G. Zhu et al., THE EFFECT OF VINCRISTINE-POLYANION COMPLEXES IN STEALTH LIPOSOMES ONPHARMACOKINETICS, TOXICITY AND ANTI TUMOR-ACTIVITY, Cancer chemotherapy and pharmacology, 39(1-2), 1996, pp. 138-142
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.