title: Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer.
abstract: BACKGROUND
  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) and efficacy of PEGylated liposomal doxorubicin (PLD) with non-liposomal doxorubicin (NonL-doxo) in an intracranial model of BC.
  
  
  METHODS
  Athymic mice were inoculated intracerebrally with MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing mice were administered PLD or NonL-doxo at 6 mg/kg IV × 1 and were euthanized prior to and 0.083, 1, 3, 6, 24, 72 and 96 h post-treatment. Samples were processed to measure sum total doxorubicin via HPLC. PLD and NonL-doxo were administered IV weekly as single agents (6 mg/kg) or in combination (4.5 mg/kg) with the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival and bioluminescence.
  
  
  RESULTS
  Treatment with PLD resulted in approximately 1,500-fold higher plasma and 20-fold higher intracranial tumor sum total doxorubicin AUC compared with NonL-doxo. PLD was detected at 96 h; NonL-doxo was undetectable after 24 h in plasma and tumor. Median survival of PLD-treated animals was 32 days (d, [CI] 31-38), which was significantly longer than controls (26d [CI 25-28]; p = 0.0012) or NonL-doxo treatment (23.5d [CI 18-28], p = 0.0002). Combination treatment with PLD/ABT-888 yielded improved survival compared to NonL-doxo/ABT-888 (35d [CI 31-38] versus 29.5d [CI 25-34]; p = 0.006).
  
  
  CONCLUSIONS
  PLD provides both PK and efficacy advantage over NonL-doxo in the treatment of an in vivo model of BCBM. The results provide preclinical rationale to translate findings into early phase trials of PLD, with or without ABT-888, for patients with BCBM.
authors: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Carey K
authors: CK
authors: Anders
authors: Barbara
authors: B
authors: Adamo
authors: Olga
authors: O
authors: Karginova
authors: Allison M
authors: AM
authors: Deal
authors: Sumit
authors: S
authors: Rawal
authors: David
authors: D
authors: Darr
authors: Allison
authors: A
authors: Schorzman
authors: Charlene
authors: C
authors: Santos
authors: Ryan
authors: R
authors: Bash
authors: Tal
authors: T
authors: Kafri
authors: Lisa
authors: L
authors: Carey
authors: C Ryan
authors: CR
authors: Miller
authors: Charles M
authors: CM
authors: Perou
authors: Norman
authors: N
authors: Sharpless
authors: William C
authors: WC
authors: Zamboni
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000008:administration & dosage; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; C506643:liposomal doxorubicin; C521013:veliparib; D011092:Polyethylene Glycols; D004317:Doxorubicin
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