cancer treatment.

胰腺癌的低血供、高纤维基质形成纳米制剂递药的双重屏障。Abraxane可穿透纤维基质，是唯一获批用于胰腺癌一线治疗的纳米制剂，但其递药效率仍受限于低血供及自身血滞留弱的不足。为此我们设计了肿瘤微环境响应的多级白蛋白脂质纳米递药系统（CT/HP）。CT/HP形成西仑吉肽（CL）纳米化前药，在肿瘤血管酶触发下可持续释放低浓度CL，发挥增血供作用；热敏脂质包载可增强白蛋白-紫杉醇复合物（HP）血滞留，在肿瘤热刺激下又可迅速释放高浓度HP，从而有利于其肿瘤吸收，并保留其基质渗透性能。已构建肿瘤球、荷瘤裸鼠等模型，将进行CT/HP增血供、增强血滞留、纤维基质渗透、药效学等评价。CT/HP有望同时增强血供及药物血滞留，保留HP渗透性能，可穿透双重屏障。CT/HP将进一步增强Abraxane递药效率，提高现有胰腺癌纳米制剂化疗水平，有极高的临床应用前景，将为开发新型胰腺癌化疗手段提供有力基础和实践依据。

胰腺癌低血供、高纤维基质的生理病理特征，严重制约了化疗药物向肿瘤细胞的递送，是其临床化疗效果不佳的重要原因。脂质体不仅可延长药物的血滞留，而且可利用肿瘤EPR（enhanced penetration and retention，EPR）效应将药物靶向递送至肿瘤组织。然而，受限于低血供，脂质体在肿瘤组织难以达到足够的递送量，同时，脂质体不能穿透高纤维基质，大部分分布在肿瘤近血管区域，难以接触到肿瘤细胞。在临床上，阿霉素脂质体（Doxil）用于胰腺癌病人未观察到明显疗效。为此，我们通过MT1-MMP可裂解的肽linker（KRRQLGLPALSβAla）将低密度西仑吉肽（cilengitide，CL）修饰至包载阿霉素（doxorubicine，DOX）的热敏脂质体（thermosensitive liposomes，TSLs）表面，即得MC-T-DOX。MC-T-DOX可被肿瘤内皮细胞表面选择性表达的MT1-MMP活化，释放出游离CL。这些局部释放的CL可特异性促进肿瘤血管生成及增强肿瘤血供，从而提高MC-T-DOX的瘤内递送。MC-T-DOX在肿瘤局部热作用下，可在间质释放出DOX；不同于脂质体包裹的DOX，这些游离DOX可穿透高纤维基质被肿瘤细胞摄取，从而显著提高DOX在肿瘤细胞的暴露量。通过有效克服胰腺癌低血供、高纤维基质的双重屏障，MC-T-DOX在胰腺癌荷瘤鼠产生了显著的治疗效果，且未在正常组织引起额外毒性。本项目的顺利实施可为用于胰腺癌治疗的纳米载体设计提供理论依据及实践基础。