Journal
PHARMACEUTICAL RESEARCH
Volume 38, Issue 7, Pages 1209-1219Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-021-03072-2
Keywords
curcumin; cytotoxicity; dual drug loaded liposomes; efflux transporter; gemcitabine; pharmacokinetics
Funding
- Marsden Fund [UOA1201]
- Royal Society of New Zealand
- Auckland Medical Research Fund [1113026]
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Co-delivery of curcumin with gemcitabine using PSL not only increased the intracellular gemcitabine concentration and cytotoxicity to MIA PaCa-2 cells, but also significantly improved the pharmacokinetic profiles for both drugs.
Purpose PEGylated pH-sensitive liposomes (PSL) dual-loaded with gemcitabine and curcumin were investigated for the potential application in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC) treatment. Curcumin was employed as an inhibitor of the efflux transporter, multidrug resistance protein 5 (MRP5) in PDAC cells. Methods Liposomes were prepared with gemcitabine in the core and curcumin in the bilayers. The effects of curcumin on pH-sensitivity and 'endosome escape' of PSL with different PEGylation were investigated using a calcein self-quench assay. The effects of curcumin on intracellular gemcitabine concentrations, and cytotoxicity to a MIA PaCa-2 PDAC cell line was evaluated. The pharmacokinetics were investigated in rats following intravenous injection. Results The addition of curcumin to the PSL bilayers (0.21 mol%)slightly decreased the pH-sensitivity of PSL, but to a less extent than PEGylation (0-5 mol%). Co-treatment with curcumin increased gemcitabine cellular accumulation in a concentration-dependent manner, and resulted in synergistic cytotoxicity towards MIA PaCa-2cells.Both these effects were augmented by the use of PSL, particularly when the two drugs were co-loaded in PSL. In rats, the dual-drug loaded PSL produced significantly reduced (p < 0.05) plasma clearance (CL) and volume of distribution (V-d) for both drugs, alongside 3 to 4-fold increases in the area-under-the-concentration-time curves compared to the free drugs. Additionally, curcumin slightly increase the plasma concentrations of gemcitabine possibly also via the MRP5 inhibition effect. Conclusion Co-delivery of curcumin with gemcitabine using PSL not only increased the intracellular gemcitabine concentration thus cytotoxicity to MIA PaCa-2 cells but also significantly improved the pharmacokinetic profiles for both drugs.
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