Nowadays, biodegradable polymers such as poly(lactic acid) (PLA), poly(D,L-lactic--glycolic acid) (PLGA) and poly(-caprolactone) (PCL) remain the most common biomaterials to produce drug-loaded nanoparticles (NPs). Pipemidic acid (PIP) is a poorly soluble antibiotic with a strong tendency to crystallize. PIP incorporation in PLA/PLGA NPs was challenging because of PIP crystals formation and burst release. As PIP had a poor affinity for the NPs, an alternative approach to encapsulation was used, consisting in coupling PIP to PCL. Thus, a PCL-PIP conjugate was successfully synthesized by an original drug-initiated polymerization in a single step without the need of catalyst. PCL-PIP was characterized by NMR, IR, SEC and mass spectrometry. PCL-PIP was used to prepare self-assembled NPs with PIP contents as high as 27% (/). The NPs were characterized by microscopy, DLS, NTA and TRPS. This study paves the way towards the production of NPs with high antibiotic payloads by drug-initiated polymerization. Further studies will deal with the synthesis of novel polymer-PIP conjugates with ester bonds between the drug and PCL. PIP can be considered as a model drug and the strategy developed here could be extended to other challenging antibiotics or anticancer drugs and employed to efficiently incorporate them in NPs.

Metal-organic frameworks (MOFs), comprised of organic ligands and metal ions/metal clusters

Tremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies, but few of them are capable to produce drug particles with sizes less than a few nanometers. This challenge has been addressed here by using biocompatible versatile -cyclodextrin (-CD) metal-organic framework (CD-MOF) large molecular cages in which azilsartan (AZL) was successfully confined producing clusters in the nanometer range. This strategy allowed to improve the bioavailability of AZL in Sprague-Dawley rats by 9.7-fold after loading into CD-MOF. The apparent solubility of AZL/CD-MOF was enhanced by 340-fold when compared to the pure drug. Based on molecular modeling, a dual molecular mechanism of nanoclusterization and complexation of AZL inside the CD-MOF cages was proposed, which was confirmed by small angle X-ray scattering (SAXS) and synchrotron radiation-Fourier transform infrared spectroscopy (SR-FTIR) techniques. In a typical cage-like unit of CD-MOF, three molecules of AZL were included by the -CD pairs, whilst other three AZL molecules formed a nanocluster inside the 1.7 nm sized cavity surrounded by six -CDs. This research demonstrates a dual molecular mechanism of complexation and nanoclusterization in CD-MOF leading to significant improvement in the bioavailability of insoluble drugs.