Nanoparticles of MOFs for the treatment of HIV infections and opportunistic bacterial infections – VIRMIL

Biodegradable Nanoparticles of porous MOFs with suitable pore sizes, non toxic compositions (Fe, Ca, Mg and carboxylates), different topologies (channels, cages), being either rigid or flexible, will be synthesized. We will focus first on MOFs whose synthesis at the nanoscale has already been reported. Then, the synthesis of other MOFs reported only at the micrometric level will be done using top of the art techniques (microwave assisted synthesis, ultrasounds…). We will also try the synthesis of nanoMOFs using bioactive molecules as the linker. Their degradation in different biological medium will be investigated as well as the stability of the nanoparticles solutions. In a second step, a screening of encapsulation and release of several drugs of interest for AIDS treatment such as antiretroviral molecules (AZT-TP, Efavirenz (EFV) and delavirdine (DLV) or a combination of them to reconstitute triterapy), and resistant anti-bacterial treatment (antuberculous : ciprofloxacine, isoniazid...) will be performed. Quantitative Structure Activity Relationship (QSAR) study on the encapsulation will be used to predict the best MOF for each drug of interest. Based on the stability and encapsulation results, a few selected MOFs (2 or 3) will be surface functionalized using several surface agent molecules (PEGs, Ig-G…). The drug nano-sponge interactions and of drug delivery will be studied using calorimetry combined to molecular simulations of a selected anti-HIV drugs. Methods of producing and conserving stable formulations will be also developed. In a third step, anti-VIH activity tests and antibacterial activity tests will be done as well as a study of the mechanism of the anti-VIH activity of the nanosponges. Finally, the synthesis of labelled nanoparticles (fluorescence or radioactivity) will help to analyse the crossing of physiological barriers by the nanosponge. We will investigate also the cell internalization kinetics and mechanisms of the nanosponges. The mechanism of the antimicrobial agent delivery from the nanosponges as well as the in vivo toxicity and biodistribution of the drug loaded nanoparticles will be the last part of the project.