Effect of liposome size on peritoneal retention and organ distribution after intraperitoneal injection in mice.

ABSTRACT

Peritoneal carcinomatosis is a serious concern when treating digestive or ovarian tumors. Treatment with systemic chemotherapy suffers from poor penetration of cytotoxic agents into the peritoneal cavity and is not quite effective. Local delivery of drugs, especially as controlled-release delivery systems like liposomes, could provide sustained and higher drug levels and reduce systemic toxicity. In order to investigate the effect of liposome size on peritoneal retention, liposomes composed of distearoylphosphatidylcholine and cholesterol (DSPC/CHOL, molar ratio 21) were prepared at four sizes of 100, 400, 1000 and 3000 nm. Subsequently, these liposomes were labeled with (99m)Tc complex of hexamethylpropyleneamineoxime ((99m)Tc-HMPAO) and injected into mouse peritoneum. Then, mice were sacrificed at eight different time points and the percentage of injected radiolabel in the peritoneal cavity and the organ distribution in terms of percentage injected dose/gram tissue (%ID/g) were obtained. Results showed that the free label ((99m)Tc-HMPAO) was cleared very rapidly from the cavity so that after 5 min and 7h only 6.89+/-2.51% and 0.91+/-0.51% of the injected dose was recovered, respectively. However, for the liposomal formulations, this recovery value ranged from 8.47+/-1.62% to 29.99+/-12.06% at 7h. Peritoneal retention of the vesicles was increased with their size, and the highest retention rate was obtained with 1000 nm liposomes with an AUC value 15.51 times that of (99m)Tc-HMPAO. In blood, as expected, 100 nm liposomes showed much higher levels because of their greater stability. Their greater blood concentration also caused increased levels in the heart and kidneys, although their organ to blood AUC ratio was the lowest. Overall, among the different sized neutral liposomes investigated, the 1000 nm vesicles seemed to be the most optimal, achieving a greater peritoneal level and retention.