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

癌症干细胞靶向硅酸盐前药纳米颗粒可对抗复发

基本信息

批准号：
10076078
负责人：
THOMAS R. HOYE
金额：
$ 29.81万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10076078
关键词：
Abraxane Address Affect Affinity Antibodies Antineoplastic Agents Apoptotic Blood Vessels Breast Cancer Model Breast Cancer Patient Characteristics Cytotoxic agent Development Disease Drug Delivery Systems Drug Efflux Drug resistance Environment Esters Exploratory/Developmental Grant Exploratory/Developmental Grant for Diagnostic Cancer Imaging Formulation Foundations Goals Human Hydrolysis Hydrophobicity Hypoxia In Vitro Knowledge Laboratories Ligands Membrane Proteins Modeling Monitor Mus Natural regeneration New Agents Organ Paclitaxel Parents Particle Size Penetration Performance Pharmaceutical Preparations Polymers Population Preparation Prevention Prodrugs Property Proteins Recurrence Research Safety Silicates Silicic Acid Site Specificity Structure Surface System Techniques Technology Testing Therapeutic Therapeutic Index Time TimeLine Toxic effect Treatment Efficacy anti-cancer therapeutic cancer recurrence cancer stem cell chemotherapy clinical development combat copolymer cytotoxic density design docetaxel human model improved in vivo in vivo regeneration innovation invention malignant breast neoplasm mouse model nanoformulation nanomedicine nanoparticle nanoparticulate neoplastic cell next generation novel novel strategies novel therapeutics overexpression particle preclinical development self-renewal stem cells stem-like cell taxane therapeutic effectiveness therapy development therapy outcome treatment response triple-negative invasive breast carcinoma tumor

项目摘要

-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.

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（CSC），一个亚群，具有“干细胞样”自我更新特性的肿瘤细胞，有助于疾病复发。目前的治疗方法无法有效根除CSC。我们的研究表明，针对CSC的细胞毒性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，使用高亲和力递送纳米颗粒制剂中的细胞毒性剂，所述纳米颗粒制剂针对CSC 我们的一个实验室最近开发的靶向配体。纳米颗粒输送系统的尺寸范围约为。100 nm显示诱人的肿瘤积累和肿瘤内渗透性质。目前纳米医学在这个小范围内的一个主要限制是，然而，尺寸方案是它们不能被配制成具有高药物负载水平或持续药物释放，更别说两者都有了在R21奖的支持下，我们的团队发现了一种新的策略，紫杉醇的水解不稳定硅酸酯（PTX），即[PTX-Si（OR）3]作为前药构建体。的当与快速纳米沉淀（FNP）结合使用时，这些硅酸盐具有更大的疏水性，用于纳米颗粒（NP）合成的方法，独特地允许制备稳定的、小的嵌段共聚物，受保护的NP含有高达前所未有的60- 75wt%的货物，这里是前药。在一个独立的推力，我们已经成功地开发了单链可变片段（scFv），识别CD 133，这是CSC表面上的独特标记。我们现在提议让这两位通过开发CD 133靶向（使用我们的新scFv），100 nm纳米纳米颗粒，（前）药物货物的百分比，并且显示有效载荷释放的延长的持续时间。我们预计这些这些制剂具有极大改善的治疗功效。我们的具体目标是：目的1）开发具有高载药量和可调节的CSC靶向的硅酸盐前药负载纳米粒。药物再生谱目的2）确定CSC靶向的硅酸盐前药负载的NP的体内安全性和功效。通过将我们的新型硅酸盐前药策略与FNP技术合作，将得到具有高药物负载（>50重量%）和延长的再生时间表的小NP。释放PTX（目标是≥1周释放一半的NP有效载荷）。新型CSC靶向配体的用途大大提高了方法。除了开发针对CSC的NP作为高效的抗癌疗法，我们将推进更全面的理解之间的基本关系， NP的物理化学性质及其治疗性能。