Effect Of Liposomal Doxorubicin Research Articles

The Accumulation and Effects of Liposomal Doxorubicin in Tissues Treated by Radiofrequency Ablation and Irreversible Electroporation in Liver: In Vivo Experimental Study on Porcine Models.

To compare the accumulation and effect of liposomal doxorubicin in liver tissue treated by radiofrequency ablation (RFA) and irreversible electroporation (IRE) in in vivo porcine models. Sixteen RFA and 16 IRE procedures were performed in healthy liver of two groups of three pigs. Multi-tined RFA parameters included: 100W, target temperature 105°C for 7min. 100 IRE pulses were delivered using two monopolar electrodes at 2250V, 1Hz, for 100 µsec. For each group, two pigs received 50mg liposomal doxorubicin (0.5mg/kg) as a drip infusion during ablation procedure, with one pig serving as control. Samples were harvested from the central and peripheral zones of the ablation at 24 and 72h. Immunohistochemical analysis to evaluate the degree of cellular stress, DNA damage, and degree of apoptosis was performed. These and the ablation sizes were compared. Doxorubicin concentrations were also analyzed using fluorescence photometry of homogenized tissue. RFA treatment zones created with concomitant administration of doxorubicin at 24h were significantly larger than controls (2.5 ± 0.3cm vs. 2.2 ± 0.2cm; p = 0.04). By contrast, IRE treatment zones were negatively influenced by chemotherapy (2.2 ± 0.4cm vs. 2.6 ± 0.4cm; p = 0.05). At 24h, doxorubicin concentrations in peripheral and central zones of RFA were significantly increased in comparison with untreated parenchyma (0.431 ± 0.078µg/g and 0.314 ± 0.055µg/g vs. 0.18 ± 0.012µg/g; p < 0.05). Doxorubicin concentrations in IRE zones were not significantly different from untreated liver (0.191 ± 0.049µg/g and 0.210 ± 0.049µg/g vs. 0.18 ± 0.012µg/g). Whereas there is an increased accumulation of periprocedural doxorubicin and an associated increase in ablation zone following RFA, a contrary effect is noted with IRE. These discrepant findings suggest that different mechanisms and synergies will need to be considered in order to select optimal adjuvants for different classes of ablation devices.

Trastuzumab and Liposomal Doxorubicin in the Treatment of MCF-7 Xenograft Tumor-Bearing Mice: Combination Does Not Affect Drug Serum Levels

We assessed the combination of doxorubicin or liposomal doxorubicin with trastuzumab for alterations in peak serum drug levels, as these agents are increasingly being paired in the treatment of aggressive breast cancer. We hypothesized that trastuzumab would exhibit a slower rate of elimination from the serum when in combination with liposomal doxorubicin based on the known effects of liposomal doxorubicin on phagocytic cells of the mononuclear phagocyte system (MPS), which are responsible in part for the uptake and degradation of antibodies. Doxorubicin and trastuzumab serum levels were assessed following injection of free doxorubicin, liposomal doxorubicin, or trastuzumab into female RAG2-M mice bearing subcutaneous MCF-7(HER-2) tumors. The effects of combination drug treatment on tumor growth were compared to single-agent treatment. Peak serum trastuzumab levels were not altered as a result of addition of doxorubicin therapy, nor were doxorubicin levels altered over 24 h as a result of coadministration of trastuzumab. Liposomal doxorubicin administration did result in serum doxorubicin levels 200- to 1000-fold higher than with injection of free doxorubicin. For the specific combination of trastuzumab with doxorubicin, either in free or liposomal form, coadministered in mice, there was no impact of one drug on the other in terms of peak serum drug levels or efficacy.

Targeting liver tumors by administering liposomal doxorubicin into the hepatic artery.

The plasma levels, organ distribution, and in vivo anti-tumor activity of liposomal doxorubicin administered i.v. or i.a. (hepatic) in rats bearing W256 liver tumors were studied. I.a. administration of liposomal doxorubicin resulted in 4-fold and 1.3-fold higher liver tumor and liver parenchyma doxorubicin levels, respectively, than i.v. administration, thus suggesting a more preferential distribution of liposomal doxorubicin into the liver tumor with i.a. administration. By contrast, the heart, spleen, and plasma AUCs were decreased 3.8-, 3.2-, and 16-fold, respectively, after i.a. administration. Cumulative urinary excretion at 8 hr was also 14 times lower in animals that received liposomal doxorubicin i.a. In good correlation with these findings, i.a. administration markedly enhanced the anti-tumor effect of liposomal doxorubicin against liver W256 tumors as measured by tumor growth inhibition 5 days after treatment (-16% for i.a. administration vs. +89% for i.v. administration, p less than or equal to 0.05) and prolongation of survival (ILS: 108% for i.a. administration vs. 26% for i.v. administration, p less than or equal to 0.05). Our results show that i.a. administration of liposomal doxorubicin results in preferential distribution of the anti-tumor agent into the tumor tissue and increased anti-tumor activity, while increasing the cardioprotective effect of the liposome carrier by decreasing the plasma peak and heart-tissue levels of the drug.