EFFECT OF PARTICLE-SIZE AND CHARGE ON THE DISPOSITION OF LIPID CARRIERS AFTER INTRATUMORAL INJECTION INTO TISSUE-ISOLATED TUMORS

Purpose, Pharmacokinetic properties of various lipid carriers (liposom e and emulsions) after intratumoral injection were studied in perfusio n experiments using tissue-isolated tumor preparations of Walker 256 c arcinosarcoma. Methods, Four types of lipid carriers, large emulsion ( 254 nm), small emulsion (85 nm), neutral liposomes (120 nm) and cation ic liposomes (125 nm) were prepared. We'quantified their recovery from the tumor, leakage from the tumor surface and venous outflow after in tratumoral injection into perfused tissue-isolated tumors, and analyze d venous appearance curves based on a pharmacokinetic model. Results, In contrast to the small emulsion and neutral liposomes, which immedia tely appeared in the venous outflow perfusate following intratumoral i njection, the appearance of the cationic liposomes and the large emuls ion was highly restricted, clearly demonstrating that intratumoral cle arance of these formulations can be greately retarded by the cationic charge and large particle size, respectively. The venous appearance ra te-time profiles were fitted to equations derived from a two-compartme nt model by nonlinear regression analysis. When the calculated paramet ers were compared among these four formulations, the venous appearance rate did not exhibit such a large difference; however, the rate of tr ansfer from the injected site to the compartment which involves cleara nce by venous outflow was all very different. Conclusions, The results of this study indicate that the determining factor which alters the p harmacokinetic properties of these lipid carriers after intratumoral i njection is not the rate of transfer from the interstitial space to th e vascular side but the rate of intratumoral transfer from the injecti on site to the well-vascularized region.