Targeted Nanotherapy for prostate cancer

前列腺癌的靶向纳米疗法

基本信息

批准号：
9118920
负责人：
Rajesh Singh
金额：
$ 35.38万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118920
关键词：
Affect Affinity Analytical Chemistry Androgens Antineoplastic Agents Antioxidants Binding Biodistribution Biological Assay Biological Availability Bromides Carrier Proteins Cell Death Cells Characteristics Charge Chronic Clinic Clinical Cytotoxic agent Data Development Disease Disease-Free Survival Distant Dose Down-Regulation Drug Combinations Drug Efflux Drug Kinetics Drug Transport Engineering FDA approved Folic Acid Formulation Half-Life Health Home environment Hour Human In Vitro Inflammatory Legal patent Longevity Luciferases Malignant neoplasm of prostate Maximum Tolerated Dose Measures Metastatic Neoplasm to the Bone Methods Modeling Morehouse School of Medicine Mus Normal Cell Organism Outcome P-Glycoprotein PC3 cell line Particle Size Pharmaceutical Preparations Pharmacodynamics Photons Plants Polymers Polysaccharides Preventive Property Prostate Cancer therapy Prostatic Neoplasms Quality of life Resveratrol Reticuloendothelial System Safety Schedule Specificity Starch Surface Technology Testing Tetrazolium Therapeutic Therapeutic Effect Tissues Toxic effect Tumor Cell Line Work base bone cancer cell cancer therapy caprolactone chemotherapy clinical application design diphenyl docetaxel ethylene glycol folate-binding protein hormone refractory prostate cancer improved in vivo innovation mouse model nano nanocarrier nanoparticle nanotherapy neoplastic cell novel novel anticancer drug overexpression particle polyphenol pre-clinical prostate cancer cell targeted agent targeted delivery therapy outcome trans-resveratrol treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): The proposed studies will evaluate a novel method for targeted delivery of resveratrol alone or in combination with docetaxel at desired rates. Our preliminary studies show, nano-formulated resveratrol can be made to bind high affinity folate receptors on prostate cancer (PCa) cells via folate conjugated poly (ϵ-caprolactone)/poly (ethylene glycol) co-polymer coating of the PBM nanoparticles. We have used a natural polysaccharide (i.e., starch; which is FDA approved) as a core for PBM nanoparticles. These particles have shown, in our preliminary studies, to be rapidly internalized and induce significant cancer cell death at lower doses, than compared to unformulated resveratrol. Importantly, negative controls showed that PBM nanoparticles without resveratrol or docetaxel have no toxic effects on PCa cells. Our exciting preliminary data show that resveratrol potently synergizes with docetaxel to inhibit proliferation and induce cell death in hormone-refractory prostate cancer cells. Since docetaxel is associated with various debilitating toxicities at its maximum tolerated doses besides other formulation issues, a synergistic combination of resveratrol-docetaxel could provide a more potent therapeutic effect at lower drug concentrations that are less likely to result in severe toxicity. Our in vitro data strongly suggest that we can reduce dos levels of docetaxel and compensate it with non-toxic resveratrol. This resveratrol-docetaxel combination uniquely presents 'chemotherapy lite' and low 'chronic' doses instead of 'intermittent maximal doses' would not allow the tumor 'to recover' and thus maximize antitumor outcomes without compromising the quality of life. Through this application, we propose to test this hypothesis by evaluating in vivo potential synergistic effects of resveratrol-docetaxel in inhibiting skeletal metastases of androgen-independent or dependent prostate cancer noninvasively in preclinical mice models. We are optimistic that the successful completion of these studies would directly impact the development of successful treatment strategies using resveratrol as a single agent and/or in combination with lower doses of docetaxel for this pernicious disease with a focus on disease-free survival with diminished toxicity.

描述（由申请人提供）：拟议的研究将评估一种以所需速率单独靶向递送白藜芦醇或与多西紫杉醇联合靶向递送的新方法。我们的初步研究表明，纳米制剂的白藜芦醇可以与前列腺上的高亲和力叶酸受体结合。我们通过 PBM 纳米颗粒的叶酸缀合聚（ε-己内酯）/聚（乙二醇）共聚物涂层来治疗癌症（PCa）细胞。使用天然多糖（即淀粉；经 FDA 批准）作为 PBM 纳米颗粒的核心，在我们的初步研究中，这些颗粒已显示出可快速内化并诱导显着的作用。与未配制的白藜芦醇相比，在较低剂量下，癌细胞死亡。重要的是，阴性对照表明不含白藜芦醇或多西紫杉醇的 PBM 纳米颗粒对 PCa 细胞没有毒性作用。由于多西紫杉醇在其最大耐受剂量下除了其他剂量外还与各种使人衰弱的毒性有关。制剂问题，白藜芦醇-多西紫杉醇的协同组合可以在较低的药物浓度下提供更有效的治疗效果，并且不太可能导致严重毒性。我们的体外数据强烈表明，我们可以降低多西紫杉醇的剂量水平并用非紫杉醇补偿它。 -有毒的白藜芦醇。这种白藜芦醇-多西紫杉醇组合独特地呈现出“精简化疗”和低“慢性”剂量，而不是“间歇性最大剂量”，不允许出现这种情况。肿瘤“恢复”，从而在不影响生活质量的情况下最大限度地提高抗肿瘤效果，我们建议通过评估白藜芦醇-多西他赛在抑制雄激素非依赖性或依赖性前列腺癌骨骼转移方面的体内潜在协同作用来检验这一假设。我们乐观地认为，这些研究的成功完成将直接影响使用白藜芦醇作为单一药物的成功治疗策略的制定。和/或与较低剂量的多西紫杉醇联合治疗这种恶性疾病，重点是无病生存并降低毒性。