Oral administration of M13-loaded nanoliposomes is safe and effective to treat colitis-associated cancer in mice

ABSTRACT

Objective

Colitis-associated cancer (CAC) treatment lacks effective small-molecule drugs and efficient targeted delivery systems. Here, we loaded M13 (an anti-cancer drug candidate) to colon-targeting ginger-derived nanoliposomes (NL) and investigated if orally administered M13-NL could enhance the anticancer effects of M13 in CAC mouse models.

Methods

The biopharmaceutical properties of M13 were assessed by physicochemical characterizations. The in vitro immunotoxicity of M13 was assessed against PBMCs using FACS and the mutagenic potential of M13 was evaluated by the Ames assay. The in vitro efficacy of M13 was tested in 2D- and 3D-cultured cancerous intestinal cells. AOM/DSS-induced CAC mice were used to evaluate the therapeutic effects of free M13 or M13-NL on CAC in vivo.

Results

M13 has beneficial physiochemical properties, including high stability, and no apparent immunotoxicity or mutagenic potential in vitro. M13 is effective against the growth of 2D- and 3D-cultured cancerous intestinal cells in vitro. The in vivo safety and efficacy of M13 were significantly improved by using NL for drug delivery (p < 0.001). Oral administration of M13-NL exhibited excellent therapeutic effects in AOM/DSS-induced CAC mice.

Conclusion

M13-NL is a promising oral drug formulation for CAC treatment.

KEYWORDS:

• biopharmaceutical properties
• colon-targeted drug delivery
• glutathione conjugation
• self-assembled nanoliposomes
• AOM/DSS-induced CAC

Article highlights

• The tripeptide conjugate of 6-shogaol, known as M13, exhibits remarkable biopharmaceutical and biosafety properties.

• M13 specifically targets the viability of cancer cells and cancer stem cells while sparing normal cells.

• By encapsulating M13 in nanoliposomes, its bioavailability in the colon, the intended target, is significantly improved.

• The encapsulation of M13 in nanoliposomes enhances its therapeutic effects against colitis-associated cancers in a relevant mouse model.

• The utilization of nanoliposome encapsulation boosts the potency of M13 without causing any notable side effects.

Author contributions

D Long: methodology, data curation, formal analysis, investigation, writing – original draft, funding acquisition. Z Alghoul: methodology, resources, investigation. J Sung: resources, investigation. C Yang: conceptualization, project administration, supervision, methodology, data curation, investigation, writing – review & editing. D Merlin: conceptualization, supervision, investigation, funding acquisition, writing – review & editing.

Declaration of interest

D Long is a recipient of the Research Fellowship Award from Crohn’s and Colitis Foundation (CCF Award # 689659). D Merlin is a recipient of a Senior Research Career Scientist Award (BX004476) from the Department of Veterans Affairs. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425247.2023.2231345.

Additional information

Funding

This work was supported by grants from the Crohn’s and Colitis Foundation (689659), the National Institute of Diabetes and Digestive and Kidney Diseases (RO1-DK-116306), and the Department of Veterans Affairs (BX002526 and BX004476).