title: Development of biodegradable polymeric implants of RGD-modified PEG-PAMAM-DOX conjugates for long-term intratumoral release.
abstract: BACKGROUND
  The sustained release implants can be directly implanted in tumor site by surgery and are promising for cancer treatment.
  
  
  OBJECTIVE
  RGD-modified PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) conjugated by acid-sensitive linkage (RGD-PPCD) was a potential conjugate for tumor-targeted therapy. In order to enhance tumor retention ability and long-term effect of drug, we developed the DOX and its conjugate implants using poly(dl-lactic-co-glycolic acid) (PLGA), poly(dl-lactic acid) (PLA) and polyethylene glycol (PEG) as carrier materials.
  
  
  METHODS
  The implants were prepared by a simple solvent evaporation method. Different formulations with varying ratios of three polymers were designed, prepared and evaluated on the basis of viscosity, in vitro release and drying time. Furthermore, in vivo biodistribution and antitumor activity of the implants were studied in mice with subcutaneous C6 xenografts.
  
  
  RESULTS
  The optimized formulation was obtained with the 3:1 ratio of PLGA/PLA (w/w) and 1% PEG (wt.%). The drug release behavior of DOX, PPCD and RGD-PPCD implants prepared by the optimized formulation was similar according to the assessment of similarity factor f2, and the release curves were fell into three phases, including a lag-period, then the second phase which was consistent with zero-order model followed by a plateau. Data of total DOX remained in implants indicated the release were faster in vivo than in vitro. Moreover, intratumoral drug amount of RGD-PPCD implants was the highest 45 days after implantation. Correspondingly, the RGD-PPCD implants exhibited the strongest antitumor activity compared with PPCD and free DOX implants.
  
  
  CONCLUSIONS
  This paper presents an exploratory research on macromolecule-drug conjugates, including RGD-PPCD and PPCD, which have the potential to be developed into long-term effect implants for tumor therapy with high efficiency and low systematic toxicity.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University , Shanghai , People's Republic of China and.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Qian
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zheng
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D050091:Dendrimers / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D004343:Drug Implants; D065546:Drug Liberation; D008297:Male; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D050091:Dendrimers; D004337:Drug Carriers; D004343:Drug Implants; D009842:Oligopeptides; C522249:PEG-PAMAM; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin
keywords: Conjugates; doxorubicin; gliomas; implants; polymer