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

描述(由申请人提供)：有效的癌症化疗的一个关键障碍是癌细胞中多药耐药(MDR)的发展。该项目的广泛和长期目标是开发先进的纳米医学方法来治疗多药耐药癌症。我们认为，纳米药物疗法可以同时提供抑制MDR的RNAi疗法和诱导癌细胞死亡的化疗药物，在应对癌症化疗中的MDR挑战方面将特别有兴趣。具体地说，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，有效地将RNAi和抗癌药与紫杉烷耐药的肺癌和前列腺癌细胞协同作用。我们将比较不同耐药蛋白在癌症多药耐药中的作用。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和化疗的联合传递安全有效。此外，在R00独立阶段，纳米颗粒平台将被精确设计，以控制单个药物的时间释放，并实现靶向药物输送。我们假设，时空可控的纳米治疗药物可以最大限度地发挥RNAi和抗癌药对多药耐药癌症的预期效果，同时将其毒副作用降至最低。如果成功，该项目将为基于纳米技术的癌症和其他疾病的靶向联合疗法的更广泛应用奠定基础。 与公众健康相关：在这个项目中，我们将使用复乳技术结合自组装技术来合成纳米颗粒。通过调整颗粒表面特征、成分、载药量/比率、药物释放曲线和靶向配基密度，将形成一个杂化脂质-聚合物纳米粒的库，以优化RNAi和抗癌药物的联合输送，以治疗多药耐药癌症(例如肺癌和前列腺癌)。该纳米颗粒平台可用于为各种治疗应用而靶向输送不同药物组合的多功能载体的产生。

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.