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Phage derived peptides for targeting of doxorubicin conjugates to solid tumours
A G Schatzlein1, C Rutherford, F Corrihons
1CRC Department of Medical Oncology, University of Glasgow, G61 1BD, Glasgow, UK. Andreas.Schatzlein@beatson.gla.ac.uk
Abstract:
Barriers are frequently hampering targeting of drugs and toxins to solid tumours and their microenvironment. Nano-conjugates are low molecular weight conjugates of a small drug or toxin and a targeting ligand coupled through a cleavable linker group. They offer potential advantages for tumour specific delivery in diffusion-limited situations. We have exploited fd phage-derived peptides for the targeting of low molecular weight drug conjugates to solid tumours. As a model we have chosen doxorubicin conjugates targeted to the transferrin receptor (TfR). A library of phage expressing a cyclic nona-peptide was panned against TfR. The apparent affinity of phages determined by surface plasmon resonance (SPR) increased with each cycle of the panning procedure. After five rounds approximately 80% of phages expressed the same peptide, which mediated a 30-50-fold increased receptor specific cellular uptake of the phages. The corresponding peptide was synthesised using solid phase peptide chemistry on a sulfonamide based safety catch resin. Crude mixtures of the peptide, as well as transferrin itself, were able to inhibit the phage uptake significantly. The doxorubicin conjugate of the peptide containing a cleavable linker was prepared and endosomal uptake confirmed by fluorescence microscopy.
Insights
Researchers developed novel peptide-drug conjugates for targeted cancer therapy. These nano-conjugates show enhanced cellular uptake, offering a promising strategy for delivering drugs like doxorubicin to solid tumors via the transferrin receptor (TfR).
Area of Science:
- Biotechnology
- Nanomedicine
- Pharmacology
Background:
- Targeting drugs and toxins to solid tumors is challenging due to biological barriers.
- Nano-conjugates offer improved tumor-specific delivery in diffusion-limited environments.
- Phage-derived peptides present a novel approach for targeting therapeutic agents.
Purpose of the Study:
- To develop and evaluate phage-derived peptide nano-conjugates for targeted drug delivery to solid tumors.
- To investigate the targeting potential of peptides against the transferrin receptor (TfR).
- To assess the efficacy of doxorubicin-peptide conjugates for cancer therapy.
Main Methods:
- Panning a phage display library to identify peptides targeting TfR.
- Surface Plasmon Resonance (SPR) to determine phage-TfR binding affinity.
- Solid-phase peptide synthesis and preparation of doxorubicin-peptide conjugates with cleavable linkers.
- Assessing cellular uptake via fluorescence microscopy.
Main Results:
- Phage panning yielded a cyclic nonapeptide with high affinity and specificity for TfR.
- The selected peptide mediated a 30-50-fold increase in TfR-specific cellular uptake.
- Synthesized peptide and transferrin inhibited phage uptake, confirming receptor-mediated targeting.
- Doxorubicin conjugate demonstrated successful endosomal uptake.
Conclusions:
- Phage-derived peptides are effective targeting ligands for nano-conjugates.
- TfR-targeted doxorubicin conjugates show potential for enhanced cancer therapy.
- This strategy offers a promising route for improving drug delivery to solid tumors.