In vitro and in vivo anti-tumor activities of nanoparticles based on doxorubicin-PLGA conjugates

Doxorubicin was chemically conjugated to a terminal end group of poly(D,L-l actic-co-glycolic acid) [PLGA] by an ester linkage and the doxorubicin-PLGA conjugate was formulated into nanoparticles. A carboxylic acid end group o f PLGA was conjugated to a primary hydroxyl group of doxorubicin. The prima ry 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 1-month period, whereas those containing unconjugated free doxorubicin showed a rapid doxorubicin releas e within 5 days. Doxorubicin release patterns could be controlled by conjug ating doxorubicin to PLGA having different molecular weights. The conjugate d doxorubicin nanoparticles showed increased uptake within a HepG2 cell lin e, which was quantitated by a flow cytometry and visualized by confocal mic roscopy. The nanoparticles exhibited slightly lower IC50 value against the HepG2 cell line compared to that of free doxorubicin. In vivo anti-tumor ac tivity assay also showed that a single injection of the nanoparticles had c omparable activity to that of free doxorubicin administered by daily inject ion. The conjugation approach of doxorubicin to PLGA was potentially useful for the formulation of nanoparticles that requires targeting for cancer ce lls as well as sustained release at the site. (C) 2000 Elsevier Science B.V . All rights reserved.