超高载药量乏氧响应性仿生纳米药物的构建及其用于晚期乳腺癌靶向治疗的研究

The efficient encapsulation of drugs in nanomedicine, targeted delivery of drugs into tumor cells, and the specific release of drugs in tumors serve as the critical challenges for the successful treatment of advanced breast cancer. In the current study, we aim to develop the neutrophil membranes coated nanoparticles with high drug loading to solve these critical challenges against targeted anticancer therapy. (1) We synthesize the paclitaxel (PTX) dimer to achieve high drug loading by reducing the π-π interaction between drugs. (2) We design the neutrophil membranes coated nanoparticles that can be recruited by tumor tissue and further activated by inflammatory stimuli in tumor microenvironment to achieve targeted anticancer treatment of tumor cell and circulating tumor cell. (3) Based on the severe hypoxic environment in advanced breast cancer, we design the hypoxia-responsive PTX dimer that can realize specific PTX release in tumor site to enhance anticancer efficacy. This study provides a useful strategy for efficient drug loading and targeted anticancer therapy.

纳米药物用于治疗晚期乳腺癌的关键在于如何实现药物的高效包载、靶向递送和肿瘤部位的特异性释放。本项目发展一种具有超高载药量、中性粒细胞膜包衣的靶向药物递送体系，用于解决药物的靶向递送和抗肿瘤治疗过程中的几个关键问题：（1）设计紫杉醇二聚体前药，通过二聚体结构削弱药物之间的π-π相互作用，实现药物的高效包载。（2）设计中性粒细胞膜包衣的纳米药物，通过肿瘤组织招募、肿瘤微环境炎症刺激的激活，实现对肿瘤细胞、循环肿瘤细胞的有效靶向。（3）设计乏氧敏感的紫杉醇二聚体前药，利用晚期乳腺癌瘤内严重的乏氧环境，实现肿瘤部位药物的特异性释放，提高抗肿瘤疗效。本项目对实现纳米药物的高效载药和靶向抗肿瘤治疗具有重要意义。

乳腺癌是女性常发的恶性肿瘤之一，在肿瘤晚期时瘤内存在严重的乏氧环境，且循环肿瘤细胞会和中性粒细胞形成细胞簇，促进肿瘤转移。化疗是治疗晚期乳腺癌常用的手段，但缺乏选择性，会产生严重的毒副作用。纳米药物在肿瘤治疗上展示出了显著的优势，但载药量低、肿瘤靶向性弱、药物无法特异性释放限制其进一步发展。为解决以上问题，本项目成功构建了具有超高载药量、中性粒细胞膜包衣的仿生纳米药物用于肿瘤和抗转移治疗。其中，紫杉醇前药的二聚体结构可削弱药物之间的π-π相互作用，实现药物的高效包载；二聚体结构中的乏氧敏感键可在晚期乳腺癌的乏氧环境下断裂，实现紫杉醇的特异性释放；中性粒细胞膜包衣的纳米递送载体基于中性粒细胞膜的炎症趋向性，一方面可靶向递送药物至肿瘤部位，另一方面可干扰血液中中性粒细胞-循环肿瘤细胞簇的形成，抑制肿瘤转移，实现多位点同时抑制肿瘤的生长和转移。本项目对实现纳米药物高效载药和靶向治疗肿瘤和转移具有重要意义。