Sensitize Chemoresistant Breast Cancer by Nano-delivery of siRNA and Cisplatin

描述（由申请人提供）：尽管在早期检测方面取得了进展，并且对乳腺癌生物学的分子基础的理解有所增加，但大约30%的早期乳腺癌患者患有复发性疾病。在大多数乳腺癌病例中，复发的肿瘤是转移性的，并且对初始药物方案的后续治疗是难治的。最近的证据表明，获得性耐药可能源于化疗诱导的突变，并增加肿瘤细胞修复或耐受DNA损伤的能力。因此，通过RNAi疗法消除参与这些途径的关键基因产物（例如Rev 1和Rev 3）可以恢复肿瘤对治疗的化学敏感性。尽管已经做出了相当大的努力来探索用于化学治疗剂和小干扰RNA（siRNA）的各种递送系统，但仍然迫切需要工程化临床相关的、生物相容的、有效的并且可以针对特定疾病靶标定制的纳米载体。本提案的目的是开发一种能够共同递送siRNA（抗Rev 1和Rev 3）和顺铂的多功能纳米载体平台，通过协同效应增强乳腺癌的治疗。这项拟议的研究是基于这样一种假设，即抑制致突变的translesion DNA聚合酶可以防止治疗期间出现化疗耐药性，并恢复乳腺肿瘤对治疗的化疗敏感性。因此，能够同时递送基因特异性siRNA（抗Rev 1和Rev 3）和顺铂的纳米载体为乳腺癌治疗提供了有希望的纳米方法。拟议项目的主要目标是开发一种创新的“二合一”纳米医学方法来共同递送治疗性siRNA（例如，抗Rev 1和Rev 3siRNA）和基于铂的化疗剂（例如，顺铂）在单个聚合物-脂质混合纳米颗粒（NP）内用于乳腺癌治疗。将使用阳离子脂质化合物和聚（丙交酯-共-乙交酯）-b-聚（乙二醇）（PLGA-PEG）开发具有可调物理化学性质的杂合NP库。PLGA-PEG共聚物（PLGA和PEG）的结构单元广泛用于FDA批准的植入式和注射式药物递送系统，并且作为安全的可生物降解材料具有悠久的历史，其能够封装具有广泛理化性质的小分子和大分子有效载荷，并且可以设计用于通过聚合物降解和药物扩散的组合来控制释放。这项研究通过不同治疗方法之间的协同作用和独特的机制，提出了一个有前途的治疗策略。如果成功，可以显着改善现有疗法服务不足的乳腺癌患者的治疗结果，从而提高他们的生活质量。

DESCRIPTION (provided by applicant): Despite advances in early detection and increased understanding of the molecular basis of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease. In most breast cancer cases, the relapsed tumors are metastatic and refractory to subsequent treatment of the initial drug regimen. Recent evidence has implicated that acquired resistance can arise from chemotherapy-induced mutations and increase tumor cell capacity to either repair or tolerate DNA damage. Therefore, the depletion of crucial gene products involved in these pathways (e.g. Rev1 and Rev3) by RNAi therapeutics may restore the tumors chemosensitivity to treatment. Although considerable efforts have been made to explore various delivery systems for chemotherapeutics and small interfering RNA (siRNA), there remains a pressing need towards engineering nanocarriers that are clinically relevant, biocompatible, efficient, and can be tailored to specific disease targets. The objective of this proposal is to develop a versatile nanocarrier platform capable of co- delivering siRNA (anti-Rev1 and Rev3) and cisplatin for enhanced treatment of breast cancer through synergistic effects. This proposed research is based on the hypothesis that suppression of the mutagenic translesion DNA polymerases could prevent chemoresistance from arising during treatment and restore breast tumors' chemosensitivity to treatment. Thus, nanocarriers capable of simultaneously delivering gene specific siRNA (anti-Rev1 and Rev3) and cisplatin present a promising nanotherapeutic approach for breast cancer treatment. The major objective of the proposed project is to develop an innovative "two-in-one" nanomedicinal approach to codeliver therapeutic siRNA (e.g., anti-Rev1 and Rev3 siRNA) and platinum-based chemotherapeutics (e.g., cisplatin) within a single polymer-lipid hybrid nanoparticle (NP) for breast cancer treatment. A library of hybrid NPs with tunable physicochemical properties will be developed using cationic lipid compounds and poly (lactide-co-glycolide)-b-poly (ethylene glycol) (PLGA-PEG). The building blocks of the PLGA-PEG copolymer (PLGA and PEG) are widely used in FDA-approved implantable and injectable drug delivery systems and have a long history as safe, biodegradable materials, which are capable of encapsulating small- and macro-molecular payloads with a wide range of physiochemical properties, and can be designed for controlled release through a combination of polymer degradation and drug diffusion. This research presents a promising therapeutic strategy through the synergy among different therapeutics with unique mechanisms. If successful, could significantly improve therapeutic outcomes for breast cancer patients that are underserved by existing therapies and so enhance their quality of life.