Phage derived peptides for targeting of doxorubicin conjugates to solid tumours.
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.
Schatzlein
A G
AG
CRC Department of Medical Oncology, University of Glasgow, G61 1BD, Glasgow, UK. Andreas.Schatzlein@beatson.gla.ac.uk
Rutherford
C
C
Corrihons
F
F
Moore
B D
BD
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000962:Antimalarials / Q000494:pharmacology; D001419:Bacteria / Q000378:metabolism / Q000821:virology; D001435:Bacteriophages / Q000378:metabolism*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage*; D006801:Humans; D010455:Peptides / Q000008:administration & dosage*; D011990:Receptors, Transferrin / Q000096:biosynthesis / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D000962:Antimalarials; D010455:Peptides; D011990:Receptors, Transferrin; D004317:Doxorubicin; D002738:Chloroquine