Targeted Platinates/siRNA Combination Therapy for Resistant Lung Cancer

描述（由申请人提供）：在男性和女性中，肺癌造成的死亡人数超过任何其他类型的癌症，2012年在美国估计有226,160例新病例和160,770例死亡。铂类药物虽然在肺癌化疗中发挥了非常重要的作用，但其主要局限性在于全身性毒性和快速获得耐药。因此，迫切需要开发一种替代策略，以一种没有相关毒性负担的临床有意义的方式有效治疗难治性肺癌。RNA干扰治疗是一种下调铂耐药相关基因的有效方法，因此可以与细胞毒性化疗协同作用于难治性肺癌患者。本R21提案的主要目的是评估在CD44和表皮生长因子受体（EGFR）靶向生物相容性透明质酸（HA）自组装纳米系统中使用亲脂（脂尾）铂酸衍生物和小干扰rna （sirna）联合治疗肺癌的治疗潜力。作为初步研究的一部分，我们已经开发了一系列改性的HA衍生物，使用“点击”化学偶联，允许组合设计的配方开发方法，用于包封疏水（例如，脂尾铂酸盐）和亲水/带电（例如，siRNA）分子。此外，模块化纳米平台允许合并额外的功能，包括EGFR特异性肽，用于肺癌的双重靶向。建议的具体目的如下：(1)综合

DESCRIPTION (provided by applicant): Lung cancer accounts for more deaths than any other types of cancer in both men and women, with an estimated 226,160 new cases and 160,770 deaths in 2012, in the United States. Although platinum drugs have played a very important role in the chemotherapy of lung cancer, their major limitations are systemic toxicity and the rapid acquisition of resistance. As such, there is an urgent need to develop alternative strategies to effectively treat refractory lung cancer in a clinically-meaningful way without the associated toxicity burden. RNA interference therapy can be a powerful approach to down-regulate specific genes involved in platinum resistance and, therefore, can work synergistically with cytotoxic chemotherapy in refractory lung cancer patients. The main objective of this R21 proposal is to evaluate the therapeutic potential for combination lung cancer therapy using lipophilic (lipid-tailed) platinate derivatives and small interfering RNAs (siRNAs) delivered in CD44- and epidermal growth factor receptor (EGFR)-targeted biocompatible hyaluronic acid (HA) based self-assembling nano-systems. As part of the preliminary studies, we have developed a series of modified HA derivatives, using "click" chemical conjugation that allow for combinatorial- designed formulation development approach for encapsulation of hydrophobic (e.g., lipid-tailed platinates) and hydrophilic/charged (e.g., siRNA) molecules. Additionally, the modular nano-platform allows for incorporation of additional functionalities, including EGFR specific peptide, for dual targeting in lung cancer. The specific aims of the proposal are as follows: (1) synthesis and characterization of "lipid tailed" platinate derivatives and encapsulation, along with siRNA duplexes, in HA-based self-assembling nano- systems, (2) evaluation of in vitro gene silencing and cell-kill efficacy using single (lipid-tailed platinate alone) and combination (siRNA+platinate therapy in sensitive A549 and cisplatin-resistant A549DDP human non-small cell lung cancer cells, and (3) establish A549 and A549DDP tumor xenografts in athymic (nu/nu) mice and in vivo evaluation of anti-tumor efficacy and safety of single and combination siRNA/platinate therapy using dual targeting HA-based self-assembled nano-systems. This study is highly significant in evaluating gene silencing strategy in vivo for overcoming tumor drug resistance using a safe and effective delivery system. Following successful completion, future studies in the R01 phase will focus on evaluation of multiple gene silencing and combination therapy delivered with dual targeted HA nanoparticles in a transgenic human lung cancer model.