BIODEGRADABLE NANOPARTICLE FORMULATED TAXOL FOR TARGETED THERAPY OF HEAD AND NECK

用于头颈靶向治疗的生物可降解纳米颗粒配方紫杉醇

• 批准号: 7300628
• 负责人: SHUMING NIE
• 金额: $ 36.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7300628
• 关键词: Abraxane; Advisory Committees; Aftercare; Albumins; Animals; Antineoplastic Agents; Apoptotic; Appendix; Area; Binding; Biodistribution; Biological Markers; Biomedical Engineering; Body Weight; Body Weight decreased; Bone Marrow; Brain; CCNE1 gene; Cancer Center; Cancer cell line; Cell Cycle; Chemicals; Class; Clinical; Clinical Research; Clinical Trials; Complex; Cultured Cells; Data; Development; Dose; Down-Regulation; Drug Delivery Systems; Drug Kinetics; Drug resistance; Drug toxicity; Dyes; End Point; Epothilones; Evaluation; Exhibits; Fluorescence; Folic Acid; Funding; Goals; Grant; Head; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Heparin; Human; In Vitro; Interdisciplinary Study; Intestines; Kidney; Label; Lesion; Ligands; Link; Liver; Lung; Malignant Neoplasms; Mediating; Microtubule Polymerization; Modeling; Molecular; Moods; Mus; Nanotechnology; Normal tissue morphology; Organ; Oryctolagus cuniculus; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Polymers; Population; Procedures; Production; Property; Radiolabeled; Recurrence; Refractory; Reproduction spores; Research; Research Personnel; Resistance; Scheme; Scientist; Serum; Signal Pathway; Solutions; Specificity; Specimen; Spleen; Structure; Taxane Compound; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxicology; Translations; Treatment Efficacy; Tubulin; Tumor Cell Line; Tumor Tissue; United States Food and Drug Administration; Work; Xenograft Model; Yang; antiangiogenesis therapy; biodegradable polymer; cancer therapy; chemical synthesis; chemotherapy; clinical application; cytotoxic; cytotoxicity; docetaxel; efficacy evaluation; folate-binding protein; head and neck cancer patient; improved; in vivo; malignant breast neoplasm; multidisciplinary; nano; nanofilament; nanoparticle; nanotherapeutic; nanotherapy; neoplastic cell; novel; pharmacokinetic model; pre-clinical; preclinical study; programs; radiotracer; receptor; response; targeted delivery; taxane; therapeutic target; tumor; tumor growth; tumor xenograft

The use of nanoparticles for tumor targeting and drug delivery is one of the most exciting and clinically auspicious areas in nanotechnology. The proposed research aims to develop a new class of self-assembled and biodegradable nanoparticles carrying the chemotherapy drug Taxol for the targeted therapy of head and neck cancer. Our research group has shown that over 50% of cancer tissues from head and neck cancer patients express a high level of folate receptor, raising exciting possibilities for the development of novel folate receptor-targeted therapeutics for this patient population. Our team has recently developed a "ternary" nanoparticle structure by linking both a hydrophobic cancer drug (Taxol-TM) and a tumor-targeting ligand [folic acid (FA)] to a hydrophilic and biodegradable polymer [heparin (Hep)], resulting in a tumor-targeted Taxol delivery nanoparticle (Hep-FA-Taxol). We demonstrate 17-fold higher tumor growth inhibition compared to free Taxol in a head and neck tumor xenograft model after systemic delivery of Hep-FA-Taxol nanocomplexes. In this project, we will further develop and characterize this ternary nanoparticle therapeutic drug. We plan to conduct preclinical studies to determine the specificity and efficacy of the Hep-FA-Taxol nanoparticle in head and neck tumor xenograft models. We will then determine biodistribution, toxicology, pharmacokinetic (PK), and pharmacodynamic (PD) in animals. The ultimate goal of this study is to bring this promising tumor targeted Taxol-nanoparticle (Hep-FA-Taxol) to a phase Ib clinical trial. Combined, these studies will test the hypotheses that delivery of Taxol using Hep-FA-Taxol nanoparticles will improve (1) specific distribution of Taxol in tumor lesions expressing a high level of folate receptors, (2) intracellular concentration of Taxol to overcome drug resistance, and (3) therapeutic efficacy for the treatment of head and neck cancer. The proposed research will allow us to conduct preclinical and clinical studies to bring this novel nanotherapeutic drug from bench top to clinical application. The development of this tumor targeted Taxol delivery nanoparticle may provide head and neck cancer patients with an effective treatment while reducing systemic toxicity

纳米粒子用于肿瘤靶向和药物输送是最令人兴奋和临床上最有价值的方法之一。 纳米技术的吉祥领域。这项拟议的研究旨在开发一类新的自组装 和携带化疗药物紫杉醇的可生物降解纳米粒靶向治疗头部和 颈癌。我们的研究小组发现，超过50%的头颈部癌组织 患者表达高水平的叶酸受体，为新的开发增加了令人兴奋的可能性 针对这一患者群体的叶酸受体靶向疗法。我们的团队最近开发出了一种“三元” 通过连接疏水性抗癌药物(紫杉醇-TM)和肿瘤靶向配体的纳米颗粒结构 [叶酸(FA)]到亲水性和可生物降解的聚合物[肝素(HEP)]，导致肿瘤靶向 紫杉醇纳米粒(HEP-FA-紫杉醇)。我们的肿瘤生长抑制率高出17倍 Hep-FA-Taxol全身给药后与游离紫杉醇在头颈部肿瘤移植模型中的比较 纳米复合体。在这个项目中，我们将进一步开发和表征这种三元纳米治疗药物 毒品。我们计划进行临床前研究，以确定HEP-FA-紫杉醇的特异性和有效性 头颈部肿瘤异种移植模型中的纳米颗粒。然后我们将确定生物分布，毒物学， 动物体内的药代动力学(PK)和药效学(PD)。这项研究的最终目标是实现这一点 有望进行Ib期临床试验的肿瘤靶向紫杉醇纳米粒(HEP-FA-Taxol)。加在一起，这些 研究将验证使用HEP-FA-紫杉醇纳米粒的紫杉醇释放将改善的假设(1) 紫杉醇在高水平叶酸受体表达的肿瘤病变中的特异性分布，(2)细胞内 抗耐药紫杉醇的浓度，以及(3)治疗头部的疗效 和颈癌。拟议的研究将使我们能够进行临床前和临床研究，以实现这一点 新型纳米治疗药物从台面到临床应用。这种肿瘤的发展具有靶向性 紫杉醇纳米粒可为头颈部癌症患者提供有效的治疗 降低全身毒性