A Silicate Prodrug Strategy for Enhancing Nanoparticle Delivery of Taxanes

增强紫杉烷类纳米粒子递送的硅酸盐前药策略

• 批准号: 8045613
• 负责人: Chris Macosko
• 金额: $ 17.76万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045613
• 关键词: Abraxane; Acetone; Adverse effects; Antineoplastic Agents; Biocompatible; Biodistribution; Biological; Biological Assay; Caliber; Cancer Patient; Clinical; Dependency; Development; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Stability; Effectiveness; Esters; Ethylene Glycols; Event; Excipients; Feedback; Glycolic-Lactic Acid Polyester; Goals; Human; Hydrolysis; Hydrophobicity; In Vitro; Kinetics; Measures; Minnesota; Molecular Weight; Mus; Paclitaxel; Particle Size; Pharmaceutical Preparations; Pharmacology; Plasma; Powder dose form; Prodrugs; Property; Relative (related person); Research; Research Personnel; Science; Silicates; Site; Solid Neoplasm; Synthesis Chemistry; Taxane Compound; Technology; Testing; Tumor Cell Line; Universities; Water; Weight; abstracting; antitumor agent; antitumor drug; base; copolymer; cytotoxicity; design; docetaxel; ethylene glycol; improved; in vivo; innovation; meetings; nanoparticle; particle; pre-clinical; public health relevance; research study; taxane; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): Hypothesis: Silicate prodrugs of taxane antitumor agents, customized to have proper hydrophobicity and hydrolytic lability, can be formulated with amphiphilic block copolymers into nanoparticles that are effective drugs and that have advantages over Taxol(R), Abraxane(R), and Taxotere(R). To test the essential issues underlying this hypothesis, we have assembled a team of University of Minnesota Investigators with diverse and complementary expertise in synthetic chemistry (co-I Hoye), materials science (PI Macosko), and pharmacology (co-I Panyam). The specific experiments discussed will be those using paclitaxel (the active agent in Taxol(R) and Abraxane(R)), but the approach is entirely analogous to that for docetaxel (the active agent in Taxotere(R)) as well as other taxane derivatives. Our hypothesis is guided by the innovation that silicate ester derivatives of drugs [i.e., DRUG-O- Si(OR)3] can function as prodrugs. This idea is new and unexplored. The silicate moiety can be tailored to dictate, independently, both the hydrophobicity of the prodrug as well as its rate of hydrolysis. These silicate prodrugs will be co-precipitated with biocompatible block copolymers (BCPs), using flash nanoprecipitation (FNP), to produce nanoparticles (NPs) in a size regime ideal for exploiting the enhanced permeation and retention (EPR) effect (ca. 100 nm diameter) for localization of particles at solid tumor sites. More specifically, we postulate that: i) the ability to alter the hydrophobic character of the prodrug allows control of a) the loading efficiency of the prodrug into NPs derived from amphiphilic block copolymers; b) the stability of the prodrug-loaded NPs; and c) the release rate of drug from the NPs. ii) The ability to alter the rate of hydrolysis of the prodrug, in a pH sensitive manner, allows control of the rate of conversion to free drug and the release rate of drug from the NPs. iii) The block size (both absolute and relative) and the amount (load ratio) of the BCP influences essential properties of the loaded NPs: size, stability, drug loading levels, and release rate of drug. iv) properly harnessed, this approach provides taxane-based drug formulations that are superior to those currently in clinical use [higher drug loading and less excipient, more selective accumulation, more selective drug release at (the more acidic) tumor sites, and fewer side effects]. Our goal is to be able to judge, objectively, at the end of this two-year R21 project whether a more comprehensive plan for full preclinical development through an R01 application and project is warranted. Chart I. Summary of the disciplinary expertise assembled to meet project Aims. Cross-disciplinary feedback will inform the integrated studies throughout. I. Silicate Prodrug and BCP Synthesis (Chemistry) prodrug hydrophobicity and hydrolysis/release rates; prodrug hydrophobicity and lability optimization particle formation (FNP), size, and stability II. Prodrug-Loaded BCP Nanoparticles (Materials Science) drug load levels; nanoparticle biodistribution; particle size and stability optimization III. Drug Delivery; Biological Efficacy (Pharmacology) PUBLIC HEALTH RELEVANCE: A Silicate Prodrug Strategy for Enhancing Nanoparticle Delivery of Taxanes Taxol(R), Abraxane(R), and Taxotere(R) are important chemotherapeutics for cancer patients. We propose to develop improved forms of these drugs by formulating the active anticancer agents (the 'taxanes') into very small particles that will selectively accumulate at tumors and then release their active payload at those sites.

