Drug delivery of paclitaxel for an intraperitoneal chemotherapy

Peritoneal carcinomatosis (PC) is a frequent phenomenon in the course of gastroinstestinal and ovarian cancer and is responsible for a high mortality. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has been introduced as an alternative treatment. An interesting drug for HIPEC is paclitaxel. However, the use of paclitaxel is hampered by its poor solubility and the currently used formulation vehicle (Cremophor EL(R)/ethanol). Therefore, the objective of this research project was to develop a tensioactive- and solvent-free paclitaxel formulation suitable for HIPEC. A second objective was to evaluate this novel formulation on cell lines for its efficiency in comparison to Taxol(R). A third objective was an in vivo evaluation of the toxicity, bioavailability and tumour growth delay (TGD) of both formulations (Taxo(R) and Pac/RAME-beta-CD). The formulation study yielded the following formulation: 1/20 (mol/mol) complex of paclitaxel and randomly-methylated-beta-cyclodextrins (Pac/RAME-beta-CD) dissolved in phosphate buffered saline (PBS) supplemented with 0.1% (w/v) hydroxypropylmethylcellulose (HPMC). This formulation showed sufficient physical stability at room temperature and under HIPEC conditions. Initially, both formulations showed similar (<= 10% difference) cytotoxic activity on two cancer cell lines (CC531s and CaCo-2) and no influence of the addition of hyperthermia was seen. Increasing the cell concentration and reducing the contact time resulted in a loss of equipotency. This loss was explained by the presence of multi drug resistant (MDR) cells. Resensitization of these MDR cells was achieved via the addition HPPP, a non-selective glucosylceramide synthase inhibitor. In vivo evaluation showed that the toxicity of both formulations was similar (maximum tolerated dose (MTD) of 0.24 mg/ml for both). Bioavailability, however, was significantly increased for Pac/RAME-beta-CD (i.e. 40-fold increase for the area under the curve). Preliminary results from the TGD study allowed to establish the study protocol for a future in-depth TGD study. In conclusion, this project has shown that it is possible to formulate paclitaxel using beta-cyclodextrins without loosing its activity on cancer cell lines. In vivo evaluation between Taxol(R) and Pac/RAME-betal-CD has shown a similar toxicity profile but a significant difference in bioavailability, which might, according to the TGD study, have implications on their TGD.

Grantor dc:publisher

Ghent University. Faculty of Pharmaceutical Sciences

Year dc:date

2009

Author dc:creator

• Bouquet-Geerardyn, Wim

Contributors dc:contributor

• Remon, Jean Paul
• Vervaet, Chris

• Medicine and Health Sciences
• paclitaxel
• cyclodextrine
• intraperitoneal chemotherapy

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://biblio.ugent.be/publication/689040
https://biblio.ugent.be/publication/689040/file/4334985

OAI identifier oai:identifier

oai:archive.ugent.be:689040