Synthesis of Prostaglandin E₁ Phosphate Derivatives and Their Encapsulation in Biodegradable Nanoparticles

Purpose Prostaglandin E₁ (PGE₁) is an effective treatment for peripheral vascular diseases. The encapsulation of PGE₁ in nanoparticles for its sustained-release would improve its therapeutic effect and quality of life (QOL) of patients. Methods In order to encapsulate PGE₁ in nanoparticles prepared with a poly(lactide) homopolymer (PLA) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA), we synthesized a series of PGE₁ phosphate derivatives and tested their efficacy. Results Among them, PGE₁ 2-(phosphonooxy)ethyl ester sodium salt (C2) showed the most efficient hydrolysis to yield PGE₁ in human serum. An in vitro platelet aggregation assay showed that C2 inhibited aggregation only after pre-incubation in serum, suggesting that C2 is a prodrug of PGE₁. In vivo, intravenous administration of C2 caused increase in cutaneous blood flow. In the presence of zinc ions, all of the synthesized PGE₁ phosphate derivatives could be encapsulated in PLA-nanoparticles. Use of l-PLA instead of d,l-PLA, and high molecular weight PLA resulted in a slower release of C2 from the nanoparticles. Conclusions We consider that C2-encapsulated nanoparticles prepared with l-PLA and PEG-d,l-PLA have good sustained-release profile of PGE₁, which is useful clinically.