Somatostatin Receptor Subtype‑2 Targeting System for Specific Delivery of Temozolomide

Temozolomide (TMZ) is a DNA alkylating agent that produces
objective
responses in patients with neuroendocrine tumors (NETs) when the DNA
repair enzyme O6-methylguanine-DNA methyltransferase (MGMT)
is inactivated. At high doses, TMZ therapy exhausts MGMT activity
but also produces dose-limiting toxicities. To reduce off-target effects,
we converted the clinically approved radiotracer 68Ga-DOTA-TOC
into a peptide-drug conjugate (PDC) for targeted delivery of TMZ to
somatostatin receptor subtype-2 (SSTR2)-positive tumor cells. We used
an integrated radiolabeling strategy for direct quantitative assessment
of receptor binding, pharmacokinetics, and tissue biodistribution. In vitro studies revealed selective binding to SSTR2-positive
cells with high affinity (5.98 ± 0.96 nmol/L), internalization,
receptor-dependent DNA damage, cytotoxicity, and MGMT depletion. Imaging
and biodistribution analysis showed preferential accumulation of the
PDC in receptor-positive tumors and high renal clearance. This study
identified a trackable SSTR2-targeting system for TMZ delivery and
utilizes a modular design that could be broadly applied in PDC development.