title: Polymeric nanoparticles conjugate a novel heptapeptide as an epidermal growth factor receptor-active targeting ligand for doxorubicin.
abstract: BACKGROUND
  This study was performed to develop a functional poly(D,L-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG)-bearing amino-active end group for peptide conjugation.
  
  
  RESULTS
  PLGA was preactivated following by copolymerization with PEG diamine. The resulting amphiphilic PLGA-PEG copolymer bearing 97.0% of amino end groups had a critical micelle concentration of 3.0 × 10⁻⁸ mol/L, and the half-effective inhibition concentration (IC₅₀) of the prepared PLGA-PEG nanoparticles was >100 mg/mL, which was much higher than that of PLGA nanoparticles (1.02 ± 0.37 mg/mL). The amphiphilic properties of PLGA-PEG spontaneously formed a core-shell conformation in the aqueous environment, and this special feature provided the amino group on the PEG chain scattered on the surface of PLGA-PEG nanoparticles for efficient peptide conjugation. The peptide-conjugated PLGA-PEG nanoparticles showed three-fold higher uptake than peptide-free PLGA-PEG nanoparticles in a SKOV3 cell line with high expression of epidermal growth factor receptor. Both peptide-conjugated and peptide-free PLGA-PEG nanoparticles were used as nanocarriers for delivery of doxorubicin. Although the rate of release of doxorubicin from both nanoparticles was similar, drug release at pH 4.0 (500 U lipase) was faster than at pH 7.4. The IC₅₀ of doxorubicin-loaded peptide-conjugated PLGA-PEG nanoparticles in SKOV3 cells (0.05 ± 0.03 μg/mL) was much lower (by 62.4-fold) than that of peptide-free PLGA-PEG nanoparticles (3.12 ± 1.44 μg/mL).
  
  
  CONCLUSIONS
  This in vivo biodistribution study in SKOV3 tumor-bearing mice was further promising in that accumulation of doxorubicin in tumor tissue was in the order of peptide-conjugated PLGA-PEG nanoparticles > peptide-free PLGA-PEG nanoparticles > doxorubicin solution.
authors.affiliation: Graduate Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia Wen
authors.initials: CW
authors.lastname: Liu
authors.forename: Wen Jen
authors.initials: WJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D045744:Cell Line, Tumor; D004317:Doxorubicin; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D008024:Ligands; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry*; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010455:Peptides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry*; D011098:Polyglactin 910 / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D008024:Ligands; D053769:Nanocapsules; D010455:Peptides; C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D004815:Epidermal Growth Factor; D004317:Doxorubicin