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Active and passive tumor targeting of a novel poorly soluble cyclin dependent kinase inhibitor, JNJ-7706621.

Abstract
The anti-cancer cyclin dependent kinase (CDK) inhibitors are poorly soluble drugs. The aims of this work were (i) to formulate a novel CDK inhibitor, JNJ-7706621, in polymeric micelles and nanoparticles, (ii) to compare passive and active targeting on tumor growth and (iii) to evaluate the potential synergy of JNJ-7706621 with Paclitaxel. Therefore, JNJ-7706621 was encapsulated in self-assembling diblock copolymers made up of epsilon-caprolactone (CL) and trimethylene carbonate (TMC) (PEG-p-(CL-co-TMC)) polymeric micelles and in (poly(lactide-co-glycolide)) (PLGA)-based PEGylated nanoparticles (passive targeting) as well as in RGD-grafted nanoparticles (active targeting). In vivo, the transplantable liver tumor growth was more decreased by active targeting with RGD-grafted nanoparticles than by passive targeting with micelles or ungrafted nanoparticles. Moreover, a synergy between JNJ-7706621 and Paclitaxel was demonstrated. Therefore, active targeting of JNJ-7706621-loaded nanocarriers may be considered as an effective anti-cancer drug delivery system for cancer chemotherapy, particularly in combination with Paclitaxel.
AuthorsFabienne Danhier, Bernard Ucakar, Nicolas Magotteaux, Marcus E Brewster, Véronique Préat
JournalInternational journal of pharmaceutics (Int J Pharm) Vol. 392 Issue 1-2 Pg. 20-8 (Jun 15 2010) ISSN: 1873-3476 [Electronic] Netherlands
PMID20226846 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2010 Elsevier B.V. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Drug Carriers
  • JNJ-7706621
  • Lactones
  • Micelles
  • Polyesters
  • Protein Kinase Inhibitors
  • TMC-ECL copolymer
  • Triazoles
  • Polyglactin 910
  • Cyclin-Dependent Kinases
  • Paclitaxel
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Apoptosis (drug effects)
  • Cell Survival (drug effects)
  • Cyclin-Dependent Kinases (antagonists & inhibitors)
  • Dose-Response Relationship, Drug
  • Drug Carriers (chemistry)
  • Drug Compounding
  • Drug Synergism
  • HeLa Cells
  • Humans
  • Lactones (chemistry)
  • Liver Neoplasms, Experimental (drug therapy)
  • Mice
  • Mice, Inbred Strains
  • Micelles
  • Nanoparticles
  • Paclitaxel (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Particle Size
  • Polyesters (chemistry)
  • Polyglactin 910 (chemistry)
  • Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Solubility
  • Surface Properties
  • Triazoles (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Xenograft Model Antitumor Assays

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