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将化疗药物输送到癌细胞的可行性。纳米颗粒是合成的，旨在封装药物并携带特异性标记物，这些标记物有效地将毒性作用靶向肿瘤细胞，同时保护其他组织，从而降低全身毒性。所讨论的纳米颗粒与其他合成递送装置的不同之处在于其更大的负载能力，改善的药物保留和更好的靶向效率。然而，它们的设计中最大的挑战是如何优化它们的作用特异性。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，靶向和吸收如何通过其尺寸，机械，化学和膜特性进行调节。从头颈部癌症的体外实验室实验中产生的数据将用于为参数化和验证的数学方法提供信息。然后，我们将扩展经验证的模型，以预测体内肿瘤的治疗效果，重点是已经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集中体内实验计划。这将允许在最低成本和使用动物模型的情况下，对技术上困难和数据收集有限的不同实验情况进行研究。这些靶向问题通常与递送领域相关，因此我们的模型也将作为其他肿瘤以及其他病理条件的靶向递送的框架。该项目的目标是：（i）开发纳米颗粒与癌细胞的配体-受体结合的新数学模型，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。(ii)使用癌细胞培养实验生成的数据来参数化和验证数学模型，并评估细胞群中的浸润和递送模式，并确定非特异性和实际靶向的条件。(iii)开发时空偏微分方程模型，以预测不同粒径、流动性和膜性质以及不同载量和具有不同疏水-亲水性质的细胞毒性药物组合的纳米颗粒稳定性和治疗效率。(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过早释放。(v)利用数学模型，通过生成用于确定治疗效率的可检验假设，为体内实验提供信息。

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.