靶向P选择素的微波响应型载阿霉素纳米粒协同微波消融治疗肝癌基础研究

In order to solve the bottleneck of local residuals and secondary metastases after microwave ablation (MWA) of hepatic carcinoma, the models of residual and lung matastasis in nude mice were established after orthotopic liver cancer ablation. Utilizing confinement effect of nano shell and high selectivity of Fi to target P-selectin, the fucoidan (Fi) mediated microwave responsive liposome nanoparticles (FiDOX@MW) were fabricated after encapsulating Doxorubicin (DOX).First of all, targeting delivery of FiDOX@MW to residuals in situ and metastases can be attained at the same time through P-selectin mediated circulating tumor cells to distant metastases. Afterwards, the controlled release of drugs based on the microwave response of FiDOX@MW can be used for treatment of both residual cancer cells and metastases. In addition, the synergistic possibiity of microwave irradiation as a new exogenous stimulus on FiDOX@MW-targeted metastases is investigated for the achievement of high enrichment and accurate release of FiDOX@MW in the therapeutic targets as well as augmentation of chemo-thermal anticancer therapy. The successfully prepared FiDOX@MW can be used to achieve the safe and efficient drug delivery and controlled release, which is expected to provide a new method for the therapy of residual tumor and distant metastases after MWA.

针对肝癌微波消融（Microwave ablation, MWA）术后残存甚至继发远处转移的瓶颈问题，建立裸鼠原位肝癌消融术后残存模型和肺转移模型，利用纳米壳层的限域效应和岩藻聚糖硫酸酯（Fucoidan，Fi）对P选择素的高靶向力，设计构建微波响应型载阿霉素靶向纳米粒（FiDOX@MW）。首先，通过P选择素介导循环肿瘤细胞向远处转移的性质，同时靶向输送FiDOX@MW至原位残存灶和远处转移灶。然后，借助FiDOX@MW的微波响应特性实现药物控释，不仅灭活原位残留，而且靶向治疗远处转移。此外，尝试研究微波作为一种新的外源性刺激，进一步增强P选择素在肿瘤细胞表面高表达的可能性，最终实现纳米药物在治疗靶区的高浓度富集和精准控释，协同MWA提高抗肿瘤治疗水平。预期制备成功的FiDOX@MW可以实现安全、高效的药物递送和控释，有望为MWA术后残存肿瘤和远处转移灶的治疗提供一种新的方法和策略。

肝癌伴广泛转移的患者5年生存率极低。很多临床一线治疗手段，包括手术切除、肝移植、热消融等，虽然对早期肝癌患者能够实现根治的效果，但往往不适用于进展期肝癌伴全身多处转移者。在本项研究中，为探讨一种肝癌治疗的新策略，研制了一种新型靶向微波控释载药纳米递送系统（TBP@DOX）。通过表面修饰特异靶分子物质（岩藻依聚糖），内核包载化疗药物（阿霉素）和微波增敏剂（离子液体），实现了原位肝癌和远处转移灶的同时靶向聚集和高效释放。结果显示，在局部体外微波辐照条件下，TBP@DOX对裸鼠原位肝癌的治疗效果不仅是非靶向纳米粒（BP@DOX）的1.95倍、非微波响应纳米粒（TP@DOX）的1.6倍，更是单纯阿霉素治疗组的10倍。而且，TBP@DOX还表现出对远处肺转移灶最好的治疗效果，并有效预防了全身微小转移灶的形成，延长了裸鼠生存时间。此外，相较于单纯阿霉素治疗，TBP@DOX并未发现明显毒副作用，显示出良好的生物安全性能。因此，这种靶向微波控释载药纳米系统有望为肝癌，尤其是进展期肝癌伴全身多处转移者，提供一种新的治疗策略。