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In vitro co-delivery of 5-fluorouracil and all-trans retinoic acid by PEGylated liposomes for colorectal cancer treatment

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Abstract

Background

Single-target inhibitors have not been successful in cancer treatment due to the development of drug resistance. Nevertheless, therapeutic agents capable of simultaneously inhibiting multiple targets have revealed encouraging results in inducing apoptosis and overcoming drug resistance in cancerous cells. Here, we designed a composite liposomal nano-carrier co-loading 5-Fluorouracil (5-FU) with all-trans retinoic acid (ATRA) to assess anticancer efficacy of the combined drugs in colorectal cancer (CRC).

Methods

A PEGylated liposomal nano-carrier with phospholipid/cholesterol/DSPE-PEG (2000) was synthesized by the thin film hydration technique for co-delivery of ATRA and 5-FU. After characterizing, the role of 5-FU and ATRA co-loaded liposomal nano-carrier in proliferation, epithelial-mesenchymal transition (EMT), apoptosis, and cancer stem cells (CSCs) were investigated by using colony forming and MTT assay, RT-qPCR and Annexin V/PI kit.

Results

The average size of liposomes (LPs) was < 150 nm with uniform size distribution. Drug release analyses indicated that both ATRA and 5-FU could simultaneously release from LPs in a sustained release manner. The synergistic inhibitory effects of ATRA and 5-FU loaded in LPs were verified with a combination index of 0.43. Dual drug LPs showed the highest cytotoxicity, enhanced inhibition of cell proliferation, increased apoptotic potential, decreased CSCs, and attenuated EMT-associated biomarkers. Also, dual drug LPs decreased β-catenin gene expression more than other liposomal formulations.

Conclusion

These findings suggest that using LPs to achieve a synergistic effect of ATRA and 5-FU is an effectual approach to increase the therapeutic effect of 5-FU toward CRC cells.

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Data availability

All data generated or analyzed during this study are included in this published article.

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Funding

This study was supported by the Hamadan University of Medical Sciences (9904172448).

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Authors and Affiliations

  1. Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

    Zahra Azarifar, Razieh Amini, Saeid Afshar & Rezvan Najafi

  2. Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Hamid Tanzadehpanah

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  1. Zahra Azarifar
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  2. Razieh Amini
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  3. Hamid Tanzadehpanah
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  4. Saeid Afshar
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  5. Rezvan Najafi
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Correspondence to Rezvan Najafi.

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This study was confirmed by the Hamadan University of Medical Sciences ethics committee (IR.UMSHA.REC.1399.266).

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Azarifar, Z., Amini, R., Tanzadehpanah, H. et al. In vitro co-delivery of 5-fluorouracil and all-trans retinoic acid by PEGylated liposomes for colorectal cancer treatment. Mol Biol Rep 50, 10047–10059 (2023). https://doi.org/10.1007/s11033-023-08888-2

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