title: Albumin-bound nanoparticle (nab) paclitaxel exhibits enhanced paclitaxel tissue distribution and tumor penetration.
abstract: OBJECTIVE
  nab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms.
  
  
  METHODS
  Uptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation.
  
  
  RESULTS
  Live imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose.
  
  
  CONCLUSIONS
  Compared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel.
authors.affiliation: Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors.forename: Nianhang
authors.initials: N
authors.lastname: Chen
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Brachmann
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Xiping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Pierce
authors.affiliation: Presage Biosciences, Seattle, WA, USA.
authors.forename: Joyoti
authors.initials: J
authors.lastname: Dey
authors.affiliation: Presage Biosciences, Seattle, WA, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Kerwin
authors.affiliation: Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors.forename: Shihe
authors.initials: S
authors.lastname: Hou
authors.affiliation: Presage Biosciences, Seattle, WA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Carleton
authors.affiliation: Presage Biosciences, Seattle, WA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Klinghoffer
authors.affiliation: Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Palmisano
authors.affiliation: Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA. rachopra@celgene.com.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008819:Mice, Nude; D008845:Microinjections; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism; D000075462:Serum Albumin, Human; D014018:Tissue Distribution; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C422455:ALB protein, human; D000972:Antineoplastic Agents, Phytogenic; D012709:Serum Albumin; D050257:Tubulin Modulators; D017239:Paclitaxel; D000075462:Serum Albumin, Human
keywords: Albumin; Cremophor EL; Nanoparticle; Taxane; nab-paclitaxel