Figure 1.
Sum Total Doxorubicin Concentrations from NonL-doxo.
Individual and mean sum total doxorubicin concentration in plasma, brain tumor, contralateral non-tumor brain, and peri-tumoral brain of female athymic nude (nu/nu) mice bearing intracranial MDA-MB-231-BR human triple-negative breast cancer xenografts following administration of nonliposomal doxorubicin (NonL-doxo) at 6 mg/kg IV ×1. Samples (n = 3 mice at each time point) were obtained at 0.083, 1, 3, 6, 24, 72 and 96 hours following administration of NonL-doxo. Concentrations were undetectable after 3 hours (contralateral non-tumor brain), 6 hours (peri-tumoral brain), and 24 hours (plasma and tumor) of administration. (A) 0–96 h; (B) 0–6 h.
Table 1.
Pharmcokinetic parameters for PLD and NonL-doxo.
Figure 2.
Sum Total Doxorubicin Concentrations from PLD.
Individual and mean sum total doxorubicin concentration in plasma, brain tumor, contralateral non-tumor brain, and peri-tumoral brain of female athymic nude (nu/nu) mice bearing intracranial MDA-MB-231-BR human triple-negative breast cancer xenografts following administration of PEGylated liposomal-doxorubicin (PLD) at 6 mg/kg IV ×1. Samples (n = 3 mice at each time point) were obtained at 0.083, 1, 3, 6, 24, 72, and 96 hours following administration of PLD. (A) 0–96 h; (B) 0–6 h.
Figure 3.
Efficacy Studies in an intracranial model of breast cancer.
(A) Median survival (from the time of intracranial cell line injection) of animals treated with control (PBS, black), non-liposomal doxorubicin (NonL-doxo, green) 6mg/kg IV weekly and PEGylated liposomal doxorubicin (PLD, blue) 6mg/kg IV weekly in a murine model of intracranial breast cancer. (B) Median survival of animals treated with control (PBS, black), NonL-doxo 4.5 mg/mg IV weekly plus ABT-888 25 mg/kg OG daily (yellow) versus PLD (red) 4.5mg/mg IV weekly plus ABT-888 25 mg/kg OG daily in a murine model of intracranial breast cancer.
Table 2.
Median survival of intracranial breast cancer model.
Figure 4.
Sequential and combination treatment of the MDA-MB-231-BR cell line with ABT-888 and non-liposomal doxorubicin (NonL-doxo).
(A) Percentage of viable cells treated in each of three treatment arms (72 hours [h] ABT-888 followed by 72 h NonL-doxo [blue], 72 h NonL-doxo followed by 72 h ABT-888 [red], and 72 h concurrent schedule of NonL-doxo and ABT-888 in combination [green]). (B) Combination index (CI) analysis in each arm compared to treatment with single agents. Note: CI <0.1–0.9, synergy; CI 0.9–1.1, additivity; CI >1.1, antagonism.
Figure 5.
Bioluminescence imaging of TNBC intracranial tumor model.
(A) Dynamic changes in intracranial tumor growth after treatment as measured by bioluminescence imaging in photons/second. Groups are as follows: Control (black), non-liposomal doxorubicin (NonL-doxo, green), PEGylated liposomal doxorubicin [PLD] (blue), ABT-888 (purple), NonL-doxo/ABT-888 (yellow) and PLD/ABT-888 (red). The median fold changes are connected over time for each treatment group. The vertical bars indicate the interquartile rages (25th–75th percentiles). Points are only plotted when there were at least 2 animals in a treatment group. (B) Representative images of intracranial bioluminescence by treatment group 14 days post-treatment initiation.