Study of FA12 peptide-modified PEGylated liposomal doxorubicin (PLD) as an effective ligand to target Muc1 in mice bearing C26 colon carcinoma: in silico, in vitro, and in vivo study

ABSTRACT

Objectives

This study tried to achieve active targeting of Muc1 in cancer; the surface of PEGylated liposomal doxorubicin (PLD/Doxil®) was decorated with FA12 peptide.

Methods

According to docking results, FA12 was selected for this study, among four different peptides. MD simulation was also conducted as an additional confirmation of the binding interaction between FA12 and Muc1. Liposomal formulations were prepared; ¹HNMR and HPLC techniques were used to verify peptide conjugation to DSPE-PEG2000-COOH. Afterward, DSPE-PEG2000-FA12 was post-inserted into the PLD at 50, 100, 200, and 400 peptides per liposome. The size, zeta potential, release profile, cytotoxicity (IC₅₀), and cell uptake (using fluorescence microscopy and flow cytometry) were evaluated. In vivo biodistribution and antitumor activities were studied on mice bearing C-26 colon carcinoma.

Results

Cell uptake and cytotoxicity results revealed that PLD-100 (targeted PLD with 100 FA12 per liposome) could significantly enhance cellular binding. Furthermore, PLD-100 demonstrated higher antitumor efficacy, indicating more remarkable survival compared to PLD and other targeted PLDs. PLD-100 exhibited higher doxorubicin tumor accumulation compared to PLD.

Conclusions

FA12 peptide is a promising targeting ligand for PLD to treat cancers with a high level of Muc1 expression and merits further investigations.

Plain Language Summary

In this work, we used an antimicrobial peptide, FA12, to target Muc1 glycoprotein on the surface of colon cancer cells. The interaction between the peptide and Muc1 as a receptor was verified by molecular dynamics simulation. FA12 peptide was affixed to the surface of the liposomal form of doxorubicin (PLD) specifically to facilitate drug delivery transfer to the tumor site. The main benefits of this novel formulation were improvement of therapeutic efficacy and enhancement of survival time in mice bearing colon cancer.

KEYWORDS:

• Colon cancer
• docking and MD simulation
• FA12 peptide
• Muc1
• PEGylated liposomal doxorubicin (PLD)
• targeted drug delivery

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Conception and design: M Jaafari, A Biabangard; Analysis and interpretation of data and drafting of the paper: A Biabangard, A Asoodeh, M Mashreghi; Revising it critically for intellectual content: All authors. All authors have read and agreed to the published version of the manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425247.2022.2147505

Additional information

Funding

This paper was funded by the Research and Technology Council of the Ferdowsi University of Mashhad, Mashhad-Iran (grant number: 3/46317, 1396/12/22).