Liposomal formulations can be advantageous in a number of scenarios such as targeted delivery to reduce the systemic toxicity of highly potent Active Pharmaceutical Ingredients (APIs), to increase drug bioavailability by prolonging systemic circulation, to protect labile APIs from degradation in the gastrointestinal tract, or to improve skin permeation in dermal delivery. However, not all APIs are suitable for encapsulation in liposomes. Some of the issues are too high permeability of the API across the lipid bilayer, which may lead to premature leakage, too low permeability, which may hinder the drug release process, or too strong membrane affinity, which may reduce the overall efficacy of drug release from liposomes. Since the most reliable way to test API encapsulation and release from liposomes so far has been experimental, an in silico model capable of predicting API transport across the lipid bilayer might accelerate formulation development. In this work, we demonstrate a new in silico approach to compute the temperature dependent permeability of a set of compounds across the bilayer of virtual liposomes constructed by molecular dynamics simulation. To validate this approach, we have conducted a series of experiments confirming the model predictions using a homologous series of fluorescent dyes. Based on the performance of individual molecules, we have defined a set of selection criteria for identifying compatible APIs for stable encapsulation and thermally controlled release from liposomes. To further demonstrate the in silico-based methodology, we have screened the DrugBank database, identified potent drugs suitable for liposome encapsulation and successfully carried out the loading and thermal release of one of them - an antimicrobial compound cycloserine.

中文翻译：

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电子筛选热响应脂质体制剂的候选药物

脂质体制剂在许多情况下可能是有利的，例如靶向递送以降低强效活性药物成分（API）的全身毒性，通过延长全身循环来增加药物的生物利用度，保护不稳定的API免受胃肠道降解，或以改善皮肤在真皮输送中的渗透。但是，并非所有API都适合封装在脂质体中。其中一些问题是API跨脂质双层的渗透性过高，可能导致过早泄漏；渗透性过低，这可能会阻碍药物释放过程，或者过强的膜亲和力，可能会降低药物释放的总体功效来自脂质体。由于到目前为止，测试API封装和从脂质体释放的最可靠方法是实验性的，能够预测API跨脂质双层运输的计算机模型可以加速制剂开发。在这项工作中，我们演示了一种新的计算机模拟方法，该方法可计算通过分子动力学模拟构建的虚拟脂质体双层中一组化合物的温度依赖性渗透率。为了验证该方法，我们进行了一系列实验，使用同源系列的荧光染料确认了模型预测。基于单个分子的性能，我们定义了一组选择标准，用于鉴定相容的API，以稳定地封装脂质体并进行热控制释放。为了进一步展示基于计算机模拟的方法，我们筛选了DrugBank数据库，