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Investigating the Cellular Specificity in Tumors of a Surface-Converting Nanoparticle by Multimodal Imaging
Francois Fay, Line Hansen1, Stefanie J C G Hectors
1Interdisciplinary Nanoscience Center (iNANO), Aarhus University , Aarhus DK-8000, Denmark.
Abstract:
Active targeting of nanoparticles through surface functionalization is a common strategy to enhance tumor delivery specificity. However, active targeting strategies tend to work against long polyethylene glycol's shielding effectiveness and associated favorable pharmacokinetics. To overcome these limitations, we developed a matrix metalloproteinase-2 sensitive surface-converting polyethylene glycol coating. This coating prevents nanoparticle-cell interaction in the bloodstream, but, once exposed to matrix metalloproteinase-2, i.e., when the nanoparticles accumulate within the tumor interstitium, the converting polyethylene glycol coating is cleaved, and targeting ligands become available for binding to tumor cells. In this study, we applied a comprehensive multimodal imaging strategy involving optical, nuclear, and magnetic resonance imaging methods to evaluate this coating approach in a breast tumor mouse model. The data obtained revealed that this surface-converting coating enhances the nanoparticle's blood half-life and tumor accumulation and ultimately results in improved tumor-cell targeting. Our results show that this enzyme-specific surface-converting coating ensures a high cell-targeting specificity without compromising favorable nanoparticle pharmacokinetics.
Insights
This study introduces a smart nanoparticle coating that hides targeting ligands until reaching the tumor. This enzyme-activated coating improves nanoparticle delivery and tumor cell targeting without affecting their blood circulation time.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Drug Delivery
Background:
- Active targeting enhances nanoparticle specificity but can conflict with the pharmacokinetic benefits of polyethylene glycol (PEG) shielding.
- Existing strategies often face challenges in balancing targeting efficiency with prolonged circulation.
- Developing methods to overcome PEG shielding specifically at the tumor site is crucial for effective targeted therapy.
Purpose of the Study:
- To develop and evaluate a novel surface-converting PEG coating for nanoparticles that is sensitive to matrix metalloproteinase-2 (MMP-2).
- To investigate if this MMP-2 sensitive coating can improve nanoparticle pharmacokinetics and tumor-specific targeting.
- To assess the efficacy of this approach in a preclinical breast tumor mouse model.
Main Methods:
- Fabrication of nanoparticles with a surface-converting PEG coating sensitive to MMP-2.
- Utilized a multimodal imaging approach including optical, nuclear, and magnetic resonance imaging.
- Evaluated nanoparticle biodistribution, blood half-life, tumor accumulation, and tumor cell targeting in a breast cancer mouse model.
Main Results:
- The surface-converting PEG coating significantly enhanced nanoparticle blood half-life.
- Demonstrated increased nanoparticle accumulation within the tumor interstitium.
- Confirmed improved targeting of tumor cells upon cleavage of the PEG coating by MMP-2.
- Showcased enzyme-specific activation of targeting ligands within the tumor microenvironment.
Conclusions:
- The MMP-2 sensitive surface-converting PEG coating effectively shields targeting ligands in circulation and activates them within the tumor.
- This strategy successfully improves nanoparticle pharmacokinetics and achieves high tumor cell targeting specificity.
- The developed coating offers a promising approach for enhancing the efficacy of targeted nanoparticle drug delivery systems.
