Abstract
In an effort to devise schemes to site-specifically deliver drugs “on demand” we have leveraged the inducible expression properties of the well-characterized class of stress-response factors, the heat shock proteins. We asked whether a small molecule ligand selective for such proteins could be used as a potential theranostic platform. By conjugating a fluorescent dye to a recently identified nucleoside analog with modest affinity for heat shock protein 70 (HSP70), we have found that cellular uptake can be enhanced following transient heat shock in vitro. The in vivo performance of this compound was further evaluated in nude mice subjected to locoregional hyperthermia which showed a modest level of accumulation in the treated muscle. This effect correlates with relative levels of HSP70 over expression in the treated tissue, supporting the hypothesis that molecular targeting can be enhanced by inducing endogenous proteins through external means.
Highlights
The ability to control the site-specific delivery of drugs on demand may circumvent many of the pharmacological dilemmas in achieving desired cytotoxicity to malignant tumors or sites of diseased tissue versus reducing systemic toxicity
Western blot analysis of heat shock protein 70 (HSP70) expression showed a relatively high level of baseline HSP70 expression in exponentially growing M21 cells which mildly increased following heat shock. This effect did not appear to directly correspond with the observed levels of Adenosine-derived HSP70 inhibitor-12 (AD12)-FAM uptake in heat-exposed M21 cells, suggesting that this compound may target other heat shock proteins (HSP) class members that are likely to be over-expressed. This possibility is plausible since the adenosine analog targets the ATPase domain which are structurally similar for several HSP70 isoforms [24] .Interestingly, we have found that other cell lines tested for baseline expression of HSP70 was variably high, consistent with other reports in the literature
These in vitro results prompted us to evaluate the vivo uptake of this compound by testing for accumulation in normal tissue subjected to localized hyperthermia
Summary
The ability to control the site-specific delivery of drugs on demand may circumvent many of the pharmacological dilemmas in achieving desired cytotoxicity to malignant tumors or sites of diseased tissue versus reducing systemic toxicity. This notion prompted us to hypothesize that the class of well-characterized heat shock proteins (HSP) may be used as key targets to enhance intracellular drug delivery. Our approach was to use a high affinity ligand for such inducible proteins as a targeting moiety conjugated to another compound which may be an imaging molecule (or radionuclide) or cytotoxic compound, to form a suitable HSP-targeted drug complex.
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