title: Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery.
abstract: BACKGROUND
  Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol) (MPEG)-doxorubicin (DOX) conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting.
  
  
  METHODS
  Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP). Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP). Nanoparticles were then prepared using a dialysis procedure.
  
  
  RESULTS
  The synthesized DendGDP was confirmed with (1)H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and revealed stronger fluorescence intensity than at other body sites while doxorubicin and DendDP nanoparticles showed strong fluorescence intensity in the various organs, indicating that DendGDP has cathepsin B sensitivity.
  
  
  CONCLUSIONS
  DendGDP is sensitive to cathepsin B in tumor cells and can be used as a cathepsin B-responsive drug targeting strategy. We suggest that DendGDP is a promising vehicle for cancer cell targeting.
authors.affiliation: Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Jeong
authors.affiliation: Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyung-Kyu
authors.initials: HK
authors.lastname: Park
authors.affiliation: Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea ; Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Gyeongnam, Republic of Korea.
authors.forename: Dae Hwan
authors.initials: DH
authors.lastname: Kang
authors.affiliation: Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Jong-Suk
authors.initials: JS
authors.lastname: Oh
authors.affiliation: Department of Physical and Rehabilitation Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Sam-Gyu
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000737:chemistry; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy; D009842:Oligopeptides / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D050091:Dendrimers; C504380:Gly-Phe-Leu-Gly; D009842:Oligopeptides; C027224:carbodiimide binding proteins; D011092:Polyethylene Glycols; D004317:Doxorubicin; D002401:Cathepsin B
keywords: CT26 cell; cathepsin B; enzyme-sensitive dendrimer; tetra peptide; tumor targeting