Cancer Stem Cell-Targeted, Silicate Prodrug Nanoparticles to Combat Recurrence

-耐药性和肿瘤复发仍然是影响治疗的重要挑战 乳腺癌患者的预后。最近的研究表明，癌症干细胞(CSCs)是一种亚群 具有“干细胞样”自我更新特性的肿瘤，有助于疾病复发。目前的治疗方法是 不能有效根除CSCs。我们的研究表明，针对CSCs的靶向细胞毒药物可以减少 乳腺癌小鼠模型中的肿瘤复发。我们现在建议在这一令人兴奋的发现的基础上，通过 使用高亲和力将细胞毒剂以纳米制剂形式输送至CSCs 靶向配体是最近在我们的一个实验室开发出来的。 大小约为100纳米的纳米颗粒递送系统显示出诱人的肿瘤 蓄积和肿瘤内的穿透特性。当前纳米医学在这个小领域的一个主要限制 然而，大小机制是它们不能被配制成具有高药物负荷水平或持续药物释放， 更别说两者兼而有之了。在R21奖项的支持下，我们的团队发现了一种新颖的策略，它使用 易水解的紫杉醇硅酸酯(PTX)，即[PTX-Si(OR)3]，作为前药构建体。这个 当与闪光纳米沉淀法(FNP)结合使用时，这些硅酸盐的疏水性更强 用于纳米颗粒(NP)合成的装置，独特地允许制备稳定的、小的、嵌段共聚物- 受保护的NPs含有史无前例的60%-75%的货物，这里是前药。 在一个独立的推力中，我们成功地开发出了一种单链可变片段(ScFv)，它可以 识别CD133，这是一种存在于CSCs表面的独特标记。我们现在提议为这两个人通婚 通过开发CD133靶向(使用我们的新ScFv)，100 nm高含量的纳米粒子来实现令人兴奋的发明 (亲)药物货物的百分比，并显示有效载荷释放持续时间延长。我们期待着这些 这些制剂极大地提高了疗效。 我们的具体目标是： 目的1)开发具有高载药量和可调性的CSC靶向硅酸盐前药纳米粒 药物再生概况 目的2)研究CSC靶向硅酸盐前药纳米粒的体内安全性和有效性。 创新将通过将我们的新型硅酸盐前药战略与FNP技术合作实现， 加在一起，将提供具有高载药量(&gt；50wt%)和延长再生时间的小NP 免费Ptx(目标是≥1周释放一半的NP有效载荷)。新型CSC靶向配体的应用 极大地增强了方法。除了开发针对CSC的NPs作为高效 在抗癌治疗方面，我们将更全面地理解 纳米粒的物理化学性质及其治疗性能。

-Drug resistance and tumor recurrence continue to be important challenges affecting the therapeutic outcomes for breast cancer patients. Recent studies suggest that cancer stem cells (CSCs), a sub-population of the tumor with `stem cell-like' self-renewal properties, contribute to disease recurrence. Current therapies do not effectively eradicate CSCs. Our studies show that targeting cytotoxic drugs specifically to CSCs reduces tumor recurrence in a mouse model of breast cancer. We now propose to build on this exciting finding by delivering the cytotoxic agent in a nanoparticle formulation that is directed to CSCs using a high affinity targeting ligand recently developed in one of our laboratories. Nanoparticulate delivery systems that are in the size range of ca. 100 nm show enticing tumor accumulation and intra-tumoral penetration properties. A major limitation of current nanomedicines in this small size regime, however, is their inability to be formulated to have high drug load levels or sustained drug release, let alone both. With the support of an R21 award, our team has discovered a novel strategy that uses a hydrolytically labile silicate ester of paclitaxel (PTX), namely [PTX-Si(OR)3], as a prodrug construct. The greater hydrophobicity of these silicates, when used in conjunction with flash nanoprecipitation (FNP) as the means for nanoparticle (NP) synthesis, uniquely allows the preparation of stable, small, block copolymer- protected NPs containing up to an unprecedented 60-75 wt% of cargo, here the prodrug. In an independent thrust, we have successfully developed a single chain variable fragment (scFv) that recognizes CD133, a unique marker presented on the surface of CSCs. We now propose to marry these two exciting inventions by developing CD133-targeted (using our new scFv), 100 nm NPs that contain high percentages of (pro)drug cargo and that show a prolonged duration of payload release. We expect these formulations to have greatly improved therapeutic efficacy. Our Specific Aims are to: Aim 1) Develop CSC-targeted, silicate prodrug-loaded NPs that have high drug loading and adjustable drug regeneration profiles Aim 2) Determine the in vivo safety and efficacy of CSC-targeted, silicate prodrug-loaded NPs. Innovations will be enabled by partnering our novel silicate prodrug strategy with FNP technology that, together, will give small NPs that have high drug loading (>50 wt%) and prolonged timelines for regeneration of free PTX (a goal is ≥1 week for release of half of the NP payload). Use of the novel CSC targeting ligand substantially enhances the approach. In addition to developing CSC-targeted NPs as highly effective anticancer therapeutics, we will advance a fuller understanding of the fundamental relationship between the physicochemical properties of NPs and their therapeutic performance.