DHP23002 as a next generation oral paclitaxel formulation for pancreatic cancer therapy
Autoři:
Eunseo Jang aff001; Minhee Son aff002; Junhee Jang aff002; In-Hyun Lee aff002; Sol Kim aff002; Taejun Kwon aff001; Yong-hyun Jeon aff001; Woo-Suk Koh aff001; Kil-Soo Kim aff001; Sang Kyoon Kim aff001
Působiště autorů:
Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea
aff001; Dae Hwa Pharmaceutical Co. Ltd., Pangyo Research Laboratory, Sungnam City, South Korea
aff002; College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea
aff003
Vyšlo v časopise:
PLoS ONE 14(11)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0225095
Souhrn
Objective
This study aimed to develop a new oral paclitaxel formulation (DHP23002) and to evaluate its absorption and antitumor effects in a pancreatic tumor mouse model.
Methods
To investigate the oral absorption of DHP23002, a newly developed lipid-based orally active paclitaxel formulation, a pharmacokinetic study of DHP23002, was conducted in mice (62.5 and 125 mg/kg). Moreover, to evaluate the antitumor effect of DHP23002 in pancreatic cancer treatment, the drug was administered to female athymic nude mice at 0 (vehicle), 25, 62.5, and 125 mg/kg on alternate days; the efficacy of the agent was compared with the efficacy of intravenous Taxol® injections at 10 mg/kg once per week. After 3 weeks of administration, tumor growth in mice belonging to each group was further monitored for 4 weeks after discontinuing medication. Moreover, to examine paclitaxel (DHP23002) accumulation in the tumor tissue, the amount of paclitaxel in tumor/blood was quantified using liquid chromatography with quadruple-TOF mass spectrometry.
Results
In the mouse pharmacokinetic study, oral Taxol® showed a negligible absorption, whereas DHP23002 showed a high absorption rate dependent on dosage, with a bioavailability of approximately 40% at a dose of 62.5 mg/kg. In efficacy-related studies, DHP23002 administration at a dose of 25, 62.5, or 125 mg/kg on alternate days for 3 weeks showed a superior tumor inhibitory effect of 80%, 92%, and 97% in a xenograft mouse model, respectively, after 7 weeks. Paclitaxel accumulation in tumors persisted for >24 h in mice, when orally administered once at doses of 25, 62.5, and 125 mg/kg DHP23002.
Conclusion
Oral chemotherapy with DHP23002 showed excellent absorption in animals owing to a strong antitumor activity in a pancreatic cancer mouse model. This demonstrates that paclitaxel is largely distributed and persists for a prolonged period at the tumor site owing to oral DHP23002 administration.
Klíčová slova:
Apoptosis – Blood – Cancer treatment – Drug administration – Mouse models – Oral administration – Pancreatic cancer – Drug absorption
Zdroje
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