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

摘要 有效的癌症化疗的一个关键障碍是产生多药耐药性 (MDR)在癌细胞中。该项目的广泛和长期目标是开发先进的 治疗多药耐药癌症的纳米医学方法。我们相信 纳米药物疗法，可以同时提供RNAi疗法来抑制MDR和 用来诱导癌细胞死亡的化疗药物，将在 应对癌症化疗中多药耐药的挑战。具体来说，我们将设计和开发 纳米颗粒平台用于RNAi和抗癌药物的有效共传递 对紫杉烷耐药的肺癌和前列腺癌细胞的协同药物比例，通过使用可生物降解和 生物相容聚合物和脂类。不同耐药蛋白在癌症中的作用 将对MDR进行比较。纳米颗粒的物理化学性质也将得到优化，以 克服体内生理障碍，同时保持RNAi和化疗的共同传递 安全有效。此外，在R00独立阶段，纳米颗粒平台将 精确设计以控制单个药物的时间释放并实现靶向药物 送货。我们假设，时空受控的纳米治疗药物的传递可以 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，这个项目将为更广泛的 基于纳米技术的靶向联合疗法在癌症等领域的应用 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.