P4-17-04: Pharmacokinetic Disposition of PEGylated Liposomal Doxorubicin Compared with Non-Liposomal Doxorubicin in an Intracranial Breast Cancer Murine Model.

Abstract

Abstract Background Breast cancer brain metastases are an increasingly common consequence of advanced breast cancer associated with poor prognosis and survival. Systemic therapies capable of crossing the blood brain barrier to control both intra- and extracranial disease are few. Nanoparticle agents, such as liposomes, achieve a higher concentration and prolonged exposure in solid tumors. Liposomal formulations of anti-cancer agents have also been shown in preclinical and clinical studies to enhance delivery to tumors within the brain. We compared the pharmacokinetic (PK) disposition of PEGylated liposomal doxorubicin (Doxil®; PLD) with non-liposomal doxorubicin (NLD) in an intracranial breast cancer model. Methods: Athymic (nu/nu) mice (∼8wks) were inoculated with MDA-MB-231-BR (brain subclone) cells expressing luciferase (2×105 cells/injection) in 5% methylcellulose (5 μL) into the right caudate nucleus. On day 18, tumor-bearing mice via bioluminescence imaging were administered PLD or NLD at 6 mg/kg IV x 1 via tail vein. Mice (n=3) were sacrificed at 6 and 24h for PLD and NLD; and 72h for PLD. Plasma and intracranial tumor were processed to measure sum total doxorubicin via high-performance liquid chromatography (HPLC, lower limit of quantification=10 ng/mL). T-tests were used to compare means between treatment groups. Results: Treatment with PLD resulted in higher plasma sum total doxorubicin concentrations compared with NLD (Table). PLD was detected at 72h in plasma. There were higher intracranial tumor sum total doxorubicin concentrations at 6 and 24h for PLD compared with NLD; NLD was below limit of quantification (BLQ) at both time points. Consistent with the plasma PK of PLD, intracranial tumor sum total doxorubicin concentrations for PLD remained elevated at 72h. Conclusions: Liposomal formulations of anti-cancer agents represent a promising treatment strategy to treat aggressive breast cancer brain metastases due to extended circulation time in plasma and higher exposure in intracranial tumor compared with small molecule counterparts. In this proof-of-concept preclinical study, PLD exhibits both higher and prolonged plasma and intracranial tumor exposure compared with NLD. The mechanism of higher intracranial tumor exposure with liposomal agents is unknown, however may be due to prolonged exposure in plasma, diffusion of encapsulated and/or released drug across the blood brain barrier, or enhanced permeation and retention effect in tumors. The improved PK profile and tumor distribution of PLD compared with NLD in this intracranial BC model are hypothesized to translate to improved efficacy and toxicity profiles over that of non-liposomal formulations and may represent a promising treatment strategy for a disease with limited treatment options. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-04.