Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation.
The clinically and commercially successful taxanes, paclitaxel and docetaxel suffer from two major drawbacks, namely their very low aqueous solubility and the risk of developing resistance. Here, we present a method that overcomes both drawbacks in a very simple manner. We formulated 3rd generation taxoids, able to avoid common drug resistance mechanisms with doubly amphiphilic poly(2-oxazoline)s (POx), a safe and highly efficient polymer for the formulation of extremely hydrophobic drugs. We found excellent solubilization of different 3rd generation taxoids irrespective of the drug's chemical structures with essentially quantitative drug loading and final drug to polymer ratios around unity. The small, highly loaded micelles with a hydrodynamic diameter of less than 100nm are excellently suited for parenteral administration. Moreover, a selected formulation with the taxoid SB-T-1214 is about one to two orders of magnitude more active in vitro than paclitaxel in the multidrug resistant breast cancer cell line LCC6-MDR. In contrast, in wild-type LCC6, no difference was observed. Using a q4d×4 dosing regimen, we also found that POx/SB-T-1214 significantly inhibits the growth of LCC6-MDR orthotropic tumors, outperforming commercial paclitaxel drug Taxol and Cremophor EL formulated SB-T-1214.
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
Professur für Makromolekulare Chemie, Department Chemie, Technische Universität Dresden, Mommsenstr. 4, 01069 Dresden, Germany.
Anita
A
Schulz
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
Department of Chemistry, Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA.
Joshua
J
Seitz
Professur für Makromolekulare Chemie, Department Chemie, Technische Universität Dresden, Mommsenstr. 4, 01069 Dresden, Germany.
Herdis
H
Bludau
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 Y
DY
Alakhova
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
Department of Chemistry, Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA.
Iwao
I
Ojima
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.
Alexander V
AV
Kabanov
Functional Polymer Materials, Chair for Chemical Technology of Materials Synthesis, Universität Würzburg, 97070 Würzburg, Germany.
Robert
R
Luxenhofer
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D010080:Oxazoles / Q000737:chemistry*; D010316:Particle Size; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D008823:Micelles; D010080:Oxazoles; D043823:Taxoids; C577913:poly(2-oxazoline)
Drug delivery; In vitro; In vivo; LCC6; Multi-drug resistance; Nanomedicine; Orthotopic tumor model; Paclitaxel; Poly(2-oxazoline); Taxoids