Novel DZ-SIM Conjugate Targets Cancer Mitochondria and Prolongs Survival in Pancreatic Ductal Adenocarcinoma

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Pancreatic ductal adenocarcinoma (PDAC) remains a significant challenge with limited effective treatments.
• Current therapies often face resistance, necessitating novel therapeutic strategies.

Purpose of the Study:

• To develop and evaluate a novel targeted therapy, DZ-SIM, for pancreatic ductal adenocarcinoma (PDAC).
• To assess the efficacy of DZ-SIM in inhibiting PDAC growth, metastasis, and improving survival in preclinical models.

Main Methods:

• Developed DZ-SIM, a drug combining a tumor-targeting ligand, near-infrared dye (HMCD), and simvastatin (SIM).
• Utilized fluorescence imaging for targeting assessment, Seahorse and flow cytometry for mitochondrial function, and various assays for apoptosis and invasion markers.
• Evaluated DZ-SIM efficacy in Kras/Trp53/Pdx-1 (KPC) transgenic mice and syngeneic/subcutaneous PDAC models.

Main Results:

• DZ-SIM demonstrated specific tumor-targeting capabilities via NIR fluorescence imaging.
• The drug significantly inhibited PDAC tumor growth and metastasis, and increased survival in multiple animal models.
• DZ-SIM induced cancer cell death by disrupting mitochondrial bioenergetics, decreasing ATP production, and increasing ROS, with effects dependent on mitochondrial function.

Conclusions:

• DZ-SIM represents a novel and effective targeted therapy for PDAC, showing significant preclinical efficacy.
• The drug's mechanism involves targeting cancer cell mitochondria, offering a new therapeutic avenue for this challenging disease.
• DZ-SIM holds potential for re-sensitizing resistant PDAC cells to conventional treatments, improving overall therapeutic outcomes.