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Co-Delivery Using pH-Sensitive Liposomes to Pancreatic Cancer Cells: the Effects of Curcumin on Cellular Concentration and Pharmacokinetics of Gemcitabine

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Abstract

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 (0.2-1 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 (Vd) 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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ACKNOWLEDGMENTS AND DISCLOSURES

The financial support from a Marsden Fund (UOA1201) provided by the Royal Society of New Zealand and an Auckland Medical Research Fund (1113026).

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Authors and Affiliations

  1. School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    Hongtao Xu & Zimei Wu

  2. Department of Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

    Yan Li & James W. Paxton

  3. Auckland University of Technology, Auckland, New Zealand

    Yan Li

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  1. Hongtao Xu
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  2. Yan Li
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  4. Zimei Wu
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Correspondence to Zimei Wu.

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Xu, H., Li, Y., Paxton, J.W. et al. Co-Delivery Using pH-Sensitive Liposomes to Pancreatic Cancer Cells: the Effects of Curcumin on Cellular Concentration and Pharmacokinetics of Gemcitabine. Pharm Res 38, 1209–1219 (2021). https://doi.org/10.1007/s11095-021-03072-2

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