DUPA Conjugation of a Cytotoxic Indenoisoquinoline Topoisomerase I Inhibitor for Selective Prostate Cancer Cell Targeting

Prostate-specific membrane antigen
(PSMA) is overexpressed in most
prostate cancer cells while being present at low or undetectable levels
in normal cells. This difference provides an opportunity to selectively
deliver cytotoxic drugs to prostate cancer cells while sparing normal
cells that lack PSMA, thus improving potencies and reducing toxicities.
PSMA has high affinity for 2-[3-(1,3-dicarboxypropyl)­ureido]­pentanedioic
acid (DUPA) (Ki = 8 nM). After binding
to a DUPA–drug conjugate, PSMA internalizes, unloads the conjugate,
and returns to the surface. In the present studies, an indenoisoquinoline
topoisomerase I inhibitor was conjugated to DUPA via a peptide linker
and a drug-release segment that facilitates intracellular cleavage
to liberate the drug cargo. The DUPA–indenoisoquinoline conjugate
exhibited an IC50 in the low nanomolar range in 22RV1 cell
cultures and induced a complete cessation of tumor growth with no
toxicity, as determined by loss of body weight and death of treated
mice.