具酸敏感内核的共载siRNA/阿霉素仿生低密度脂蛋白靶向递药系统构建与评价

Epithelial-mesenchymal transition (EMT) is the culprit of tumor invasion and metastasis, thus regulation of critical factors in EMT process will be an effective strategy of antagonizing tumor metastasis. Snail is an important zinc-finger transcription factor to induce EMT and tumor metastasis, therefore knocking down snail signal pathway by small interfere RNA (siRNA) may inhibit tumor metastasis availably. If combined with chemotherapeutics, it will inhibit the growth and metastasis of cancer more effectively. Based on this, our project designed and constructed a biomimetic low-density lipoprotein (bioLDL) nanoparticle. The hydrophobic anti-tumor drugs were embedded in the bilayer phospholipids modified with ApoB100, and Snail siRNA-loaded pH-sensitive Calcium-phosphate nanoparticles with controlled sizes were wrapped in the core of bioLDL, thus to efficiently deliver drugs and siRNA to tumor cells. This bioLDL can escape from opsonification and clearance of macrophages, accumulate in tumor tissue, penetrate into deep layers of tumor by taking advangtage of the small size, be endocytosed by tumor cells through LDL receptors, as well as escape from endosomal/lysosomal degradation on account of proton sponge effect and plasmalemma fusion, then release drugs and genes into cytoplasm, and in the end exert a synergistic effect of antagonizing tumor growth and metastasis. As a result, the project will provide a available strategy for constructing a novel cotransport drug delivery system by bionic techniques.

上皮-间质转化（EMT）是肿瘤浸润及转移的基础，针对EMT过程中关键因子的调控将成为有效的抗转移治疗策略。Snail是EMT过程中重要的锌指转录因子，可诱导EMT发生和肿瘤转移，采用siRNA下调Snail表达将是抑制转移的有效方法，若与化疗药联用将更有效抑制肿瘤生长和转移。基于此，本项目设计和构建一种低密度脂蛋白（LDL）仿生纳米粒，外层为荷载疏水性抗肿瘤药的不对称脂质体并修饰载脂蛋白ApoB100，核心为Snail siRNA与酸敏感性磷酸钙结合的粒径可控的纳米粒，用于实现药物和基因的高效递送。该仿生LDL可逃避体内巨噬细胞吞噬和调理素作用，有效富集至肿瘤组织，利用尺寸效应穿透进入肿瘤深层，并借助LDL受体实现高效内吞，同时具有质子海绵效应和质膜融合能力，实现溶酶体逃逸，最终将基因和化疗药在胞质快速释放，发挥二者协同抗肿瘤生长和转移的作用，为仿生技术构建新型共转运递药系统提供新思路。