Interaction of squalene-based anti-cancer and neuroprotective drugs with cell membranes: in silico study

Información del proyecto

SquaMem

Identificador del acuerdo de subvención: 796245

DOI

10.3030/796245

Proyecto cerrado

Fecha de la firma de la CE 3 Abril 2018

Fecha de inicio 1 Noviembre 2018

Fecha de finalización 19 Septiembre 2021

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 173 076,00

Aportación de la UE

€ 173 076,00

Coordinado por

UNIVERSITE DE FRANCHE-COMTE
France

Periodic Reporting for period 1 - SquaMem (Interaction of squalene-based anti-cancer and neuroprotective drugs with cell membranes: in silicostudy)

Período documentado: 2018-11-01 hasta 2020-10-31

Resumen del contexto y de los objetivos generales del proyecto

Squalene is a natural lipid precursor, which plays a crucial role in the biosynthesis of sterols in the cells. It is 100% biocompatible, not toxic and is able to strongly interact with the cells. This makes it very promising for creating highly efficient drugs and drug delivery systems. The so-called “squalenoylation” technology is based on the conjugation of squalenic acid with a variety of drugs. The resulting conjugated molecules spontaneously self-assemble into nanoparticles, which deliver efficiently the drugs into the target cells. Currently, anticancer (gemcitabine, doxorubicin), antiviral (dideoxycytidine) and neuroprotective (adenosine) drugs were used in this technology with great success. The next steps of these technology are to improve the ADME (Administration, Delivery, Metabolism and Excretion) profiles of the squalene-based drugs and to provide selectivity to target cells in order to reduce the side effects of therapy.

In this project we focused on interaction of squalene-based drugs with the membranes, which is crucial for an effective transport of the drugs into the cells, and their selectivity to the membranes of different composition and curvature, which may serve for targeted delivery and action, especially in oncology for discrimination between normal and cancer cells.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We have shown that the behavior of squalenoylated drug SQGem is sensitive to the changes of lipid compositions which occur in cancer cells. SQGem is more likely to escape from the membrane to cytoplasm (and thus internalize better) if the membrane asymmetry is lost, which is the case in malignant cells. This drug is less likely to escape from the curved membranes in comparison to the flat ones. This may also contribute to its selectivity to cancer cells because their membrane is often significantly more rugged.

We have also studied interactions of the squalenoylated drugs nanoparticles with proteins and lipoproteins of the blood plasma, which is crucial for their administration and toxicity. We have shown that there is a competition between serum albumin and plasma lipoproteins which both transport squalenoylated drugs and take part in the disassembly of their nanoparticles.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

In the course of this project we also studied fundamental physical properties of lipid membranes with realistic composition and curvature and developed a number of methods and software for numerical simulations and analysis of the curved membranes. Particularly, we determined non-trivial changes in thickness, order parameter and the areas per lipid, which occur in curved asymmetric membranes. We demonstrate, that permeability of the curved membranes to the ions, water and small anti-cancer drugs (gemcitabine and cisplatin) depends significantly on the membrane curvature - the fundamental property that was not known before.

This project provided important insights into the molecular mechanisms of interaction of squalenoylated drugs with the cell membranes. It was shown for the first time that the changes of lipid composition and curvature in the cancer cells could be used for selective targeted delivery of drugs into them. It is shown for the first time that the cell membrane could be considered as a druggable target, which may have important implications for the future of drug discovery.

Results of MD simulations of SQGem escape from the membranes of different composition and curvature.