Optimisation of
linkers in a polymeric prodrug system for selective prostate delivery
of drugs
Author
Dr Michael Threadgill
University
of Bath
The overall aim of the prostate
cancer research programme at Bath is to develop a novel polymeric
prodrug to release doxorubicin selectively in prostate tumours through
an innovative system. This system can also deliver other cytotoxins
selectively.
We are seeking to design
two levels of selectivity into this polymeric prodrug. Firstly,
the polymer-drug conjugate should be selectively retained in solid
tumours through the enhanced permeation and retention (EPR) effect.
Secondly, the drug is designed to be released from the polymer carrier
by the action of prostate-specific antigen (PSA), which is enzymically
active as a peptidase only in the prostate. PSA is active extracellularly
in the prostate and should cleave the short peptide sequence linking
the drug to the polymer.
However, PSA is an endopeptidase
and it is necessary to include a dipeptide-like "molecular clip"
between the recognition sequence (SSKLQ) and the drug to promote
efficient release of drug without any residual amino-acids remaining
attached to the drug.
The specific objectives of this short project are (i)
to optimise the self-immolative aminoacyl-dimethylthiaproline "molecular
clip", which, after release from the polymer by PSA, will liberate
free drug; (ii) to evaluate drug release from an advanced
model comprising the PSA-cleavable peptide joined to the drug by
the molecular clip.
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