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

J Med Chem. 2024 Feb 22;67(4):2425-2437. doi: 10.1021/acs.jmedchem.3c00223. Epub 2024 Feb 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology
  • Cell Line, Tumor
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / metabolism
  • Dacarbazine* / pharmacology
  • Dacarbazine* / therapeutic use
  • Humans
  • O(6)-Methylguanine-DNA Methyltransferase / genetics
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism
  • Receptors, Somatostatin* / metabolism
  • Temozolomide / pharmacology
  • Tissue Distribution

Substances

  • Temozolomide
  • Dacarbazine
  • Receptors, Somatostatin
  • O(6)-Methylguanine-DNA Methyltransferase
  • DNA Repair Enzymes
  • DNA Modification Methylases
  • Antineoplastic Agents, Alkylating