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Imaging pancreatic cancer with a peptide-nanoparticle conjugate targeted to normal pancreas
Xavier Montet1, Ralph Weissleder, Lee Josephson
1Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Abstract:
Designing molecules that bind to targets that become upregulated or overexpressed as normal cells become cancerous is an important strategy for both therapeutic and diagnostic drug design. We hypothesized that pancreatic ductal adenocarcinoma (PDAC) might be imaged with the inverse strategy, that is by the design of a nanoparticle-conjugate targeted to bombesin (BN) receptors present on normal acinar cells of the pancreas. Using the fluorescein hapten visualization method to assess the presence of bombesin (BN) receptors, we first demonstrated BN receptors in the normal mouse and human pancreas, but then the lack of BN binding receptors in 13 out of 13 specimens of PDAC. The BN peptide-nanoparticle conjugate, BN-CLIO(Cy5.5), was synthesized and accumulated in the mouse pancreas in receptor dependent fashion, but not in a receptor dependent fashion in other tissues, based on tissue fluorescence measurements. The BN-CLIO(Cy5.5) nanoparticle decreased the T2 of normal pancreas and enhanced the ability to visualize tumor in a model of pancreatic cancer by MRI. The use of BN-CLIO(Cy5.5) nanoparticle as a normal tissue-targeted, T2-reducing contrast agent offers a promising approach to imaging PDAC.
Insights
This study targeted normal pancreas cells using bombesin (BN) receptors to image pancreatic cancer. The nanoparticle contrast agent successfully visualized tumors by highlighting the contrast between healthy and cancerous tissue via MRI.
Area of Science:
- Biomedical Imaging
- Nanotechnology
- Oncology
Background:
- Targeting upregulated molecules is a common strategy in cancer drug design.
- Pancreatic ductal adenocarcinoma (PDAC) often overexpresses specific receptors.
- An inverse strategy targeting normal tissue receptors for PDAC imaging was hypothesized.
Purpose of the Study:
- To investigate the potential of targeting bombesin (BN) receptors on normal pancreatic acinar cells for PDAC imaging.
- To develop and evaluate a nanoparticle-conjugate targeted to BN receptors.
- To assess the efficacy of this approach in enhancing tumor visualization via MRI.
Main Methods:
- Utilized fluorescein hapten visualization to detect BN receptors in normal and cancerous pancreatic tissues.
- Synthesized a bombesin peptide-nanoparticle conjugate (BN-CLIO(Cy5.5)).
- Evaluated nanoparticle accumulation and biodistribution using fluorescence measurements and MRI in a preclinical model.
Main Results:
- Demonstrated the presence of BN receptors in normal mouse and human pancreas.
- Confirmed the lack of BN receptors in 13 out of 13 PDAC specimens.
- Showed receptor-dependent accumulation of BN-CLIO(Cy5.5) in the normal mouse pancreas.
- Observed that BN-CLIO(Cy5.5) decreased T2 relaxation in the normal pancreas, enhancing tumor visualization by MRI.
Conclusions:
- Targeting normal pancreatic acinar cells via BN receptors is a viable inverse strategy for PDAC imaging.
- BN-CLIO(Cy5.5) acts as an effective T2-reducing contrast agent for normal tissue targeting.
- This nanoparticle-based approach shows promise for improving the detection and imaging of pancreatic cancer.
