Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer
Rudra Pangeni,1,* Laxman Subedi,2,* Saurav Kumar Jha,2 Seho Kweon,3 Seo-Hee Kang,4 Kwan-Young Chang,4 Jeong Uk Choi,5 Youngro Byun,3 Jin Woo Park1,2 1College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 2Department of Bi...
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Dove Medical Press
2020
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oxaliplatin bile acid transporter-mediated permeation oral bioavailability metronomic dosing colorectal cancer Medicine (General) R5-920 |
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oxaliplatin bile acid transporter-mediated permeation oral bioavailability metronomic dosing colorectal cancer Medicine (General) R5-920 Pangeni R Subedi L Jha SK Kweon S Kang SH Chang KY Choi JU Byun Y Park JW Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer |
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Rudra Pangeni,1,* Laxman Subedi,2,* Saurav Kumar Jha,2 Seho Kweon,3 Seo-Hee Kang,4 Kwan-Young Chang,4 Jeong Uk Choi,5 Youngro Byun,3 Jin Woo Park1,2 1College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 2Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 4Global R&D Center, IcureBNP, Seoul 08511, Republic of Korea; 5College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea*These authors contributed equally to this workCorrespondence: Youngro ByunCollege of Pharmacy, Seoul National University, 1 Gwanak-Ro, Seoul 08826, Republic of KoreaTel +82 2 880 7866Fax +82 2 872 7864Email yrbyun@snu.ac.krJin Woo ParkCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National University, 1666 Youngsan-Ro, Muan-gun, Jeonnam 58554, Republic of KoreaTel +82 61 450 2704Fax +82 61 450 2689Email jwpark@mokpo.ac.krObjective: The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy.Methods: An ion-pairing complex of OP with a permeation enhancer, Nα-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF).Results: The optimized powder formulation was sized in the nanoscale range (133± 1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls.Conclusion: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.Keywords: oxaliplatin, bile acid transporter-mediated permeation, oral bioavailability, metronomic dosing, colorectal cancer |
| format |
article |
| author |
Pangeni R Subedi L Jha SK Kweon S Kang SH Chang KY Choi JU Byun Y Park JW |
| author_facet |
Pangeni R Subedi L Jha SK Kweon S Kang SH Chang KY Choi JU Byun Y Park JW |
| author_sort |
Pangeni R |
| title |
Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer |
| title_short |
Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer |
| title_full |
Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer |
| title_fullStr |
Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer |
| title_full_unstemmed |
Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer |
| title_sort |
improvements in the oral absorption and anticancer efficacy of an oxaliplatin-loaded solid formulation: pharmacokinetic properties in rats and nonhuman primates and the effects of oral metronomic dosing on colorectal cancer |
| publisher |
Dove Medical Press |
| publishDate |
2020 |
| url |
https://doaj.org/article/a943b6867fb2493f91212cc1e2cbd05e |
| work_keys_str_mv |
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oai:doaj.org-article:a943b6867fb2493f91212cc1e2cbd05e2021-12-02T10:02:39ZImprovements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer1178-2013https://doaj.org/article/a943b6867fb2493f91212cc1e2cbd05e2020-10-01T00:00:00Zhttps://www.dovepress.com/improvements-in-the-oral-absorption-and-anticancer-efficacy-of-an-oxal-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Rudra Pangeni,1,* Laxman Subedi,2,* Saurav Kumar Jha,2 Seho Kweon,3 Seo-Hee Kang,4 Kwan-Young Chang,4 Jeong Uk Choi,5 Youngro Byun,3 Jin Woo Park1,2 1College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 2Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 4Global R&D Center, IcureBNP, Seoul 08511, Republic of Korea; 5College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea*These authors contributed equally to this workCorrespondence: Youngro ByunCollege of Pharmacy, Seoul National University, 1 Gwanak-Ro, Seoul 08826, Republic of KoreaTel +82 2 880 7866Fax +82 2 872 7864Email yrbyun@snu.ac.krJin Woo ParkCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National University, 1666 Youngsan-Ro, Muan-gun, Jeonnam 58554, Republic of KoreaTel +82 61 450 2704Fax +82 61 450 2689Email jwpark@mokpo.ac.krObjective: The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy.Methods: An ion-pairing complex of OP with a permeation enhancer, Nα-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF).Results: The optimized powder formulation was sized in the nanoscale range (133± 1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls.Conclusion: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.Keywords: oxaliplatin, bile acid transporter-mediated permeation, oral bioavailability, metronomic dosing, colorectal cancerPangeni RSubedi LJha SKKweon SKang SHChang KYChoi JUByun YPark JWDove Medical Pressarticleoxaliplatinbile acid transporter-mediated permeationoral bioavailabilitymetronomic dosingcolorectal cancerMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 7719-7743 (2020) |