A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity.
The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50% wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive "T11" mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials.
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, 27599, USA.
Zhijian
Z
He
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, 27599, USA.
Xiaomeng
X
Wan
Professur für Makromolekulare Chemie, Department Chemie, Technische Universität Dresden, Mommsenstr. 4, 01069, Dresden, Germany.
Anita
A
Schulz
Professur für Makromolekulare Chemie, Department Chemie, Technische Universität Dresden, Mommsenstr. 4, 01069, Dresden, Germany.
Herdis
H
Bludau
Nanotechnology Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA.
Marina A
MA
Dobrovolskaia
Nanotechnology Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA.
Stephan T
ST
Stern
Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Stephanie A
SA
Montgomery
Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Hong
H
Yuan
Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Zibo
Z
Li
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, 27599, USA.
Daria
D
Alakhova
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, 27599, USA.
Marina
M
Sokolsky
Lineberger Comprehensive Cancer Center, The Animal Study Core, University of North Carolina at Chapel Hill, NC, 27599, USA.
David B
DB
Darr
Lineberger Comprehensive Cancer Center, The Animal Study Core, University of North Carolina at Chapel Hill, NC, 27599, USA.
Charles M
CM
Perou
Professur für Makromolekulare Chemie, Department Chemie, Technische Universität Dresden, Mommsenstr. 4, 01069, Dresden, Germany.
Rainer
R
Jordan
Functional Polymer Materials, Chair for Chemical Technology of Materials Synthesis, Julius-Maximilians-Universität Würzburg, Röntgenring 11, 97070, Würzburg, Germany. Electronic address: robert.luxenhofer@uni-wuerzburg.de.
Robert
R
Luxenhofer
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, 27599, USA; Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, 119992, Russia. Electronic address: kabanov@email.unc.edu.
Alexander V
AV
Kabanov
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010080:Oxazoles / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D010080:Oxazoles; C577913:poly(2-oxazoline); D017239:Paclitaxel
Efficacy; In vitro; In vivo; Multi-drug resistant cancer; Paclitaxel nanoformulation; Polyoxazolines