A Silicate Prodrug Strategy for Enhancing Nanoparticle Delivery of Taxanes

描述（由申请人提供）：假设：紫杉烷类抗肿瘤药物的硅酸盐前药，经过定制，具有适当的疏水性和水解稳定性，可以与两亲嵌段共聚物配制成纳米颗粒，这些纳米颗粒是有效的药物，比紫杉醇(R)、Abraxane(R)和taxoere (R)有优势。为了验证这一假设背后的基本问题，我们组建了一个明尼苏达大学的研究小组，他们在合成化学（合作的i Hoye）、材料科学（合作的PI Macosko）和药理学（合作的i Panyam）方面具有多样化和互补的专业知识。具体讨论的实验将是使用紫杉醇(紫杉醇（R)和Abraxane(R)中的活性剂）的实验，但方法完全类似于使用多西紫杉醇（紫杉醇(R)中的活性剂）以及其他紫杉烷衍生物的实验。我们的假设是基于药物的硅酸盐酯衍生物[即，DRUG-O- Si(OR)3]可以作为前药的创新。这个想法是新的，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及其水解速率。这些硅酸盐前体药物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）生产纳米颗粒（NPs），其尺寸理想，可以利用增强的渗透和保留（EPR）效应（直径约100 nm）在实体肿瘤部位定位颗粒。更具体地说，我们假设：i)改变前药疏水特性的能力允许控制a)前药进入由两亲嵌段共聚物衍生的NPs的装载效率；b)前载药NPs的稳定性；c) NPs中药物的释放速率。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NPs的释放速率。iii) BCP的块大小（绝对和相对）和数量（负载比）影响负载NPs的基本性质：大小、稳定性、药物负载水平和药物释放速度。Iv)适当利用，这种方法提供了优于目前临床使用的紫杉烷类药物配方[更高的药物负荷和更少的赋形剂，更多的选择性积累，更多的选择性药物在（酸性更强的）肿瘤部位释放，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R01申请和项目来进行更全面的临床前开发计划。图1 .为满足项目目标而汇集的专业知识摘要。跨学科的反馈将贯穿整个综合研究。1 .硅酸盐前药和BCP合成（化学）前药疏水性和水解/释放速率；药物前疏水性和稳定性优化颗粒形成（FNP），大小和稳定性II。前载BCP纳米颗粒（材料科学）药物负荷水平；纳米颗粒biodistribution;粒径及稳定性优化药物输送;生物功效（药理学）

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.