Pharmacokinetics and Efficacy of PEGylated Liposomal Doxorubicin in an Intracranial Model of Breast Cancer

摘要: Introduction Breast cancer brain metastases (BCBM) are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared pharmacokinetics (PK) efficacy PEGylated liposomal doxorubicin (PLD) with non-liposomal (NonL-doxo) in an intracranial model BC. Methods Athymic mice were inoculated intracerebrally MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing administered PLD or NonL-doxo at 6mg/kg IV×1 euthanized prior 0.083, 1, 3, 6, 24, 72 96 h post-treatment. Samples processed measure sum total via HPLC. IV weekly as single agents (6 mg/kg) combination (4.5 the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival bioluminescence. Results Treatment resulted approximately 1,500-fold higher plasma 20-fold tumor AUC NonL-doxo. detected h; undetectable after 24 tumor. Median PLD-treated animals 32 days (d, [CI] 31–38), which significantly longer than controls (26d [CI 25–28]; p = 0.0012) treatment (23.5d 18–28], 0.0002). Combination PLD/ABT-888 yielded improved NonL-doxo/ABT-888 (35d 31–38] versus 29.5d 25–34]; 0.006). Conclusions PLD provides both PK advantage over vivo BCBM. The results provide preclinical rationale translate findings into early phase trials PLD, without for patients