Niclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth

Area of Science:

• Oncology
• Pharmacology
• Nanotechnology

Background:

• Abnormal Wnt/β-catenin signaling is implicated in various diseases, notably cancer.
• The drug Niclosamide (NIC) inhibits Wnt signaling and suppresses colon cancer, but faces limitations due to poor solubility and bioavailability.
• Existing challenges with systemic drug delivery necessitate innovative formulation strategies.

Purpose of the Study:

• To enhance the therapeutic potential of Niclosamide (NIC) by improving its pharmacokinetic properties.
• To develop a novel nanoparticle drug delivery system for NIC using chimeric polypeptides (CPs).
• To evaluate the efficacy of CP-NIC nanoparticles in a preclinical model of colon cancer.

Main Methods:

• Conjugation of Niclosamide (NIC) to recombinant chimeric polypeptides (CPs).
• Spontaneous self-assembly of CP-NIC conjugates into sub-100 nm nanoparticles.
• Intravenous administration of CP-NIC nanoparticles in a human colon cancer xenograft model.
• Assessment of NIC systemic exposure and anti-tumor activity compared to free NIC.

Main Results:

• CP-NIC nanoparticles demonstrated spontaneous self-assembly into stable, sub-100 nm structures.
• Intravenous delivery of CP-NIC nanoparticles significantly increased systemic exposure to NIC compared to free NIC.
• CP-NIC nanoparticles exhibited enhanced anti-tumor activity against human colon cancer xenografts relative to NIC alone.
• The developed nanoparticles offer a promising approach to overcome NIC's pharmacokinetic limitations.

Conclusions:

• CP-NIC nanoparticles represent a viable pro-drug strategy to enhance NIC's therapeutic efficacy.
• This novel formulation holds potential for treating colon cancer and other diseases associated with abnormal Wnt activity.
• The versatile nature of NIC suggests broad applicability of CP-NIC nanoparticles for various conditions including infections and metabolic disorders.