Doxorubicin coupled to lactosaminated albumin: effect of heterogeneity in drug load on conjugate disposition and hepatocellular carcinoma uptake in rats

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
G Di StefanoPaolo Caliceti

Abstract

Coupling to lactosaminated human albumin (L-HSA) makes doxorubicin (DOXO) an effective drug against chemically induced rat hepatocellular carcinomas (HCCs). In the conjugate there is a large heterogeneity in the number of DOXO molecules bound to one L-HSA molecule. After lyophilization, the molecules with the higher DOXO load form large complexes (C-DOXOL), whereas those with low drug load (C-DOXOS) have the size of the carrier L-HSA. In the present experiments, we demonstrated that in C-DOXOL the molecules are not linked by covalent bonds, but are strongly aggregated probably because of mutual drug-drug interaction between the DOXO residues. In healthy rats and in animals with HCCs which received the same dose (1 microg/g) of DOXO injected in C-DOXOL or in C-DOXOS forms, penetration of the drug in tumors and in tissues was more rapid after administration of the former complex. Three hours after injection of both conjugate forms the intracellular release of DOXO from the carrier was completed. The AUCs from 0.5 to 4h of the levels of the released DOXO in HCCs, surrounding liver and bone marrow of animals injected with C-DOXOL were similar to those calculated in animals given C-DOXOS. This suggests that after administration of t...Continue Reading

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Citations

Apr 30, 2014·Expert Opinion on Drug Delivery·Luigi FiumeGiuseppina Di Stefano
Jul 18, 2012·Journal of Controlled Release : Official Journal of the Controlled Release Society·Il Keun KwonKinam Park
Apr 21, 2010·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Luigi Fiume, Giuseppina Di Stefano
Aug 22, 2009·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Carla BogaGiuseppina Di Stefano
Aug 30, 2008·Drug Discovery Today·Luigi FiumeGiuseppina Di Stefano
Jul 9, 2008·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·M BaglioniG Di Stefano
Nov 9, 2016·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·Bakheet ElsadekFelix Kratz
Feb 19, 2020·Small·Kenward VongKatsunori Tanaka

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