In-silico screening of drug candidates for thermoresponsive liposome formulations

Abstract

Highlights-New in silico methodology for predicting drug loading and thermal release from liposomes was developed and compared with experiments -Virtual lipid bilayers were constructed using molecular dynamics models and their interaction with penetrating solutes was studied by atomistic simulations -Rules for permeability (logPerm) and partition (logKlip/wat) coefficients were established to characterise drug compatibility with liposomes -Permeability and partition coefficients of 57 toxic compounds from DrugBank database were calculated, 5 suitable candidates identified and 1 demonstrated experimentally AbstractLiposomal 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 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.

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“…Liposomes exhibit a structure similar to that of cell membranes, making them highly biocompatible. They offer the ability to encapsulate within their internal aqueous phase (69), while lipophilic drugs can be dispersed within the lipid bilayer (70). This improves drug stability, enhances bioavailability, and reduces drug toxicity.…”