光照可逆响应的多功能纳米载体的制备及其在乳腺癌治疗中的应用

Multi-drug resistance (MDR) of tumor cells in the treatment of cancer is a great scientific challenge. An effective solution to this problem is combination therapy of chemotherapeutics and gene therapy. However, the key of the combination therapy approach for success is how to fabricate efficient, safe and controlled vectors for simultaneously drug and gene delivery. Herein, we propose a versatile and ultraviolet light-responsive nanocarrier based on coumarin modified low-generation dendrimers to co-deliver 5-fluorouracil and siRNA against P-glycoprotein in the treatment of breast cancer. The materials can efficiently encapsulate the 5-fluorouracil, and exhibits an ultraviolet light-responsive “off-on” drug release profile which avoids the burst drug release during the delivery process in vivo. In addition, this multifunctional nanocarrier performs significantly siRNA delivery efficacy. In this study, we will fabricate the light-responsive multifunctional nanocarriers, and investigated their feasibility in vitro and in vivo synergistic treatment of breast cancer. The aim of study is to provide insight into the designing of dendrimer-based multifunctional nanocarriers for for synergistic therapy of cancer.

肿瘤细胞的多药耐药性一直是癌症治疗中面临的科学难题，利用协同治疗方法将基因治疗与化疗相联合应用可以有效规避多药耐药性。而协同治疗成功的关键是制备高效、安全、可控的递送载体，将化疗药物和治疗基因根据治疗需求有序的递送到患者体内发挥作用。本项目提出设计一种基于香豆素修饰的低代数树形高分子的光照刺激响应的多功能纳米载体系统，用于递送抗肿瘤药物5-氟尿嘧啶和敲除多耐药基因(如P-糖蛋白，P-gP)的siRNA协同治疗乳腺癌。这种多功能纳米载体，在紫外光的照射下能够可逆的装载和释放5-氟尿嘧啶，有效的解决了药物在体内输送过程中的暴释问题，同时又具有很强的基因转染能力，保证了siRNA的高效输送。本项目将探索这种光照可逆响应的多功能纳米载体的制备方法，及其在体外、体内协同治疗乳腺癌的可行性。希望通过该项目的研究，为基于树形高分子的多功能纳米载体在乳腺癌疾病协同治疗中的应用打下坚实的理论基础。

将基因治疗和化疗联合应用可以有效的规避肿瘤细胞的多药耐药性，从而增强治疗基团和药物的抗肿瘤效果。本项目拟利用低代数的聚酰胺胺(PAMAM)树形高分子，通过化学改性的方法制备光照刺激响应的多功能纳米载体，用于治疗基因和抗癌药物的协同的输送，来解决肿瘤细胞的多药耐药性问题。我们选取二代的（Generation 2，G2）氨基末端的PAMAM树形高分子，利用迈克尔加成反应，将香豆素（Coumarin， CM）分子修饰在G2 PAMAM 表面的部分氨基上，形成的具有两亲性的G2-CM能够自组装形成的200nm左右的纳米颗粒。该纳米颗粒可以有效的结合核酸分子，并将其高效的输送到乳腺癌细胞内。修饰的香豆素分子能够赋予该纳米载体具有光照响应的药物输送行为。组装在纳米颗粒内部的香豆素分子能够在365nm的光照下发生自交联共价结合反应，同时在254nm的光照下共价结合键又发生解离，从而实现对抗癌药物5-氟尿嘧啶的可控装载和释放。我们利用该纳米颗粒载体共装载抗肿瘤药物5-氟尿嘧啶和治疗基团，实现了对乳腺癌细胞的协同抑制效应。结果表明，本项目制备的多功能纳米载体在肿瘤疾病的协同治疗中具有很好的应用前景。