Nanoparticle Co-delivery of RNAi and Chemotherapy for Multidrug Resistant Cancers

描述（由申请人提供）：有效癌症化疗的关键障碍是癌细胞中多药耐药性（MDR）的发展。该项目的广泛和长期目标是开发用于治疗多药耐药癌症的先进纳米医学方法。我们相信，纳米医学治疗，它可以同时提供RNAi治疗抑制MDR和化疗药物诱导癌细胞死亡，将在解决癌症化疗MDR的挑战特别感兴趣。具体来说，我们将设计和开发纳米颗粒平台，通过使用可生物降解和生物相容的聚合物和脂质，以协同药物比例将RNAi和抗癌剂有效地共同递送到紫杉烷耐药的肺癌和前列腺癌细胞。比较不同耐药蛋白对肿瘤MDR的贡献。纳米颗粒的物理化学性质也将得到优化，以克服体内的生理障碍，同时保持RNAi和化疗的共同递送安全有效。此外，在R 00独立阶段，纳米颗粒平台将被精确地设计以控制单个药剂的时间释放并实现靶向药物递送。我们假设纳米治疗剂的时空控制递送可以最大限度地提高RNAi和抗癌剂对多药耐药癌症的预期效果，同时最大限度地减少其毒副作用。如果成功，该项目将为基于纳米技术的靶向联合治疗癌症和其他疾病的更广泛应用奠定基础。 公共卫生相关性：在这个项目中，我们将使用双乳液技术结合自组装的纳米颗粒合成。将通过调节颗粒表面特征、组分、药物负载/比率、药物释放曲线和靶向配体密度来配制杂合脂质-聚合物纳米颗粒的文库，以优化RNAi和抗癌剂对多药耐药癌症（例如，肺癌和前列腺癌）。该纳米颗粒平台可用于产生多功能载体，用于靶向递送用于各种治疗应用的多种药物组合。

DESCRIPTION (provided by applicant): A critical barrier to effective cancer chemotherapy is the development of multidrug resistance (MDR) in cancer cells. The broad and long-term objective of this project is to develop advanced nanomedicinal approaches for the treatment of multidrug resistant cancers. We believe that nanomedicinal therapy, which can simultaneously deliver RNAi therapeutics to suppress MDR and chemotherapeutic agents to induce the death of cancer cells, will be of particular interest in addressing the challenge of MDR in cancer chemotherapy. Specifically, we will design and develop nanoparticulate platforms for the effective co-delivery of RNAi and anti-cancer agents with a synergistic drug ratio to taxane-resistant lung and prostate cancer cells, by using biodegradable and biocompatible polymers and lipids. The contribution of different drug-resistant proteins to cancer MDR will be compared. The physicochemical properties of the nanoparticles will also be optimized to overcome the physiological barriers in vivo, while keeping the co-delivery of RNAi and chemotherapy safe and effective. Furthermore, in the R00 independent phase, the nanoparticulate platform will be precisely engineered to control the temporal release of individual agents and to achieve targeted drug delivery. We hypothesize that the spatiotemporal controlled delivery of nanotherapeutics can maximize the desired effects of RNAi and anti-cancer agents for multidrug resistant cancers, while minimizing their toxic side effects. If successful, this project will lay the groundwork for wider applications of the nanotechnology-based targeted combination therapy for cancer and other diseases. PUBLIC HEALTH RELEVANCE: In this project we will use double-emulsion technology combined with self-assembly for nanoparticle synthesis. A library of the hybrid lipid-polymer nanoparticles will be formulated by tuning particle surface characteristics, components, drug loading/ratio, drug release profile, and targeting ligand density to optimize the co-delivery of RNAi and anti-cancer agents for multidrug resistant cancers (e.g., lung and prostate cancers). This nanoparticulate platform may be useful for the generation of versatile vehicles for targeted delivery of diverse drug combinations for a variety of therapeutic applications.