Active and passive tumor targeting of a novel poorly soluble cyclin dependent kinase inhibitor, JNJ-7706621.
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.
Université Catholique de Louvain, Louvain Drug Institute, Brussels, Belgium.
Fabienne
F
Danhier
Bernard
B
Ucakar
Nicolas
N
Magotteaux
Marcus E
ME
Brewster
Véronique
V
Préat
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D008823:Micelles; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry; D011098:Polyglactin 910 / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D012995:Solubility; D013499:Surface Properties; D014230:Triazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004337:Drug Carriers; C506121:JNJ-7706621; D007783:Lactones; D008823:Micelles; D011091:Polyesters; D047428:Protein Kinase Inhibitors; C410438:TMC-ECL copolymer; D014230:Triazoles; D011098:Polyglactin 910; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel