A Theranostic Small-Molecule Prodrug Conjugate for Neuroendocrine Prostate Cancer

Area of Science:

• Oncology
• Radiochemistry
• Medicinal Chemistry

Background:

• Prostate cancer can develop a therapy-resistant neuroendocrine phenotype (NEPC).
• Diagnosis and treatment of NEPC present significant challenges.
• Existing therapies lack targeted approaches for NEPC.

Purpose of the Study:

• To develop a theranostic small-molecule prodrug conjugate (T-SMPDC) for NEPC.
• To enable targeted positron emission tomography (PET) imaging and chemotherapy of NEPC.
• To validate the T-SMPDC design for NEPC diagnosis and treatment.

Main Methods:

• Conjugation of DOTA, octreotide (Octr), and fingolimod (FTY720) onto a triazine core with PEG linkers.
• Synthesis of the T-SMPDC: DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720.
• In vitro evaluation of SSTR2 binding, internalization, and FTY720 release/cytotoxicity.
• In vivo PET imaging of [68Ga]-labeled T-SMPDC in prostate cancer xenografts.

Main Results:

• The T-SMPDC demonstrated selective somatostatin receptor 2 (SSTR2) binding and internalization in SSTR2-high cells.
• Released FTY720 showed cytotoxicity, and cathepsin B mediated its release from the T-SMPDC.
• In vivo PET imaging revealed significantly higher accumulation of [68Ga]-T-SMPDC in SSTR2-high xenografts compared to SSTR2-low xenografts.
• Rapid renal excretion of the T-SMPDC was observed.

Conclusions:

• The T-SMPDC design is validated as a promising platform for NEPC.
• This theranostic approach offers potential for targeted diagnosis and therapy of NEPC.
• Further investigation is warranted to explore the clinical application of T-SMPDCs in NEPC.