title: PEGylated PLGA nanoparticles for the improved delivery of doxorubicin.
abstract: We hypothesize that the efficacy of doxorubicin (DOX) can be maximized and dose-limiting cardiotoxicity minimized by controlled release from PEGylated nanoparticles. To test this hypothesis, a unique surface modification technique was used to create PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating DOX. An avidin-biotin coupling system was used to control poly(ethylene glycol) conjugation to the surface of PLGA nanoparticles, of diameter approximately 130 nm, loaded with DOX to 5% (wt/wt). Encapsulation in nanoparticles did not compromise the efficacy of DOX; drug-loaded nanoparticles were found to be at least as potent as free DOX against A20 murine B-cell lymphoma cells in culture and of comparable efficacy against subcutaneously implanted tumors. Cardiotoxicity in mice as measured by echocardiography, serum creatine phosphokinase (CPK), and histopathology was reduced for DOX-loaded nanoparticles as compared with free DOX. Administration of 18 mg/kg of free DOX induced a sevenfold increase in CPK levels and significant decreases in left ventricular fractional shortening over control animals, whereas nanoparticle-encapsulated DOX produced none of these pathological changes.
  
  
  BACKGROUND
  The efficacy of doxorubicin (DOX) may be maximized and dose-limiting cardiotoxicity minimized by controlled release from PEGylated nanoparticles. Administration of 18 mg/kg of free DOX induced a sevenfold increase in CPK levels and significant decreases in left ventricular fractional shortening in mice, whereas nanoparticle-encapsulated DOX produced none of these pathological changes.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Park
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fong
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Booth
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy