Linker Optimization and Therapeutic Evaluation of Phosphatidylserine-Targeting Zinc Dipicolylamine-based Drug Conjugates

We
report that compound 13, a novel phosphatidylserine-targeting
zinc­(II) dipicolylamine drug conjugate, readily triggers a positive
feedback therapeutic loop through the in situ generation
of phosphatidylserine in the tumor microenvironment. Linker modifications,
pharmacokinetics profiling, in vivo antitumor studies, and micro-Western
array of treated-tumor tissues were employed to show that this class
of conjugates induced regeneration of apoptotic signals, which facilitated
subsequent recruitment of the circulating conjugates through the zinc­(II)
dipicolylamine–phosphatidylserine association and resulted
in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions
in colorectal and pancreatic tumor models, it also exhibited at least
5-fold enhancement in antitumor efficacy with only 40% of the drug
employed during treatment, culminating in a >12.5-fold increase
in
therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting
theranostic, with built-in complementary functional moieties between
the targeting module and the drug mechanism to expand the arsenal
of antitumor therapy.