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Optical imaging of matrix metalloproteinase-7 activity in vivo using a proteolytic nanobeacon
Randy L Scherer1, Michael N VanSaun, J Oliver McIntyre
1Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Abstract:
Matrix metalloproteinases (MMPs) are extracellular proteolytic enzymes involved in tumor progression. We present the in vivo detection and quantitation of MMP7 activity using a specific near-infrared polymer-based proteolytic beacon, PB-M7NIR. PB-M7NIR is a pegylated polyamidoamine PAMAM-Generation 4 dendrimer core covalently coupled to a Cy5.5-labeled peptide representing a selective substrate that monitors MMP7 activity (sensor) and AF750 as an internal reference to monitor relative substrate concentration (reference). In vivo imaging of tumors expressing MMP7 had a median sensor to reference ratio 2.2-fold higher than a that of a bilateral control tumor. Ex vivo imaging of intestines of multiple intestinal neoplasia (APC Min) mice injected systemically with PB-M7NIR revealed a sixfold increase in the sensor to reference ratio in the adenomas of APC Min mice compared with control intestinal tissue or adenomas from MMP7-null Min mice. PB-M7NIR detected tumor sizes as small as 0.01 cm2, and the sensor to reference ratio was independent of tumor size. Histologic sectioning of xenograft tumors localized the proteolytic signal to the extracellular matrix; MMP7-overexpressing tumors displayed an approximately 300-fold enhancement in the sensor to reference ratio compared with nonexpressing tumor cells. In APC Min adenomas, the proteolytic signal colocalized with the endogenously expressed MMP7 protein, with sensor to reference ratios approximately sixfold greater than that of normal intestinal epithelium. PB-M7NIR provides a useful reagent for the in vivo and ex vivo quantitation and localization of MMP-selective proteolytic activity.
Insights
A novel near-infrared polymer beacon, PB-M7NIR, enables sensitive in vivo detection of matrix metalloproteinase-7 (MMP7) activity. This tool accurately quantifies MMP7 in tumors and intestinal adenomas, aiding cancer research.
Area of Science:
- Biomedical Imaging
- Molecular Biology
- Oncology
Background:
- Matrix metalloproteinases (MMPs) are crucial extracellular enzymes implicated in tumor progression.
- Accurate detection and quantification of specific MMP activity are vital for understanding cancer development and for therapeutic strategies.
Purpose of the Study:
- To develop and validate a novel near-infrared (NIR) polymer-based beacon (PB-M7NIR) for in vivo detection and quantitation of matrix metalloproteinase-7 (MMP7) activity.
- To assess the efficacy of PB-M7NIR in various preclinical cancer models, including xenografts and spontaneous intestinal tumor models.
Main Methods:
- PB-M7NIR, a pegylated polyamidoamine dendrimer, was engineered with an MMP7-specific peptide substrate labeled with a NIR fluorophore (Cy5.5) and an internal reference (AF750).
- In vivo and ex vivo imaging techniques were employed in tumor-bearing mice and ApcMin/+ mice to evaluate PB-M7NIR's performance.
- Histological analysis was performed to correlate proteolytic signals with tumor characteristics and MMP7 expression.
Main Results:
- PB-M7NIR demonstrated a significantly higher sensor-to-reference ratio in MMP7-expressing tumors compared to control tumors (2.2-fold increase in vivo).
- Ex vivo imaging revealed a sixfold increase in the sensor-to-reference ratio in intestinal adenomas of ApcMin/+ mice compared to normal tissue or MMP7-null controls.
- The beacon detected small tumors (0.01 cm2) and localized the proteolytic activity to the extracellular matrix, showing a ~300-fold signal enhancement in MMP7-overexpressing xenografts.
Conclusions:
- PB-M7NIR is a sensitive and specific tool for the in vivo and ex vivo quantitation and localization of MMP7 proteolytic activity.
- This polymer-based beacon holds promise for advancing cancer diagnostics and monitoring therapeutic responses targeting MMP7.
