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最近的研究表明，癌症干细胞（CSC）是一个亚群。具有“干细胞样”自我更新特性的肿瘤，会导致疾病复发。我们的研究表明，专门针对 CSC 的细胞毒性药物不能有效地根除 CSC。我们现在建议在这一令人兴奋的发现的基础上进一步研究乳腺癌小鼠模型中的肿瘤复发。使用高亲和力将细胞毒性剂以纳米颗粒制剂的形式递送至 CSC 我们的一个实验室最近开发了靶向配体。尺寸范围约为 100 nm 的纳米颗粒递送系统显示出诱人的肿瘤作用。目前纳米药物的主要局限性在于其积累和肿瘤内渗透特性。然而，尺寸制度是它们无法配制为具有高药物负载水平或持续药物释放，更不用说两者了。在 R21 奖项的支持下，我们的团队发现了一种使用紫杉醇 (PTX) 的水解不稳定硅酸酯，即 [PTX-Si(OR)3]，作为前药构建体。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纳米粒子（NP）合成方法，独特地允许制备稳定的、小的、嵌段共聚物- 受保护的纳米颗粒含有高达 60-75 wt% 的货物，这里是前药。在独立的推动下，我们成功开发了单链可变片段（scFv），识别 CD133，这是 CSC 表面的独特标记，我们现在建议将这两者结合起来。 CD133 靶向（使用我们的新 scFv）100 nm NP 的令人兴奋的发明，其中含有高（前）药物货物的百分比以及显示有效负载释放持续时间较长的数据我们预计这些。的制剂，大大提高了治疗效果。我们的具体目标是：目标 1) 开发具有高载药量和可调性的 CSC 靶向硅酸盐前药负载纳米粒子药物再生概况目标 2) 确定 CSC 靶向、硅酸盐前药负载的 NP 的体内安全性和有效性。我们的新型硅酸盐前药策略与 FNP 技术相结合将实现创新，在一起，将产生具有高载药量（> 50 wt%）和延长再生时间的小纳米颗粒游离 PTX（目标是释放一半 NP 有效负载≥1 周）使用新型 CSC 靶向配体。除了开发针对 CSC 的高效 NP 外，还大大增强了该方法。抗癌疗法中，我们将更全面地了解两者之间的基本关系纳米粒子的理化性质及其治疗性能。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cancer stem cells and strategies for targeted drug delivery.

癌症干细胞和靶向药物输送策略。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Cao, Jin;Bhatnagar, Shubhmita;Wang, Jiawei;Qi, Xueyong;Prabha, Swayam;Panyam, Jayanth
通讯作者：
Panyam, Jayanth

Encapsulation of Andrographolide in poly(lactide-co-glycolide) Nanoparticles: Formulation Optimization and in vitro Efficacy Studies.

将穿心莲内酯封装在聚（丙交酯-乙交酯）纳米颗粒中：配方优化和体外功效研究。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Oseni, Bukola A;Azubuike, Chukwuemeka P;Okubanjo, Omotunde O;Igwilo, Cecilia I;Panyam, Jayanth
通讯作者：
Panyam, Jayanth

Perlecan-targeted nanoparticles for drug delivery to triple-negative breast cancer.

基底膜蛋白靶向纳米颗粒用于三阴性乳腺癌药物输送。

DOI：
发表时间：
2019-07
期刊：
影响因子：
0
作者：
Khanna, Vidhi;Kalscheuer, Stephen;Kirtane, Ameya;Zhang, Wenqiu;Panyam, Jayanth
通讯作者：
Panyam, Jayanth

Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer.

发现 HSPG2（Perlecan）作为三阴性乳腺癌的治疗靶点。

DOI：
发表时间：
2019
期刊：
影响因子：
4.6
作者：
Kalscheuer, Stephen;Khanna, Vidhi;Kim, Hyunjoon;Li, Sihan;Sachdev, Deepali;DeCarlo, Arthur;Yang, Da;Panyam, Jayanth
通讯作者：
Panyam, Jayanth