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

描述(申请人提供)：尽管在早期检测方面取得了进展，对乳腺癌生物学的分子基础也有了更多的了解，但所有早期乳腺癌患者中约有30%有复发疾病。在大多数乳腺癌病例中，复发的肿瘤是转移性的，对随后的初始药物方案治疗无效。最近的证据表明，获得性耐药可由化疗诱导的突变产生，并增加肿瘤细胞修复或耐受DNA损伤的能力。因此，RNAi治疗耗尽了这些通路中的关键基因产物(如Rev1和Rev3)，可能会恢复肿瘤对化疗的敏感性。尽管已经做出了相当大的努力来探索化疗药物和小干扰RNA(SiRNA)的各种递送系统，但仍然迫切需要设计出临床上相关的、生物相容的、高效的、可以针对特定疾病靶点定制的纳米载体。这项建议的目的是开发一种多功能的纳米载体平台，能够通过协同作用共同传递siRNA(抗Rev1和Rev3)和顺铂，以加强乳腺癌的治疗。这项拟议的研究是基于这样的假设，即抑制突变的跨病变DNA聚合酶可以防止在治疗过程中产生化疗耐药，并恢复乳腺肿瘤对治疗的化疗敏感性。因此，能够同时运送基因特异性siRNA(抗Rev1和Rev3)和顺铂的纳米载体为乳腺癌的治疗提供了一种很有前途的纳米治疗方法。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，在用于乳腺癌治疗的单一聚合物-脂质杂化纳米颗粒(NP)中共同传递治疗性siRNA(例如，抗Rev1和Rev3 siRNA)和基于铂的化疗药物(例如，顺铂)。利用阳离子脂类化合物和聚(丙交酯-乙交酯)-b-聚乙二醇(PLGA-PEG)，将开发出具有可调物理化学性质的杂化纳米粒文库。PLGA-PEG共聚物的构建块(PLGA和PEG)广泛用于FDA批准的植入型和注射型药物输送系统，作为安全的可生物降解材料已有很长的历史，能够包裹具有广泛物理化学性质的小分子和大分子有效载荷，并可设计为通过聚合物降解和药物扩散相结合的控制释放。这项研究提出了一种有前景的治疗策略，通过不同疗法之间的协同作用，具有独特的机制。如果成功，可以显著改善现有疗法未能提供足够服务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.