描述(由申请人提供)：假设：紫杉烷抗肿瘤药物的硅酸盐前药，定制为具有适当的疏水性和水解性，可以与两亲性嵌段共聚物制成纳米颗粒，这些纳米颗粒是有效的药物，并且比Taxol(R)、Abraxane(R)和Taxotere(R)更有优势。为了检验这一假说背后的基本问题，我们组建了一个明尼苏达大学调查小组，他们在合成化学(co-i Hoye)、材料科学(Pi Macosko)和药理学(co-i Panyam)方面具有不同和互补的专业知识。讨论的具体实验将是那些使用紫杉醇(Taxol(R)和Abraxane(R)中的活性物质)的实验，但这种方法完全类似于多西紫杉醇(Taxotere(R)中的活性物质)以及其他紫杉烷衍生物。我们的假设是由药物的硅酸酯衍生物[即药物-O-Si(OR)3]可以作为前体药物这一创新来指导的。这个想法是新的，还没有被探索过。硅酸盐部分可以被定制成独立地决定前药的疏水性以及它的水解率。这些硅酸盐前药将与生物相容性嵌段共聚物(BCP)共沉淀，使用闪光纳米沉淀法(FNP)，在尺寸范围内生产纳米颗粒(NPs)，该纳米颗粒非常适合利用增强渗透和保留(EPR)效应(直径约100 nm)，用于在实体肿瘤部位定位颗粒。更具体地说，我们假设：i)能够改变前体药物的疏水性，从而可以控制a)前体药物在由两亲嵌段共聚物衍生的纳米颗粒中的载药效率；b)负载前体药物的纳米颗粒的稳定性；以及c)药物从纳米颗粒中的释放速率。二)能够以对pH敏感的方式改变前体药物的水解率，从而能够控制转化为游离药物的速度和药物从NPs释放的速度。3)BCP的嵌段大小(绝对大小和相对大小)和载药量(载药率)影响负载纳米粒的基本性质：大小、稳定性、载药量和药物释放速率。四)如果利用得当，这种方法提供的紫杉烷类药物配方优于目前临床使用的药物配方[载药量更高，赋形剂更少，更有选择性地累积，在(更酸性的)肿瘤部位更有选择性地释放药物，副作用更少]。我们的目标是能够在这个为期两年的R21项目结束时客观地判断是否有必要通过R01的应用和项目来制定更全面的全面临床前开发计划。图一.为实现项目目标而收集的学科专门知识摘要。跨学科的反馈将贯穿整个综合研究。硅酸盐前药和BCP合成(化学)前药的疏水性和水解/释放速率；前药的疏水性和不稳定优化颗粒形成(FNP)、大小和稳定性II.前药载药BCP纳米颗粒(材料科学)载药量水平；纳米颗粒生物分布；颗粒大小和稳定性优化III.药物输送；生物功效(药理学) 与公共健康相关：用于增强紫杉烷纳米颗粒传输的硅酸盐前药战略紫杉醇(注册商标)、亚伯拉明(注册商标)和泰索帝(注册商标)是癌症患者的重要化疗药物。我们建议开发这些药物的改进形式，将活性抗癌药物(紫杉烷)制成非常小的颗粒，这些颗粒将选择性地积累在肿瘤中，然后在这些位置释放它们的活性有效载荷。