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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

基本信息

批准号：
8143529
负责人：
Chris Macosko
金额：
$ 21.11万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143529
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 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

项目摘要

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：紫杉烷类抗肿瘤剂的硅酸盐前药，定制为具有适当的疏水性和水解不稳定性，可以与两亲性嵌段共聚物一起配制成纳米颗粒，所述纳米颗粒是有效的药物，并且优于Taxol（R）、Abraxane（R）和Taxotere（R）。为了测试这一假设背后的基本问题，我们组建了一个明尼苏达大学研究人员团队，他们在合成化学（co-I Hoye），材料科学（PI Macosko）和药理学（co-I Panyam）方面具有多样和互补的专业知识。所讨论的具体实验将是使用紫杉醇（Taxol（R）和Abraxane（R）中的活性剂）的那些实验，但该方法完全类似于多西他赛（Taxotere（R）中的活性剂）以及其它紫杉烷衍生物的方法。我们的假设是由药物的硅酸酯衍生物[即，DRUG-O- Si（OR）3]可以作为前药发挥作用。这个想法是新的和未经探索的。硅酸盐部分可以被定制以独立地决定前药的疏水性以及其水解速率。这些硅酸盐前药将使用快速纳米沉淀（FNP）与生物相容性嵌段共聚物（BCP）共沉淀，以产生对于利用增强的渗透和保留（EPR）效应而言理想的尺寸方案的纳米颗粒（NP）（ca. 100 nm直径）用于在实体瘤部位定位颗粒。更具体地，我们假设：i）改变前药的疏水特性的能力允许控制a）前药到衍生自两亲性嵌段共聚物的NP中的负载效率; B）负载前药的NP的稳定性;和c）药物从NP的释放速率。 ii）以pH敏感的方式改变前药水解速率的能力允许控制转化为游离药物的速率和药物从NP的释放速率。 iii）嵌段尺寸（绝对和相对）和BCP的量（负载比）影响负载的NP的基本性质：尺寸、稳定性、药物负载水平和药物释放速率。 iv）适当地利用，该方法提供了上级目前临床使用的那些的基于紫杉烷的药物制剂[更高的载药量和更少的赋形剂，更有选择性的积累，在（酸性更强的）肿瘤部位更有选择性的药物释放，以及更少的副作用]。我们的目标是能够客观地判断，在这个为期两年的R21项目结束时，是否有必要通过R 01申请和项目制定一个更全面的临床前开发计划。图一为满足项目目标而汇集的学科专业知识的总结。跨学科的反馈将贯穿整个综合研究。I.硅酸盐前药和BCP合成（化学）前药疏水性和水解/释放速率;前药疏水性和不稳定性优化颗粒形成（FNP）、大小和稳定性II.载药前体BCP纳米颗粒（材料科学）载药量水平;纳米颗粒生物分布;粒度和稳定性优化III.药物递送;生物学有效性（药理学）公共卫生关系：用于增强紫杉烷纳米颗粒递送的硅酸盐前药策略紫杉醇（R）、Abraxane（R）和Taxotere（R）是用于癌症患者的重要化疗药物。我们建议通过将活性抗癌剂（“紫杉烷”）配制成非常小的颗粒来开发这些药物的改进形式，这些颗粒将选择性地积聚在肿瘤处，然后在这些部位释放其活性有效载荷。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Effects of amphiphilic diblock copolymer on drug nanoparticle formation and stability.

DOI：
10.1016/j.biomaterials.2013.09.015
发表时间：
2013-12
期刊：
BIOMATERIALS
影响因子：
14
作者：
Zhu, Zhengxi
通讯作者：
Zhu, Zhengxi

Flash nanoprecipitation: particle structure and stability.

DOI：
10.1021/mp400337f
发表时间：
2013-11-04
期刊：
Molecular pharmaceutics
影响因子：
4.9
作者：
Pustulka KM;Wohl AR;Lee HS;Michel AR;Han J;Hoye TR;McCormick AV;Panyam J;Macosko CW
通讯作者：
Macosko CW

A simple confined impingement jets mixer for flash nanoprecipitation.