Nanocrystals for the Treatment of Multidrug Resistance in Cancer

描述(申请人提供)：最近，我们开发了能够输送抗癌药物的纳米晶。这些纳米晶具有低毒、高载药率和克服肿瘤细胞体内多药耐药(MDR)的特点。这项研究计划的总体目标是进一步开发和研究用于MDR癌症治疗的多功能纳米晶。这一建议的科学基础源于我们最近开发的三相纳米颗粒工程(3PNE)方法，该方法包括第一阶段，无定形沉淀；第二阶段，水合无定形聚集体；以及第三阶段，稳定的纳米晶体(NCS)。3PNE已被应用于棒状NCS的开发，以实现有效的抗癌药物输送。为了实现这一目标，我们提出了三个目标：特定目标1，研究NCS增强物理稳定性，克服MDR的机制，以及它们在体内的行为；特定目标2，开发携带靶配体的NCS，将PTX输送到肿瘤；以及特定目标3，建立共输送疏水药物(即紫杉醇)和亲水抗癌药物(即5-氟尿嘧啶)的NCS，通过不同的细胞机制协同杀伤肿瘤细胞。这些特定目标的实现将进一步开发用于治疗癌症，特别是多药耐药癌症的高效纳米药物载体。

DESCRIPTION (provided by applicant): Recently, we have developed nanocrystals capable of delivering anticancer drugs. These nanocrystals with possess low toxicity, high drug loading ratio, and overcome multidrug resistance (MDR) in cancer cells in vitro and in vivo. The overall goal of this research proposal is to further develop and investigate multifunctional nanocrystals for MDR cancer therapy. The scientific basis for this proposal originated from our three-phase nanoparticle engineering (3PNE) method recently developed, which includes phase 1, amorphous precipitate; phase 2, hydrated amorphous aggregate; and phase 3, stabilized nanocrystals (NCs). The 3PNE has been applied to the development of rod-shaped NCs for effective anticancer drug delivery. To achieve this goal, we propose three aims: specific aim 1, to examine the mechanisms of the NCs for their ability to enhance physical stability, overcome MDR, and their in vivo behavior; specific aim 2, to develop NCs that carry target ligands to deliver PTX to tumor; and specific aim 3, to establish the NCs for co-delivering a hydrophobic drug (i.e., Paclitaxel) and a hydrophilic anti-cancer drug (i.e., 5-fluorouracil) to synergistically kill tumor cells through different cellular mechanisms. Accomplishing these specific aims will further develop efficient nano-drug carriers for the treatment of cancer, particularly MDR cancer.