A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel.
A novel injectable thermosensitive in situ gelling hydrogel has been developed. The system, which falls under the BST-Gel platform technology developed at Biosyntech Inc. (Laval, QC, Canada), consists of a chitosan solution (C) neutralized with beta-glycerophosphate (GP) that is liquid at room temperature but gels when heated to body temperature. We propose to use this thermosensitive hydrogel for the sustained release of paclitaxel at tumor resection sites in order to prevent local tumor recurrence. The in vitro release profiles demonstrated controlled delivery over 1 month. The initial drug loading substantially affected the release. Local delivery of paclitaxel from the formulation injected intratumorally was investigated using EMT-6 tumors implanted subcutaneously on Balb/c mice. These experiments showed that one intratumoral injection of the thermosensitive hydrogel containing paclitaxel was as efficacious as four intravenous injections of Taxol in inhibiting the growth of EMT-6 cancer cells in mice, but in a less toxic manner. Further histological analysis revealed that while the proportion of necrotic areas was similar for the C/GP/paclitaxel and the Taxol-treated tumors, a disparity between tumor-associated inflammatory cell populations may suggest differing anti-tumor mechanisms.
Ruel-Gariépy
Eve
E
Canada Research Chair in Drug Delivery, Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada.
Shive
Matthew
M
Bichara
Ali
A
Berrada
Mohammed
M
Le Garrec
Dorothée
D
Chenite
Abdellatif
A
Leroux
Jean-Christophe
JC
D000818:Animals; D001831:Body Temperature / Q000502:physiology*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004355:Drug Stability; D005069:Evaluation Studies as Topic; D005260:Female; D005720:Gamma Rays; D005994:Glycerophosphates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020100:Hydrogels / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015552:Injections, Intralesional / Q000379:methods*; D007275:Injections, Intravenous; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000648:ultrastructure; D008422:Materials Testing / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D012996:Solutions / Q000528:radiation effects; D013242:Sterilization / Q000379:methods
D005994:Glycerophosphates; D020100:Hydrogels; D012996:Solutions; D048271:Chitosan; D017239:Paclitaxel