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 specif...

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Bibliographic Details
Published in:Journal of controlled release 2001-07, Vol.74 (1), p.357-362
Main Authors: Schatzlein, A.G., Rutherford, C., Corrihons, F., Moore, B.D.
Format: Article
Language:English
Subjects:
Antibiotics, Antineoplastic - administration & dosage
Antimalarials - pharmacology
Antineoplastic agents
Bacteria - metabolism
Bacteria - virology
Bacteriophages - metabolism
Biological and medical sciences
Cell Line
Chemotherapy
Chloroquine - pharmacology
Cleavable linker
doxorubicin
Doxorubicin - administration & dosage
Doxorubicin conjugate
General pharmacology
Humans
Medical sciences
Peptide ligand
Peptides - administration & dosage
Phage display
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Receptors, Transferrin - biosynthesis
Receptors, Transferrin - genetics
transferrin receptors
Tumour targeting
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Summary: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.
ISSN:0168-3659
1873-4995
DOI:10.1016/S0168-3659(01)00347-9