Tumor heterogeneity is associated with the therapeutic failures of targeted
therapies. To overcome such heterogeneity, a novel targeted
therapy is proposed that could kill
tumor populations with diverse phenotypes by delivering nonselective
cytotoxins to target-positive cells as well as to the surrounding
tumor cells via a recurrent bystander killing effect. A representative
prodrug is prepared that targets
integrin αvβ3 and releases
cytotoxins upon entering cells or by
caspase-3. This allows the
prodrug to kill
integrin αvβ3-positive cells and upregulate
caspase-3, which in turn, activates the
prodrug to release a
cytotoxin that could subsequently diffuse into and kill the neighboring
tumor cells. Apoptotic cells further upregulate and release
caspase-3, which activate more
prodrugs leading to another round of adjacent cell death and
caspase-3 release. Thus, the bystander killing effect could occur repeatedly, leading to augmented and widespread anticancer activity. This strategy provides an avenue that could advance the current targeted
therapy.