同时抑制普通肿瘤细胞和肿瘤干细胞的药物/microRNA共传递系统的研究

In the past decades, polymeric nano-drug delivery system has made great progress in the treatment of malignant tumor. However, the tumor faces recurrence and metastasis when stopping target drug or gene therapy, resulting in more serious complications. Recent study revealed that this phenomenon lies in the existence of a small group of specific cells in the cancer cells, called “cancer stem cells”, which are highly tolerant of normal chemotherapy and genetherapy. Although specific microRNAs can effectively inhibit the growth and metastasis of cancer stem cells. The solo treatment of cancer stem cells can't effective inhibit the proliferation of tumor, because there were a large number of common cancer cells existing in tumor tissues, and mature common cancer cells possibly mutated into cancer stem cells. This project plans to design a kind of reduction sensitivite cationic polymeric micelles. In the hydrophilic cationic outer shell, the micelles complex microRNAs via electrostatic interaction which can inhibit the growth and metastasis of cancer stem cells and promote cancer stem cells differentiation into common cancer cells; Meanwhile, in the hydrophobicity inner core, the micelles load adriamycin with efficient anti-proliferation effect to common tumor cells, in order to achieve the purpose of inhibiting both common cancer cells and cancer stem cells simultaneously, and enhancing anti-tumor therapeutic effect, preventing recurrence and metastasis of tumor.

近年来，高分子纳米医药传递系统在恶性肿瘤的治疗方面取得了长足的进步。但是，当停止药物或基因治疗后，肿瘤往往再次复发和转移，导致病情恶化。最新研究发现，造成这一现象的重要原因之一在于肿瘤细胞中存在的一小群对常规化疗和基因治疗有高度耐受性的细胞——肿瘤干细胞。虽然特定的miRNAs治疗能够有效的抑制肿瘤干细胞的生长和转移。但是，仅仅针对肿瘤干细胞的治疗无法高效的抑制肿瘤，因为肿瘤组织大量存在的是普通肿瘤细胞，而且成熟的普通肿瘤细胞还有可能畸变成为肿瘤干细胞。本项目拟设计一类还原敏感性的阳离子高分子胶束，在其亲水性的阳离子外层通过静电相互作用装载对肿瘤干细胞具有转化抑制作用的miRNAs，一方面抑制肿瘤干细胞的生长和转移，另一方面有效促进其分化为普通肿瘤细胞；同时，在其疏水性内核装载抗普通肿瘤细胞的阿霉素，从而达到同时抑制普通肿瘤细胞和肿瘤干细胞的目的，增强抗肿瘤治疗效果，防止肿瘤的复发和转移。

本项开发了基于小分子氨基酸构建的还原敏感性的阳离子型高分子胶束载体，基于天然普鲁兰多糖的pH敏感性纳米粒子以及基于透明质酸的还原敏感性载药凝胶三类药物载体系统。这些载体系统能够高效地将单一或多种药物被动/主动靶向到肿瘤部位，并通过其还原敏感键的设计，快速将药物释放于肿瘤细胞内部，通过联合治疗，有效的增强治疗效果，降低毒副作用，为发展具有临床应用价值的抗肿瘤纳米生物医药制剂奠定基础，促进肿瘤临床化疗技术的发展。