Bicyclic peptides conjugated to an albumin-binding tag diffuse efficiently into solid tumors

Area of Science:

• Biotechnology
• Pharmacology
• Oncology

Background:

• Monoclonal antibodies offer long half-lives but limited tumor penetration.
• Small peptides distribute well but suffer from rapid renal clearance.
• Albumin-binding tags can extend plasma half-life for peptide ligands.

Purpose of the Study:

• To evaluate the tissue diffusion and tumor penetration of a bicyclic peptide conjugated to an albumin-binding tag.
• To assess the stability and concentration of the peptide conjugate in solid tumors.

Main Methods:

• Development of a 4.6 kDa peptide conjugate (1.9 kDa bicyclic peptide + 2.3 kDa albumin-binding peptide).
• Administration of the conjugate and assessment of its distribution in tumor tissues.
• Analysis of conjugate integrity and concentration in tumor tissue 24 hours post-administration.

Main Results:

• The peptide conjugate, though often bound to albumin (66.5 kDa), diffused deeply into solid tumors.
• High nanomolar concentrations of the conjugate were achieved in wide tumor areas.
• The conjugate remained largely intact in tumor tissue 24 hours after administration.

Conclusions:

• Peptide-albumin conjugates offer a promising strategy for enhanced drug delivery to solid tumors.
• The noncovalent albumin interaction allows for dissociation and penetration into regions inaccessible to larger molecules.
• Bicyclic peptides, evolved via phage display, are stable and can be engineered for high target affinity, making them suitable for tumor targeting.