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Intestinal transport mechanism and in vivo anticancer efficacy of a solid oral formulation incorporating an ion-pairing complex of pemetrexed with deoxycholic acid derivative
- Source :
- International Journal of Nanomedicine
- Publication Year :
- 2019
- Publisher :
- Dove, 2019.
-
Abstract
- Rudra Pangeni,1,* Saurav Kumar Jha,1,* Ruby Maharjan,2 Jeong Uk Choi,2 Kwan-Young Chang,3 Young Kweon Choi,3 Youngro Byun,4 Jin Woo Park11Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; 2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 3Global R&D Center, Icure BNP, Seoul 06170, Republic of Korea; 4Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea*These authors contributed equally to this workObjective: The rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy.Methods: PMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP).Results: The apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively.Conclusion: These findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.Keywords: pemetrexed, bile acid derivative, oral powder formulation, intestinal membrane permeability, oral delivery, oral metronomic chemotherapy &nbsp
- Subjects :
- medicine.medical_treatment
Cell
oral metronomic chemotherapy
Pharmaceutical Science
Administration, Oral
02 engineering and technology
Pharmacology
01 natural sciences
Intestinal absorption
Rats, Sprague-Dawley
chemistry.chemical_compound
International Journal of Nanomedicine
oral powder formulation
Drug Discovery
Membrane fluidity
pemetrexed
Original Research
bile acid derivative
Mice, Inbred BALB C
Bile acid
Chemistry
Deoxycholic acid
General Medicine
021001 nanoscience & nanotechnology
oral delivery
Intestines
medicine.anatomical_structure
Paracellular transport
0210 nano-technology
Deoxycholic Acid
medicine.drug_class
Drug Compounding
Biophysics
Biological Availability
Bioengineering
Antineoplastic Agents
010402 general chemistry
Chenodeoxycholic Acid
Permeability
Biomaterials
In vivo
medicine
Animals
Humans
Cell Proliferation
Ions
intestinal membrane permeability
Lysine
Organic Chemistry
Biological Transport
Immunotherapy
0104 chemical sciences
Caco-2 Cells
Subjects
Details
- Language :
- English
- ISSN :
- 11782013 and 11769114
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- International Journal of Nanomedicine
- Accession number :
- edsair.doi.dedup.....26db169f336ddc66f228ad0e3498b1ae