Background: Recently we developed a scalable scheme of synthesis of melphalan ester conjugate
with 1,2-dioleoyl-sn-glycerol (MlphDG) and a protocol for the fabrication of its lyophilized
Objective: Herein we compared this new convenient in use formulation of MlphDG with parent drug
Alkeran® in rats concerning several toxicological parameters and evaluated its antitumor efficacy in the
model of breast cancer in mice.
Method: Liposomes of approximately 100 nm in diameter, consisting of egg phosphatidylcholine, soybean
phosphatidylinositol, and MlphDG, or placebo liposomes without the drug were produced by extrusion
and lyophilized. Alkeran® or liposomes recovered by the addition of water were injected into the
tail vein of animals. Clinical examination of rats consisted of detailed inspection of the behavior, general
status, and hematological parameters. Mice with transplanted breast cancer WNT-1 were subjected
to multiple treatments with the drugs; tumor growth inhibition was assessed, together with cellular immunity
Results: Liposomes showed approximately two times lower acute toxicity and better tolerability than
Alkeran® in terms of behavioral criteria. The toxic effects of liposomes on hemopoiesis were manifested
at higher doses than in the case of Alkeran®, proportionally to the difference in LD50 values. The formulation
inhibited tumor growth significantly more effectively than Alkeran®, delaying the start of the
exponential growth phase and exhibiting no additional toxic effects toward bone marrow.
Conclusion: Lower toxicity of the liposomal formulation of MlphDG promises improved quality of life
for cancer patients in need of treatment with melphalan. Presumably, the list of indications for melphalan
therapy could be extended.