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.
Copyright 2010 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Cell Survival / drug effects
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Dose-Response Relationship, Drug
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Drug Carriers / chemistry*
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Drug Compounding
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Drug Synergism
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HeLa Cells
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Humans
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Lactones / chemistry
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Liver Neoplasms, Experimental / drug therapy
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Mice
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Mice, Inbred Strains
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Micelles
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Nanoparticles
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Paclitaxel / administration & dosage*
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Paclitaxel / chemistry
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Paclitaxel / pharmacokinetics
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Paclitaxel / therapeutic use
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Particle Size
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Polyesters / chemistry
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Polyglactin 910 / chemistry
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Protein Kinase Inhibitors / administration & dosage*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use
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Solubility
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Surface Properties
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Triazoles / administration & dosage*
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Triazoles / chemistry
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Triazoles / pharmacokinetics
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Triazoles / therapeutic use
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Drug Carriers
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JNJ-7706621
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Lactones
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Micelles
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Polyesters
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Protein Kinase Inhibitors
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TMC-ECL copolymer
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Triazoles
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Polyglactin 910
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Cyclin-Dependent Kinases
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Paclitaxel