Development and characterization of polymeric nanoparticles(NPs) made from functionalized poly (D,L- lactide) (PLA)polymers

Biodegradable polymeric nanoparticles (NPs) have emerged as promising drug delivery carriers for the controlled drug release and targeting. The first part of this study aimed to develop biodegradable NPs from functionalized copolymers of poly (D,L-Lactide) (PLA). Those copolymers were explored as drug delivery systems in attempt to improve the drug delivery performance of conventional PLA NPs. The effect of PLA functionalization (insertion of chemical substituents onto PLA backbone) on the physicochemical properties of the obtained NPs was investigated. Moreover, the effect of polymer architecture (mode of organization of polymer chains in the resultant copolymer) on various drug delivery aspects was also studied. To reach those goals, various PLA based copolymers namely poly(ethylene glycol) (PEG) grafted on PLA backbone at 2.5% & 7% mol/mol of lactic acid monomers (PEG2.5%-g-PLA and PEG7%-g-PLA, respectively),  palmitic acid grafted on PLA backbone at 2.5% grafting density (palmitic acid2.5%-g-PLA), and multiblock copolymer of PLA and PEG, (PLA-PEG-PLA)n were synthesized. In the second part, the effect of different PEG grafting densities over PLA backbone on the properties of PEG-g-PLA NPs either physicochemical or biological properties was investigated to reveal the optimal PEG grafting density required to develop stealth particles (long circulating NPs). Finally, functionalized PEG/PLA copolymers that showed the most satisfactory results in terms of various drug delivery aspects, such as size and size distribution, surface charge, drug loading, and controlled drug release were selected for encapsulation of itraconazole (ITZ) to improve its aqueous solubility, bioavailability and hence its antifungal activity. NPs were first prepared from functionalized PLA copolymers then analyzed for their major physicochemical parameters such as encapsulation efficiency, size and size distribution, surface charge, thermal properties, surface chemistry, % poly(vinyl alcohol) (PVA) adsorbed at the surface of NPs, and drug release pattern. Surface chemistry analysis using x-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) phase imaging were used to study the chain organization behavior of each functionalized copolymer during NPs formulation. Generally speaking, functionalized PEG/PLA copolymers showed improved drug delivery behavior in terms of narrow size and size distribution, enhanced loading efficiency, less plasma protein adsorption onto their surfaces and less macrophage uptake, and finally better antifungal activity for ITZ loaded NPs. For the surface chemistry analysis, AFM phase imaging and XPS studies revealed the possibility of existence of more PEG chains at the surface of PEG-g-PLA NPs than (PLA-PEG-PLA)n during NPs formation. Our results demonstrate that properties of PLA-based NPs can be tuned by proper selection of both polymer composition and polymer architecture. Results also suggest that PEG-g-PLA copolymers could be used efficiently as a nanocarrier to improve various drug properties e.g. solubility, stability, and bioavailability.

Keyphrases: Architecture, PEG-PLA, Poly (D,L lactide), Architecture, Chain organization, PEG-PLA