Biodegradable polymeric nanoparticles and micelles as drug carriers

Abstract

Doxorubicin was chemically conjugated to a terminal end group of poly(D,L-lacticco-glycolic acid) [PLGA] by a carbamate linkage and an ester linkage. The doxorubicin-PLGA conjugate was formulated into nanoparticles. A hydroxyl terminal group of PLGA was activated by p-nitrophenyl chloroformate and reacted with a primary amine group of doxorubicin for the conjugation. A carboxylic acid end group of PLGA was conjugated to a primary hydroxyl group of doxorubicin. The primary amine group of doxorubicin was protected during the conjugation process and then deprotected. The nanoparticles containing the conjugate exhibited sustained doxorubicin release profiles over a one-month period, whereas those containing unconjugated free doxorubicin showed a rapid doxorubicin release within 5 days. Doxorubicin release patterns could be controlled by conjugating doxorubicin to PLGA having different molecular weights. The conjugated doxorubicin nanoparticles showed increased uptake within a HepG2 cell line, which was quantitated by a flow cytometry and visualized by a confocal microscopy. The nanoparticles exhibited slightly lower IC50 value against the HepG2 cell line compared to that of free doxorubicin. In vivo anti-tumor activity assay also showed that a single injection of the nanoparticles had comparable activity to that of free doxorubicin administered by daily injection. The conjugation approach of doxorubicin to PLGA was potentially useful for the formulation of nanoparticles that requires targeting for cancer cells as well as sustained release at the site. Doxorubicin was chemically conjugated to the terminal end of a di-block copolymer composed of poly(L-lactic acid) (PLLA) and methoxy-poly(ethylene glycol) (mPEG) via two acid-cleavable linkages. A hydrazone bond and a cis-acotinyl bond were formed between doxorubicin and the terminal group of PLLA segment in the block copolymer. Doxorubicin conjugated PLLA-mPEG di-block copolymers self-assembled to form micelles in aq...