Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors.
Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors.
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DOI：
10.1016/j.biomaterials.2013.01.077
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发表时间：
2013-04
期刊：
影响因子：
14
通讯作者：
Amiji, Mansoor M.
中科院分区：
文献类型：
--
作者：
Ganesh, Shanthi;Iyer, Arun K.;Morrissey, David V.;Amiji, Mansoor M.
关键词：
利用RNA干扰机制的抗肿瘤治疗具有序列特异性沉默靶基因的潜力。然而，将siRNA靶向递送至肿瘤组织和细胞，更重要的是，它们在感兴趣部位的细胞内释放仍然是一个主要挑战，在该技术成为临床可行的选择之前需要解决。在目前的研究中，我们设计并筛选了一系列基于CD 44靶向透明质酸（HA）的自组装纳米系统，用于靶向siRNA递送。HA聚合物用不同碳链长度/氮含量的脂质以及用于评估siRNA包封的多胺官能化。从筛选中，鉴定了几种HA衍生物，其可以稳定地包封/复合siRNA并形成自组装纳米系统，如通过凝胶阻滞测定和动态光散射所确定的。许多HA衍生物可以将siRNA转染到过表达CD 44受体的癌细胞中。有趣的是，在孵育cy 3标记的siRNA负载的HA纳米组装体之前使用游离过量的可溶性HA阻断细胞上的CD 44受体导致>90%的受体介导的摄取抑制，证实了靶特异性。此外，包封在HA-PEI/PEG纳米系统中的SSB/PLK 1 siRNA在过表达CD 44受体的敏感和耐药A549肺癌细胞中均表现出剂量依赖性和靶特异性基因敲减。更重要的是，这些siRNA包封的纳米系统在实体瘤以及转移性肿瘤中表现出肿瘤选择性摄取和体内靶特异性基因敲低。因此，基于HA的纳米系统预示着是有前途的siRNA递送载体，用于全身靶向CD 44过表达的癌症，包括肿瘤起始（干）细胞和转移性病变。
Anticancer therapeutics employing RNA interference mechanism holds promising potentials for sequence-specific silencing of target genes. However targeted delivery of siRNAs to tumor tissues and cells and more importantly, their intracellular release at sites of interest still remains a major challenge that needs to be addressed before this technique could become a clinically viable option. In the current study, we have engineered and screened a series of CD44 targeting hyaluronic acid (HA) based self-assembling nanosystems for targeted siRNA delivery. The HA polymer was functionalized with lipids of varying carbon chain lengths/nitrogen content, as well as polyamines for assessing siRNA encapsulation. From the screens, several HA-derivatives were identified that could stably encapsulate/complex siRNAs and form self-assembled nanosystems, as determined by gel retardation assays and dynamic light scattering. Many HA derivatives could transfect siRNAs into cancer cells overexpressing CD44 receptors. Interestingly, blocking the CD44 receptors on the cells using free excess soluble HA prior to incubation of cy3-labeled-siRNA loaded HA nano-assemblies resulted in >90% inhibition of the receptor mediated uptake, confirming target specificity. In addition, SSB/PLK1 siRNA encapsulated in HA-PEI/PEG nanosystems demonstrated dose dependent and target specific gene knockdown in both sensitive and resistant A549 lung cancer cells overexpressing CD44 receptors. More importantly, these siRNA encapsulated nanosystems demonstrated tumor selective uptake and target specific gene knock down in vivo in solid tumors as well as in metastatic tumors. The HA based nanosystems thus portend to be promising siRNA delivery vectors for systemic targeting of CD44 overexpressing cancers including tumor initiating (stem-) cells and metastatic lesions.
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作者：
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