RGD-modified PEG-PAMAM-DOX conjugates: in vitro and in vivo studies for glioma.

Abstract

This work was based on our recent studies that a promising conjugate, RGD-modified PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) conjugated by acid-sensitive cis-aconityl linkage (RGD-PPCD), could increase tumor targeting by binding with the integrin receptors overexpressed on tumor cells and control release of free DOX in weakly acidic lysosomes. To explore the application of RGD-PPCD to glioma therapy, the effects of the conjugate were further evaluated in glioma model. For comparative studies, DOX was also conjugated to PEG-PAMAM by acid-insensitive succinic linkage to produce the PPSD conjugates, which was further modified by RGD to form RGD-PPSD. In vitro cytotoxicity of the acid-sensitive conjugates against C6 cells was higher than that of the acid-insensitive ones, and further the modification of RGD enhanced the cytotoxicity of the DOX-polymer conjugates as a result of the increased cellular uptake of the RGD-modified conjugates by C6 cells. In vivo pharmacokinetics, biodistribution and antitumor activity were investigated in an orthotopic murine model of C6 glioma by i.v. administration of DOX-polymer conjugates. In comparison with DOX solution, all the conjugates showed significantly prolonged half-life and increased AUC and exhibited higher accumulation in brain tumor than normal brain tissue. Although RGD-PPCD was more than 2-fold lower tumor accumulation than RGD-PPSD, it exhibited the longest survival times among all treatment groups, and therefore, RGD-PPCD conjugate provide a desirable candidate for targeted therapy of glioma.

• Authors: Lihong Zhang, Saijie Zhu, Lili Qian, Yuanying Pei, Yongming Qiu, Yanyan Jiang
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 79 Issue 2 Pg. 232-40 (Oct 2011) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 21496485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Dendrimers
• Drug Carriers
• Liposomes
• Oligopeptides
• PEG-PAMAM
• Polyethylene Glycols
• arginyl-glycyl-aspartic acid
• Doxorubicin
• Succinic Acid

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Brain Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Dendrimers (administration & dosage, chemistry, pharmacokinetics)
• Doxorubicin (administration & dosage, chemistry, pharmacokinetics)
• Drug Carriers (administration & dosage, chemistry)
• Glioma (drug therapy, metabolism)
• Half-Life
• Liposomes (administration & dosage, chemistry, pharmacokinetics)
• Male
• Mice
• Mice, Inbred ICR
• Oligopeptides (administration & dosage, chemistry, pharmacokinetics)
• Polyethylene Glycols (administration & dosage, chemistry, pharmacokinetics)
• Succinic Acid (chemistry)
• Tissue Distribution