CAS Key Laboratory of Brain Function and Disease and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P. R. China.
Mol Pharm. 2012 Oct 1;9(10):2863-74. doi: 10.1021/mp300193f. Epub 2012 Sep 4.
The particular characteristics of the tumor microenvironment have the potential to strongly promote tumor growth, metastasis and angiogenesis and induce drug resistance. Therefore, the development of effective, systemic therapeutic approaches specifically based on the tumor microenvironment is highly desirable. Hypoxia-inducible factor-1α (HIF-1α) is an attractive therapeutic target because it is a key transcription factor in tumor development and only accumulates in hypoxic tumors. We report here that a cationic mixed micellar nanoparticle (MNP) consisting of amphiphilic block copolymers poly(ε-caprolactone)-block-poly(2-aminoethylethylene phosphate) (PCL(29)-b-PPEEA(21)) and poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL(40)-b-PEG(45)) was a suitable carrier for HIF-1α siRNA to treat hypoxic tumors, which showed an average diameter of 58.0 ± 3.4 nm. The complex MNP(siRNA), formed by the interaction of MNP and siRNA, was transfected into PC3 prostate cancer cells efficiently, while the inhibition of HIF-1α expression by MNP loaded with HIF-1α siRNA (MNP(siHIF)) blocked PC3 cell proliferation, suppressed cell migration and disturbed angiogenesis under in vitro hypoxic mimicking conditions. It was further demonstrated that systemic delivery of MNP(siHIF) effectively inhibited tumor growth in a PC3 prostate cancer xenograft murine model without activating innate immune responses. Moreover, delivery of MNP(siHIF) sensitized PC3 tumor cells to doxorubicin chemotherapy in vitro and in vivo by downregulating MDR1 gene expression which was induced by hypoxia. The underlying concept of use of MNP(siHIF) to block HIF-1α holds promise as an example of a clinical approach using specific siRNA therapy for cancer treatment aimed at the hypoxic tumor microenvironment.
肿瘤微环境的特殊特征有可能强烈促进肿瘤生长、转移和血管生成，并诱导耐药性。因此，开发针对肿瘤微环境的有效、系统性治疗方法是非常理想的。缺氧诱导因子-1α（HIF-1α）是一个有吸引力的治疗靶点，因为它是肿瘤发展的关键转录因子，并且仅在缺氧肿瘤中积累。我们在这里报告说，由两亲性嵌段共聚物聚（ε-己内酯）-嵌段-聚（2-氨基乙基乙烯磷酸酯）（PCL（29）-b-PPEEA（21））和聚（ε-己内酯）-嵌段-聚（乙二醇）（PCL（40）-b-PEG（45））组成的阳离子混合胶束纳米颗粒（MNP）是一种合适的 HIF-1α siRNA 载体，可用于治疗缺氧肿瘤，其平均直径为 58.0±3.4nm。通过 MNP 和 siRNA 的相互作用形成的复合物 MNP（siRNA）有效地转染 PC3 前列腺癌细胞，而负载 HIF-1α siRNA 的 MNP（MNP（siHIF））抑制 HIF-1α 表达，在体外模拟缺氧条件下抑制 PC3 细胞增殖、抑制细胞迁移和扰乱血管生成。进一步证明，MNP（siHIF）的系统递送有效地抑制了 PC3 前列腺癌异种移植小鼠模型中的肿瘤生长，而没有激活先天免疫反应。此外，MNP（siHIF）的递送通过下调缺氧诱导的 MDR1 基因表达，在体外和体内增强了 PC3 肿瘤细胞对阿霉素化疗的敏感性。使用 MNP（siHIF）阻断 HIF-1α 的概念为使用针对缺氧肿瘤微环境的特异性 siRNA 治疗癌症的临床方法提供了一个范例。
