Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation
| Autor: | Jin Woo Park, Ok-Cheol Jeon, Youngro Byun, Sang Won Choi, Rudra Pangeni |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
Cell Membrane Permeability Organoplatinum Compounds Administration Oral Pharmaceutical Science 02 engineering and technology Pharmacology Rats Sprague-Dawley Mice chemistry.chemical_compound 0302 clinical medicine deoxycholic acid derivative International Journal of Nanomedicine Oral administration Antineoplastic Combined Chemotherapy Protocols Drug Discovery Tumor Cells Cultured polycyclic compounds 5-fluorouracil Original Research Mice Inbred BALB C integumentary system Deoxycholic acid General Medicine 021001 nanoscience & nanotechnology oral delivery Fluorouracil 030220 oncology & carcinogenesis Colonic Neoplasms Emulsions 0210 nano-technology medicine.drug Materials science Membrane permeability nanoemulsion Biophysics Biological Availability Bioengineering Biomaterials 03 medical and health sciences In vivo medicine Animals Humans ion-pairing complex Cisplatin oxaliplatin ion-pairingcomplex Organic Chemistry biochemical phenomena metabolism and nutrition Rats Bioavailability Oxaliplatin chemistry Nanoparticles |
| Zdroj: | International Journal of Nanomedicine INTERNATIONAL JOURNAL OF NANOMEDICINE(11) |
| ISSN: | 1178-2013 |
| DOI: | 10.2147/ijn.s121114 |
| Popis: | Rudra Pangeni,1,* Sang Won Choi,1,* Ok-Cheol Jeon,2 Youngro Byun,3 Jin Woo Park1 1Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, 2Pharosgen R&D Center, Asan Institute for Life Sciences, 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea *These authors contributed equally tothis work Abstract: Oxaliplatin (OXA) is a third-generation cisplatin analog that has been approved as first-line chemotherapy in combination with 5-fluorouracil (5-FU) for the treatment of resectable and advanced colorectal cancer. However, the therapeutic efficacy of oral OXA and 5-FU is limited by their low bioavailability due to poor membrane permeability. The aim of the present study was to develop an oral delivery system for OXA and 5-FU. We constructed an ion-pairing complex of OXA with a deoxycholic acid derivative (Nα-deoxycholyl-L-lysyl-methylester, DCK) (OXA/DCK) as a permeation enhancer. Next, we prepared multiple water-in-oil-in-water nanoemulsions incorporating OXA/DCK and 5-FU to enhance their oral absorption. To evaluate their membrane permeability, we assessed in vitro permeabilities of OXA/DCK and 5-FU through an artificial intestinal membrane and Caco-2 cell monolayer. Finally, oral bioavailability in rats and tumor growth inhibition in the colorectal adenocarcinoma cell (CT26)-bearing mouse model were investigated after oral administration of nanoemulsion containing OXA/DCK and 5-FU. The droplet size of the optimized nanoemulsion was 20.3±0.22nm with a zeta potential of -4.65±1.68mV. In vitro permeabilities of OXA/DCK and 5-FU from the nanoemulsion through a Caco-2 cell monolayer were 4.80- and 4.30-fold greater than those of OXA and 5-FU, respectively. The oral absorption of OXA/DCK and 5-FU from the nanoemulsion also increased significantly, and the resulting oral bioavailability values of OXA/DCK and 5-FU in the nanoemulsive system were 9.19- and 1.39-fold higher than those of free OXA and 5-FU, respectively. Furthermore, tumor growth in CT26 tumor-bearing mice given the oral OXA/DCK- and 5-FU-loaded nanoemulsion was maximally inhibited by 73.9%, 48.5%, and 38.1%, compared with tumor volumes in the control group and the oral OXA and 5-FU groups, respectively. These findings demonstrate the therapeutic potential of a nanoemulsion incorporating OXA/DCK and 5-FU as an oral combination therapy for colorectal cancer. Keywords: oxaliplatin, 5-fluorouracil, deoxycholic acid derivative, ion-pairing complex, nanoemulsion, oral delivery |
| Databáze: | OpenAIRE |
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