Antitumor Efficacy of Liposomal N-(Phosphonacetyl)-L-Aspartic Acid in C-26 Tumor Bearing Balb/c Mice

Abstract

We have investigated the efficacy of liposome encapsulated N-(phosphonacetyl)-L-aspartic acid (PALA) for the treatment of the C-26 murine colon tumor in Balb/c mice, and have compared it in this regard to free PALA. Healthy female Balb/c mice and C-26 tumor inoculated mice were randomized for the maximum tolerated dose (MTD) study and the in vivo therapy study, and the survival was measured after a single intraperitoneal injection of the drug. The maximum tolerated dose for intraperitoneally administered drug was found to be 750 ㎎/Kg for free PALA, and was greater than the maximum dose possible (150 ㎎/Kg) for PALA encapsulated in both DSPC and DSPG liposomes. When drug was administered one day after tumor implantation, 150 ㎎/Kg of PALA in DSPG liposomes increased the percentage of tumor bearing mice surviving at day 36 from 8% (buffer control) to 88%. In contrast, 150 ㎎/Kg free PALA increased the day 36 surviving percentage to only 25%. A 150 ㎎/Kg dose of PALA in DSPC liposomes increased the surviving percentage to 50%, while a 75 ㎎/Kg dose of PALA in sterically stabilized liposomes increased the surviving percentage to 78%. These results show that PALA in negatively charged or sterically stabilized liposomes can exhibit considerably greater potency than free PALA in C-26 tumor bearing mice. nA new technique has been developed for the preparation of Lactobacillus microcapsules to enhance the stability against high temperature, humidity, gastric acid and bile acid. Employing fluidized bed coating, primary sub-coating was processed in non-organic solvent system, so that Lactobacillus did not directly contact with organic solvent. Secondary enteric-coating was processed in organic solvent with low temperature (below 33℃) technique, which minimized the heat labilability of Lactobacillus. Survival rate of Lactobacillus within microcapsule was not less than 95% and acid tolerance was above 30% in the artificial gastric acid. Further more it was dissolved in the artificial intestine juice within 2∼3 hr. Average size of Lactobacillus microcapsules was 450 ㎛(25-50 mesh) and its viability was above 90% in the direct tableting.