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Rational Design and High throughput synthesis of nanocarriers for efficient drug delivery

用于高效药物递送的纳米载体的合理设计和高通量合成

基本信息

批准号：
9119009
负责人：
Juntao Luo
金额：
$ 19.9万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9119009
关键词：
Affinity Antineoplastic Agents Binding Biocompatible Biodistribution Cell Culture Techniques Characteristics Chemical Structure Chemistry Cholic Acids Clinical Combinatorial Synthesis Computer Assisted Computing Methodologies Data Set Development Docking Doxorubicin Drug Delivery Systems Drug Industry Drug Stability Engineering Evaluation Exhibits Experimental Designs Face Fluorescence Formulation Future Goals Health In Vitro Inherited Libraries Liver Measurable Methodology Micelles Molecular Molecular Weight Morphology Muscle Names Nude Mice Oligonucleotides Particle Size Peptides Pharmaceutical Preparations Polyethylene Glycols Polylysine Polymer Chemistry Polymers Process Property Role SN-38 Shelter facility Site Solubility Spectrometry Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Structure Structure-Activity Relationship System Testing Time Toxic effect Training Validation Vertebral column Water animal imaging aqueous base combinatorial copolymer design drug structure experimental analysis improved in vivo interest nanocarrier nanoformulation nanomedicine nanoparticle nanotherapeutic physical property screening self assembly simulation success theories tumor tumor xenograft virtual

项目摘要

DESCRIPTION: The classic compatibility/solubility theories and molecular simulations have been applied to predict the drug loading properties of polymeric nanoconstructs. However, the success of these approaches to guide nanocarrier design is still limited. At the same time, it is challenging to synthesize a variety of nanocarriers as predicted with the precise control on structure, molecular weight and functional diversity via the conventional polymer chemistry, which further limits the systematic validation and experimental evaluation of the theoretical design. The current development of nanocarriers, especially for polymeric micelle and nanoparticles, is often a trial-error process with numerous attempts on a small subset of polymers, which frequently yield nanoparticles with less optimized drug loading properties and limited opportunity for further optimization. Inspired by the well- defined structure-activity relationship in peptide chemistry, we have developed a PEG-b-dendritic oligomer system (named telodendrimer) using stepwise peptide chemistry, which assembles into micellar nanocarrier for drug delivery. A new version of telodendrimer possesses a function-segregated structure, e.g. a hydrophilic PEG shell, a facial amphiphilic oligo-cholic acid intermediate layer o shelter the interior hydrophobic drug- binding interior core. These telodendrimers inherit the features of peptide, e.g. well-defined highly engineer- able structure, therefore providing a blueprint for both computational design and the combinatorial synthesis of the nanocarriers for systematic optimization. Our hypothesis is that engineering of the core structure of nanocarriers with the introduction of drug binding moieties will be able to optimize drug loading properties within the nanocarrier. It will be tested via the following steps: (1) A training dataset will be ued to validate the computational approach in identifying drug-binding molecules (DBMs), such as, scoring function, criteria for DBM selection, experimental validation of docking energy, etc.; (2) A enhanced natural compound library will be virtually screened against three important anticancer drugs with distinct structures, e.g. cabazitaxel, SN-38 and doxorubicin. Subsequently, the rationally designed nanocarriers will be synthesized combinatorially and characterized; (3) Drug loading properties, in vitro anticancer effects and the in vivo tumor-targeted drug delivery will be characterized to validate the computational predictions. At the end of study, we expect to elucidate the structure-property relationship (SPR) of telodendrimer nanocarriers in drug delivery and several optimized nanocarriers for SN-38, cabazitaxel and doxorubicin delivery will be developed, respectively, for the further in vivo anticancer evaluation Success in this effort is able to create a paradigm shift in the field of drug delivery. It can als benefit the pharmaceutical industry potentially by providing a reliable and predictable path for nanomedicine design and development.

产品说明：经典的相容性/溶解性理论和分子模拟已被应用于预测聚合物纳米结构的载药性能。然而，这些指导纳米载体设计的方法的成功仍然有限。同时，传统的高分子化学方法难以精确控制纳米载体的结构、分子量和功能多样性，从而限制了理论设计的系统验证和实验评价。目前纳米载体的开发，特别是聚合物胶束和纳米颗粒的开发，通常是一个试错过程，在一小部分聚合物上进行了多次尝试，这通常会产生载药性能不太优化的纳米颗粒，进一步优化的机会有限。受肽化学中明确定义的结构-活性关系的启发，我们使用逐步肽化学开发了PEG-b-树枝状寡聚体系统（称为末端树枝状聚合物），其组装成用于药物递送的胶束纳米载体。端树枝状聚合物的新形式具有功能分离的结构，例如亲水性PEG壳、表面两亲性寡聚胆酸中间层以遮蔽内部疏水性药物结合内核。这些末端树枝状聚合物继承了肽的特征，例如定义明确的高度可工程化的结构，因此为纳米载体的计算设计和组合合成提供了蓝图，以进行系统优化。我们的假设是，引入药物结合部分的纳米载体的核心结构的工程化将能够优化纳米载体内的药物负载特性。将通过以下步骤进行测试：（1）使用训练数据集验证识别药物结合分子（DBM）的计算方法，例如评分函数、DBM选择标准、对接能的实验验证等; (2)增强的天然化合物库将针对具有不同结构的三种重要抗癌药物（例如卡巴他赛、SN-38和多柔比星）进行虚拟筛选。随后，将对合理设计的纳米载体进行组合合成和表征;（3）对载药性能、体外抗癌效果和体内肿瘤靶向给药进行表征，验证计算预测。在研究的最后，我们希望阐明末端树枝状聚合物纳米载体在药物递送中的结构-性质关系（SPR），并将分别开发用于SN-38、卡巴他赛和阿霉素递送的几种优化的纳米载体，用于进一步的体内抗癌评价。它也可以通过为纳米药物设计和开发提供可靠和可预测的途径而使制药行业受益。