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

摘要 有效癌症化疗的一个关键障碍是多药耐药性的发展 (MDR)在癌细胞中。该项目的广泛和长期目标是开发先进的 用于治疗多药耐药癌症的纳米医学方法。我们认为 纳米医学疗法，其可以同时递送RNAi治疗剂以抑制MDR， 诱导癌细胞死亡的化疗剂，将是特别感兴趣的， 解决癌症化疗中MDR的挑战。具体来说，我们将设计和开发 用于RNAi和抗癌剂的有效共递送的纳米颗粒平台， 通过使用可生物降解和可生物降解的药物， 生物相容性聚合物和脂质。不同耐药蛋白对癌症的贡献 将比较MDR。纳米颗粒的物理化学性质也将被优化， 克服体内生理障碍，同时保持RNAi和化疗的共递送 安全有效。此外，在R00独立阶段，纳米颗粒平台将是 精确设计以控制单个药剂的暂时释放并实现靶向药物 交付.我们假设纳米治疗剂的时空控制递送可以 最大化RNAi和抗癌剂对多药耐药癌症的预期效果， 最大限度地减少其毒副作用。如果成功，该项目将为更广泛的 基于纳米技术的靶向联合治疗癌症和其他疾病的应用 疾病

ABSTRACT 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.