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Is Tumor Cell Specificity Distinct from Tumor Selectivity In Vivo?: A Quantitative NIR Molecular Imaging Analysis of
Girgis Obaid1,2, Kimberley Samkoe3, Kenneth Tichauer4
1Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, U.S.
Abstract:
The significance and ability for receptor targeted nanoliposomes (tNLs) to bind to their molecular targets in solid tumors in vivo has been questioned, particularly as the efficiency of their tumor accumulation and selectivity is not always predictive of their efficacy or molecular specificity. This study presents, for the first time, in situ NIR molecular imaging-based quantitation of the in vivo specificity of tNLs for their target receptors, as opposed to tumor selectivity, which includes influences of enhanced tumor permeability and retention. Results show that neither tumor delivery nor selectivity (tumor-to-normal ratio) of cetuximab and IRDye conjugated tNLs correlate with EGFR expression in U251, U87 and 9L tumors, and in fact underrepresent their imaging-derived molecular specificity by up to 94.2%. Conversely, their in vivo specificity, which we quantify as the concentration of tNL-reported tumor EGFR provided by NIR molecular imaging, correlates positively with EGFR expression levels in vitro and ex vivo (Pearson's r= 0.92 and 0.96, respectively). This study provides a unique opportunity to address the problematic disconnect between tNL synthesis and in vivo specificity. The findings encourage their continued adoption as platforms for precision medicine, and facilitates intelligent synthesis and patient customization in order to improve safety profiles and therapeutic outcomes.
Insights
Receptor targeted nanoliposomes (tNLs) show improved in vivo specificity for molecular targets, addressing previous questions about their efficacy. This study quantifies tNL specificity, aiding precision medicine applications.
Area of Science:
- Nanomedicine
- Molecular Imaging
- Oncology
Background:
- Receptor targeted nanoliposomes (tNLs) efficacy in solid tumors is debated due to poor correlation between tumor accumulation/selectivity and molecular specificity.
- Existing methods often conflate tumor selectivity with true molecular targeting efficiency.
Purpose of the Study:
- To quantify the in vivo molecular specificity of tNLs for target receptors using in situ near-infrared (NIR) molecular imaging.
- To differentiate molecular specificity from tumor selectivity influenced by enhanced permeability and retention (EPR) effects.
Main Methods:
- Utilized cetuximab and IRDye conjugated tNLs in U251, U87, and 9L tumor models.
- Employed in situ NIR molecular imaging to quantitate in vivo specificity.
- Correlated imaging data with in vitro and ex vivo EGFR expression levels.
Main Results:
- Tumor delivery and selectivity of tNLs did not correlate with EGFR expression, underrepresenting molecular specificity by up to 94.2%.
- In vivo specificity, measured by tNL-reported tumor EGFR concentration via NIR imaging, positively correlated with EGFR expression (in vitro: r=0.92, ex vivo: r=0.96).
Conclusions:
- NIR molecular imaging provides accurate in vivo quantitation of tNL molecular specificity, resolving the disconnect between tNL synthesis and in vivo performance.
- Findings support tNLs as precision medicine platforms, enabling improved synthesis and patient customization for better therapeutic outcomes and safety.
