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

 描述：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，这些方法指导纳米载体设计的成功仍然是有限的。同时，通过传统的聚合物化学精确控制结构、相对分子质量和功能多样性来合成各种纳米载体具有挑战性，这进一步限制了理论设计的系统验证和实验评估。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，往往是一个试错过程，在一小部分聚合物上进行多次尝试，通常会产生载药性能较差的纳米颗粒，进一步优化的机会也很有限。受多肽化学中明确的构效关系的启发，我们利用逐步多肽化学的方法开发了聚乙二醇b树枝状低聚物体系(称为端树状分子)，它组装成胶束状纳米载体用于药物输送。一种新型的端突二聚体具有功能分离的结构，例如一个亲水的聚乙二醇壳，面部两亲性低聚胆酸中间层，以保护内部疏水药物结合的内核。这些端树状分子继承了多肽的特征，例如定义良好的高度可工程化的结构，因此为计算设计和组合合成纳米载体提供了系统优化的蓝图。我们的假设是，通过引入药物结合部分来设计纳米载体的核心结构，将能够优化纳米载体内的药物负载性能。它将通过以下步骤进行测试：(1)将使用训练数据集来验证识别药物结合分子(DBMS)的计算方法，如评分函数、DBM选择标准、对接能量的实验验证等；(2)将针对三种结构不同的重要抗癌药物(如卡巴紫杉醇、SN-38和阿霉素)进行增强的天然化合物库的虚拟筛选。随后，将对设计合理的纳米载体进行组合合成和表征；(3)表征载药性能、体外抗癌效应和体内肿瘤靶向给药，以验证计算预测。在研究结束时，我们希望阐明端树突体纳米载体在药物传递中的结构-性质关系(SPR)，并将分别开发几种针对SN-38、卡巴紫杉醇和阿霉素传递的优化纳米载体，为进一步的体内抗癌评价的成功能够创造药物传递领域的范式转变。它还可以为纳米药物的设计和开发提供可靠和可预测的途径，从而潜在地使制药业受益。

 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.