Palladium based nanoparticles for the treatment of advanced melanoma

用于治疗晚期黑色素瘤的钯基纳米颗粒

• 批准号: 9206894
• 负责人: JACK L ARBISER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206894
• 关键词: Afghanistan; Area; Award; Blood Vessels; C-KIT Mutation; Clinical Treatment; Data; Development; Diagnostic; Dose; Drug Delivery Systems; Drug Kinetics; Drug Monitoring; Drug Targeting; Drug resistance; Encapsulated; Enzymes; FarGo; Future; Genetic; Growth; Growth Factor; Growth and Development function; Human; Insulin; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Iraq; Korea; Laboratories; Legal patent; Malignant Neoplasms; Manuscripts; Mediating; Melanoma Cell; Metastatic Melanoma; Military Personnel; Modeling; Morbidity - disease rate; Mus; Mutate; Mutation; N-myristoyltransferase; Neoplasm Metastasis; Normal tissue morphology; Nude Mice; Ocular Melanoma; PTEN gene; Palladium; Pathway interactions; Peritoneum; Pharmaceutical Preparations; Pharmacodynamics; Phosphotransferases; Preparation; Prevention; Prognostic Factor; Public Health; Resistance; Solid Neoplasm; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxicology; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Tumor Suppressor Genes; UV Radiation Exposure; Veterans; Vietnam; Xenograft Model; Xenograft procedure; absorption; base; chemotherapeutic agent; drug efficacy; image guided; improved; in vivo; inhibitor/antagonist; innovation; iron oxide; melanoma; mortality; mutant; myristoylation; nanoparticle; non-invasive imaging; novel; novel therapeutics; overexpression; particle; public health relevance; receptor; response; src-Family Kinases; systemic toxicity; targeted delivery; targeted treatment; theranostics; tumor; tumor growth; tumor progression; virtual; young man; young woman

 DESCRIPTION (provided by applicant): Iron oxide nanoparticles are novel agents for the delivery of high concentrations of therapeutics to areas with leaky blood vessels. The focus of this initial proposal is the nanoparticle mediated delivery of a novel therapeutic agent, Tris DBA Palladium for the prevention and treatment of genetically diverse melanoma. We propose to assess the efficacy of IGF-1 targeted nanoparticles containing Tris DBA Palladium to mice carrying genetically diverse melanoma xenografts. This will be followed by studies on transgenic mice that develop melanoma due to expression of mutant Braf and loss of the tumor suppressor gene PTEN. Finally, we will perform pharmacokinetic and toxicology studies on optimized Tris DBA Palladium containing nanoparticles in anticipation of discussions with the FDA. Our innovation has been awarded US Patent 8,030,299. Hypothesis: The novel chemotherapeutic agent Tris DBA Palladium encapsulated in IGF-1R targeted theranostic IONPs can be selectively delivered to primary and metastatic melanoma, leading to improved therapeutic efficacy and overcome drug resistance in genetically diverse melanomas and enabling non- invasive imaging of targeted drug delivery and monitoring tumor responses to the therapy. In our initial studies with Tris DBA Palladium, we noted a significant therapeutic effect even though absorption of drug was incomplete. Thus, our initial studies likely underestimated the potential efficacy of the drug. By enhancing the delivery using novel nanoparticle carriers, it is likely that we can increase efficacy of the drug.In addition, our studies will determine when in tumor progression vessels become leaky and retain nanoparticles. This has important implications for future therapies. Specific Aims: Aim 1: We will develop of IGF-1R1 targeted theranostic IONPs carrying Tris DBA Palladium and examine the effects of targeted drug delivery and tumor growth inhibition using human melanoma xenograft models in nude mice. Aim 2: We will evaluate and compare of the effects of image-guided and targeted therapy using IGF-1R- targeted theranostic IONPs on tumor growth and development of metastases in a transgenic Braf/PTEN melanoma model. Aim 3: We will perform Pre-IND development studies including systemic toxicity, dose, and PK/PD in normal and tumor-bearing mice.

 描述（由申请人提供）： 氧化铁纳米颗粒是一种新型药物，可将高浓度的治疗药物输送到血管渗漏的区域。该初步提案的重点是纳米颗粒介导的新型治疗剂Tris DBA钯的递送，用于预防和治疗遗传多样性黑色素瘤。我们建议评估含有Tris DBA钯的IGF-1靶向纳米颗粒对携带遗传多样性黑色素瘤异种移植物的小鼠的疗效。随后将对转基因小鼠进行研究，这些小鼠由于突变型Braf的表达和肿瘤抑制基因PTEN的缺失而患上黑色素瘤。最后，我们将对优化的Tris DBA含钯纳米颗粒进行药代动力学和毒理学研究，以期待与FDA的讨论。我们的创新已获得美国专利8，030，299。假设：封装在IGF-1 R靶向治疗诊断性IONP中的新型化疗剂Tris DBA钯可以选择性地递送至原发性和转移性黑素瘤，从而提高治疗功效并克服遗传多样性黑素瘤中的耐药性，并且能够实现靶向药物递送的非侵入性成像并监测肿瘤对治疗的反应。在我们使用Tris DBA钯的初步研究中，我们注意到即使药物吸收不完全也有显著的治疗效果。因此，我们最初的研究可能低估了药物的潜在疗效。通过使用新型纳米颗粒载体增强递送，我们可能会提高药物的疗效。此外，我们的研究将确定肿瘤进展中血管何时变得渗漏并保留纳米颗粒。这对未来的治疗具有重要意义。具体目标：目标1：我们将开发携带Tris DBA钯的IGF-1 R1靶向治疗诊断IONP，并使用裸鼠中的人黑色素瘤异种移植模型来检查靶向药物递送和肿瘤生长抑制的效果。目标二：我们将在转基因Braf/PTEN黑色素瘤模型中评估和比较使用IGF-1 R靶向治疗诊断IONP的图像引导和靶向治疗对肿瘤生长和转移发展的影响。目的3：我们将在正常和荷瘤小鼠中进行IND前开发研究，包括全身毒性、剂量和PK/PD。