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Open Access 01-10-2015 | Original Article

Albumin-bound nanoparticle (nab) paclitaxel exhibits enhanced paclitaxel tissue distribution and tumor penetration

Authors: Nianhang Chen, Carrie Brachmann, Xiping Liu, Daniel W. Pierce, Joyoti Dey, William S. Kerwin, Yan Li, Simon Zhou, Shihe Hou, Michael Carleton, Richard A. Klinghoffer, Maria Palmisano, Rajesh Chopra

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2015

Abstract

Purpose

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.

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Title: Albumin-bound nanoparticle (nab) paclitaxel exhibits enhanced paclitaxel tissue distribution and tumor penetration
Authors: Nianhang Chen
Carrie Brachmann
Xiping Liu
Daniel W. Pierce
Joyoti Dey
William S. Kerwin
Yan Li
Simon Zhou
Shihe Hou
Michael Carleton
Richard A. Klinghoffer
Maria Palmisano
Rajesh Chopra
Publication date: 01-10-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2015
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2833-5

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