ABSTRACT
Nanoscale mesoporous iron carboxylates metal-organic frameworks (nanoMOFs) have recently emerged as promising platforms for drug delivery, showing biodegradability, biocompatibility and important loading capability of challenging highly water-soluble drugs such as azidothymidine tryphosphate (AZT-TP). In this study, nanoMOFs made of iron trimesate (MIL-100) were able to act as efficient molecular sponges, quickly adsorbing up to 24 wt% AZT-TP with entrapment efficiencies close to 100%, without perturbation of the supramolecular crystalline organization. These data are in agreement with molecular modelling predictions, indicating maximal loadings of 33 wt% and preferential location of the drug in the large cages. Spectrophotometry, isothermal titration calorimetry, and solid state NMR investigations enable to gain insight on the mechanism of interaction of AZT and AZT-TP with the nanoMOFs, pointing out the crucial role of phosphates strongly coordinating with the unsaturated iron(III) sites. Finally, contrarily to the free AZT-TP, the loaded nanoparticles efficiently penetrate and release their cargo of active triphosphorylated AZT inside major HIV target cells, efficiently protecting against HIV infection.
Subject(s)
Anti-Retroviral Agents/administration & dosage , Anti-Retroviral Agents/chemistry , Ferric Compounds/administration & dosage , Ferric Compounds/chemistry , Nanocomposites/chemistry , Anti-Retroviral Agents/pharmacokinetics , Cells, Cultured , Dideoxynucleotides/administration & dosage , Dideoxynucleotides/chemistry , Dideoxynucleotides/pharmacokinetics , Ferric Compounds/pharmacokinetics , HIV-1/drug effects , Humans , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , Nanocomposites/administration & dosage , Thymine Nucleotides/administration & dosage , Thymine Nucleotides/chemistry , Thymine Nucleotides/pharmacokinetics , Zidovudine/administration & dosage , Zidovudine/analogs & derivatives , Zidovudine/chemistry , Zidovudine/pharmacokineticsABSTRACT
In the domain of health, one important challenge is the efficient delivery of drugs in the body using non-toxic nanocarriers. Most of the existing carrier materials show poor drug loading (usually less than 5 wt% of the transported drug versus the carrier material) and/or rapid release of the proportion of the drug that is simply adsorbed (or anchored) at the external surface of the nanocarrier. In this context, porous hybrid solids, with the ability to tune their structures and porosities for better drug interactions and high loadings, are well suited to serve as nanocarriers for delivery and imaging applications. Here we show that specific non-toxic porous iron(III)-based metal-organic frameworks with engineered cores and surfaces, as well as imaging properties, function as superior nanocarriers for efficient controlled delivery of challenging antitumoural and retroviral drugs (that is, busulfan, azidothymidine triphosphate, doxorubicin or cidofovir) against cancer and AIDS. In addition to their high loadings, they also potentially associate therapeutics and diagnostics, thus opening the way for theranostics, or personalized patient treatments.
