Modeling targeted delivery of biomimetic polymer vesicle gene therapy to cancer

该项目的目的是评估使用纳米颗粒向癌细胞输送化疗药物的可行性。这些纳米颗粒是人工合成的，旨在包裹药物并携带特定的标记，这些标记有效地针对肿瘤细胞的毒性作用，同时保护其他组织，从而降低全身毒性。所讨论的纳米粒与其他合成给药装置的不同之处在于，它们具有更大的载药量、更好的药物保留和更好的靶向效率。然而，在它们的设计中，最大的挑战是如何优化它们的动作特异性。我们将开发新的数学模型来解决这个问题。我们将使用最新的建模技术来发现纳米颗粒的渗透、靶向和摄取是如何受到它们的尺寸、机械、化学和膜性能的调节的。从头颈部癌症的体外实验室实验中产生的数据将被用来为参数化和验证的数学方法提供依据。然后，我们将扩展经过验证的模型，以预测体内肿瘤的治疗效果，重点关注已获得血液供应的肿瘤，并开发一个模型框架，这将有助于在动物研究开始之前专注于体内实验计划。这将允许以最低的成本和动物模型的使用来调查不同的实验情况，这些情况在技术上是困难的，收集的数据有限。这些靶向问题一般与递送领域相关，因此我们的模型也将作为其他肿瘤和其他病理条件的靶向递送的框架。该项目的目标是：(I)开发新的纳米颗粒与癌细胞的配体-受体结合的数学模型，以预测如何通过调节纳米颗粒上的配体和隐形颗粒的数量来增强靶向性。(Ii)使用从癌细胞培养实验中产生的数据来参数化和验证数学模型，评估细胞群体中的渗透和输送模式，并识别非特异性和实际靶向的条件。(Iii)开发时空偏微分方程模型，以预测不同颗粒大小下纳米颗粒的稳定性和治疗效率，(Iv)修改数学模型，以确定酸性肿瘤条件是否会引发囊泡内容物的提前释放。(V)利用数学模型，通过产生可测试的假设来确定治疗效率。

The aim of the project is to assess the feasibility of using nanoparticles to deliver chemotherapeutic drugs to cancer cells. The nanoparticles are synthetic and designed to encapsulate drugs and carry specific markers that target toxic effects efficiently to the tumour cells while protecting other tissues, and thus reducing systemic toxicity. The nanoparticles in question differ to other synthetic delivery devices in terms of their greater loading capacity, improved drug retention and better targeting efficiency. The biggest challenge in their design, however, is how to optimize their specificity of action.We will develop novel mathematical models to tackle this issue. We will use the latest modeling techniques to discover how infiltration, targeting and uptake of the nanoparticles are regulated by their size, mechanical, chemical and membrane properties. Data generated from in vitro lab experiments with the head and neck cancers will be used to inform the mathematical approach for parameterisation and validation. We will then extend the validated models to predict the therapeutic effect in tumours in vivo, focussing on tumours that have acquired a blood supply and developing a model framework which will help focus an in vivo experimental program before animal studies begin. This will permit the investigation of different experimental situations which are technically difficult and the collection of data limited, at a minimum of cost and use of animal models. These targeting issues are relevant to the delivery field in general so our model will also act as a framework for targeted delivery for other tumours as well as other pathologic conditions. The aims of the project are:(i) To develop novel mathematical models of ligand-receptor binding of nanoparticles to cancer cells to predict how targeting can be enhanced by modulating the numbers of ligands and 'stealth' particles on the nanoparticles.(ii) To use data generated from cancer cell culture experiments to parameterise and validate the mathematical models and assess infiltration and delivery patterns in cell populations andidentify conditions of non-specific and actual targeting.(iii) To develop spatio-temporal partial differential equation models to make predictions about nanoparticle stability and therapeutic efficiency given different particle sizes, fluidity and membrane properties and different loads and combinations of cytotoxic drugs with different hydrophobic-hydrophilic properties.(iv) To modify the mathematical models to determine whether acidic tumour conditions can trigger premature release of the vesicle contents.(v) To utilize the mathematical models to inform in vivo experimentation by generating testable hypotheses for determining therapeutic efficiency.