A nanoplatform self-assembled by coordination delivers siRNA for lung cancer therapy

Abstract

The high incidence and mortality of lung cancer have present threaten in front of people all over the world. Researches in clinical trials find that mutations of some genes influence progress of lung cancer directly or indirectly, therefore, some kinds of molecular inhibitors benefit patients in clinical therapy, which helpfully prolong survival time of patients and show great potential in lung cancer therapy. siRNA is a kind of nucleic acid molecules which can silence targeted gene translation through binding to mRNA completely to cure diseases. The delivery of siRNA for cancer therapy mostly can be classified into loading through electrostatic interaction, physical surrounding, and chemically modification. Yet delivering siRNA by coordination has not been reported. This study unprecedently utilizes the coordination between siRNA and Fe²⁺ to form a self-assembly structure in which doxorobicin (DOX) and human serum albumin (HSA) were used to stabilize the whole nanoplatform followed polyethylenimine (PEI) coating. Through the heat incubation strategy, highly loading efficiency for siRNA and DOX was achieved. This nanoplatform with stability and sustain release of drugs exhibited good lysosome escape, gene silencing effect and cytotoxicity which provided new horizon for co-delivery of siRNA and other molecular or protein drugs.

Graphical abstract

摘要

肺癌的高发病率和高死亡率已经威胁到全世界人民的健康。临床研究发现，某些基因的突变直接或间接影响肺癌的进展，因此，在临床中，某些分子抑制剂可用于治疗，有助于延长患者的生存期，在肺癌治疗中显示出巨大的潜力。 siRNA是一种核酸分子，它可以通过与mRNA完全结合来沉默靶基因的翻译，从而治愈疾病。用于癌症治疗的siRNA的递送主要可分为静电相互作用负载、物理包覆和化学修饰。然而，通过配位递送 siRNA 暂无报道。本研究创新利用 siRNA 和 Fe²⁺ 之间的配位形成自组装结构，其中 DOX（阿霉素）和 HSA（人血清白蛋白）用于稳定纳米颗粒结构，最后以 PEI（聚乙烯亚胺）包覆。通过热孵育策略，实现了 siRNA 和 DOX 的高负载效率。这种具有药物稳定性和持续释放的纳米平台表现出良好的溶酶体逃逸、基因沉默和细胞毒性作用，为siRNA与其他分子或蛋白质药物的共递送提供了新的方法指导。