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

Authors

Solmaz AghaAmiri
Sukhen C Ghosh
Servando Hernandez Vargas
Daniel M Halperin
Ali Azhdarinia

Publication Date

2-22-2024

Journal

Journal of Medicinal Chemistry

Abstract

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.

Keywords

Humans, Temozolomide, Dacarbazine, Receptors, Somatostatin, Tissue Distribution, O(6)-Methylguanine-DNA Methyltransferase, DNA Repair Enzymes, DNA Modification Methylases, Antineoplastic Agents, Alkylating, Cell Line, Tumor

DOI

10.1021/acs.jmedchem.3c00223

PMID

38346097

PMCID

PMC10896214

PubMedCentral® Posted Date

2-12-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes