Journal
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
Volume 79, Issue 2, Pages 232-240Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejpb.2011.03.025
Keywords
Poly(amidoamine) dendrimer; Poly(ethylene glycol); RGD-peptide; Doxorubicin; Cellular uptake; Glioma
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Funding
- National Basic Research Program of China (973 Program) [2007CB935802]
- National Science and Technology Major Project [2009ZX09310-006]
- Science and Technology Commission of Shanghai Municipality [0952nm03900]
- Renji Hospital (Shanghai Jiaotong University School of Medicine) [RJ 4101307]
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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. (C) 2011 Elsevier B.V. All rights reserved.
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