Nanoparticles with high payloads of pipemidic acid, a poorly soluble crystalline drug: drug-initiated polymerization and self-assembly approach

摘要

Nowadays, biodegradable polymers such as poly(lactic acid)(PLA), poly(D,L-lactic-coglycolic acid)(PLGA) and poly(ε-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 selfassembled NPs with PIP contents as high as 27%(w/w). 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.