Biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomal cisplatin administered in Ehrlich tumor-bearing mice

Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the blo...

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Published in:	Experimental biology and medicine (Maywood, N.J.) Vol. 236; no. 7; p. 808
Main Authors:	Araújo, José Geraldo Coimbra, Mota, Luciene das Graças, Leite, Elaine Amaral, Maroni, Laís de Carvalho, Wainstein, Alberto Julius Alves, Coelho, Luiz Gonzaga Vaz, Savassi-Rocha, Paulo Roberto, Pereira, Márcio Tadeu, de Carvalho, Andréa Teixeira, Cardoso, Valbert Nascimento, De Oliveira, Mônica Cristina
Format:	Journal Article
Language:	English
Published:	England 01-07-2011
Subjects:	Animal Structures - chemistry Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Carcinoma, Ehrlich Tumor - drug therapy Cisplatin - administration & dosage Cisplatin - pharmacokinetics Cisplatin - pharmacology Disease Models, Animal Drug Carriers - administration & dosage Drug Carriers - pharmacokinetics Humans Hydrogen-Ion Concentration Liposomes - administration & dosage Liposomes - pharmacokinetics Mice Peritoneal Neoplasms - drug therapy Survival Analysis Treatment Outcome
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Summary:	Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL-CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal cavity.
ISSN:	1535-3699
DOI:	10.1258/ebm.2011.011038