THE EFFECT OF VINCRISTINE-POLYANION COMPLEXES IN STEALTH LIPOSOMES ONPHARMACOKINETICS, TOXICITY AND ANTI TUMOR-ACTIVITY

Poly(ethylene glycol) (PEG)-derivatized liposome vehicles improve anti tumor effectiveness of entrapped anthracyclines and vinca alkaloids. H owever, the plasma clearance of entrapped vincristine is substantially faster than the lipid phase or other entrapped aqueous markers, sugge sting leakage out of the liposome during transit in the blood compartm ent. We tested the effect of altering the drug's in vivo leakage rate on pharmacokinetics, toxicity, and antitumor activity of entrapped dru g in rodent models. Suramin, heparin, and dextran sulfate were tested for their ability to produce a precipitable complex in vitro. PEG-deri vatized liposomes were prepared with the complexing agent inside, and vincristine was driven inside using an ammonium gradient. The resultin g preparations were found to have plasma distribution half-lives signi ficantly longer than the formulation without a complex-forming agent. There was no increase in acute lethality, and in the case of the suram in-vincristine complex, the acute lethality was significantly reduced at the highest does level. Anti-tumor activity against the mouse mamma ry carcinoma MC2 was tested in a multiple-dose study. Free vincristine did not affect the tumor growth rate significantly, but at the same d ose level all PEG-coated liposome formulations inhibited tumor growth markedly. The suramin containing formulation was as effective as the f ormulation lacking polyanion, but the heparin and dextran sulfate cont aining formulations were less effective. Thus, compounds which form in soluble complexes with vincristine alter in vivo plasma distribution p hase pharmacokinetics without increasing acute lethality, but without a corresponding increase in anti-tumor activity.