Journal
BIOMATERIALS
Volume 31, Issue 6, Pages 1360-1371Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2009.10.044
Keywords
Poly(amidoamine) dendrimer; Poly(ethylene glycol); Doxorubicin; Acid-sensitive linkage; Antitumor activity
Funding
- National Basic Research Program of China (973 Program) [2007CB935802]
- National Natural Science Foundation of China [30672543]
- National Key Program Pharmaceutical Innovation and Development [2009ZX09310-006]
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Partly PEGylated polyamidoamine (PAMAM) dendrimers were used as the carrier for tumor-selective targeting of the anticancer drug doxorubicin (DOX). Acid-sensitive cis-aconityl linkage or acid-in sensitive succinic linkage was introduced between DOX and polymeric carriers to produce PPCD or PPSD conjugates, respectively. DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against murine B16 melanoma cells increased with, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. Confocal laser scanning microscopy confirmed the acid-sensitive release of DOX from PPCD conjugates in the lysosomes and the entrance into nuclei. Pharmacokinetic and biodistribution studies demonstrated that increasing PEGylation degree resulted in reduced liver and splenic accumulation, longer circulation time and more tumor accumulation of the conjugates. Although PPSD conjugates showed more tumor accumulation than PPCD conjugates at the same PEGylation degree, the acid-sensitive DOX release from PPCD conjugates ensured higher concentration of free DOX in tumor and more pronounced antitumor activity. Besides, the antitumor activity of PPCD conjugates increased with increasing PEGylation degree. Overall, PPCD conjugate with the highest PEGylation would be a promising candidate for solid tumor therapy. (C) 2009 Elsevier Ltd. All rights reserved.
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