Active and Passive Tumor Targeting of a Novel Poorly Soluble Cyclin Dependent Kinase Inhibitor,

International Journal of Pharmaceutics 392 (2010) 20–28

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

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

Fabienne Danhier a , Bernard Ucakar a , Nicolas Magotteaux a , Marcus E. Brewster b , Véronique Préat a,∗

a b

Université Catholique de Louvain, Louvain Drug Institute, Avenue Mounier UCL 7320, B-1200 Brussels, Belgium Johnson and Johnson, Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, 2340 Beerse, Belgium

a r t i c l e

i n f o

a b s t r a c t

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 -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. © 2010 Elsevier B.V. All rights reserved.

Article history: Received 17 December 2009 Received in revised form 2 March 2010 Accepted 4 March 2010 Available online 11 March...