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A Comprehensive Procedure to Evaluate the In Vivo Performance of Cancer Nanomedicines
Published on: March 4, 2017
Comprehensive analysis of the tumor targeting efficiency of functionalized nanoparticles in an immunocompetent
Nolan Jackson1, Nasry Bouzeineddine2, Daniel Cecchi1
1Department of Physics and Astronomy, University of Victoria, Victoria, BC, Canada.
Abstract:
The success of nanoparticle-based cancer therapeutics relies on their efficient tumor uptake and retention. Given this, improving nanoparticle localization in tumors is paramount to maximize their therapeutic potential. A common approach to achieve this is to functionalize nanoparticles with active targeting moieties that bind to specific tumor-associated receptors. Among these, arginine-glycine-aspartic acid (RGD) peptides have shown a potential to promote tumor accumulation by targeting the ανβ3 integrin receptor, a receptor commonly overexpressed by tumors owing to its role in promoting angiogenesis, metastasis and proliferation. Yet, its efficacy is commonly assessed using immunocompromised mice models. While useful, these models do not accurately account for immune-related interactions, which could lead to an overestimation of targeting efficacy. In our study, we investigated the efficacy of RGD peptides to improve the tumor accumulation of PEGylated gold nanoparticles (GNPs) using an immunocompetent mouse model. While RGD functionalization increased GNP uptake in cancer cells in vitro, it significantly reduced tumor accumulation in vivo due to enhanced off-target clearance by the mononuclear phagocyte system, with elevated accumulation in the spleen and liver. These findings highlight that RGD functionalization can promote immune-driven clearance in vivo, despite improving GNP uptake in cancer cells in vitro, emphasizing the importance of assessing targeting strategies in immunocompetent models for more physiologically relevant assessments.
Insights
Arginine-glycine-aspartic acid (RGD) peptide functionalization of gold nanoparticles (GNPs) improved cancer cell uptake in vitro but reduced tumor accumulation in vivo. Immunocompetent models revealed RGD enhanced immune clearance, highlighting the need for relevant preclinical assessments.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Nanoparticle-based cancer therapeutics require efficient tumor uptake and retention for maximum efficacy.
- Active targeting moieties, like arginine-glycine-aspartic acid (RGD) peptides, are used to enhance nanoparticle localization by binding to tumor-associated receptors such as ανβ3 integrin.
- Current assessments often use immunocompromised models, which may overestimate targeting efficacy due to unrepresented immune interactions.
Purpose of the Study:
- To investigate the efficacy of RGD peptide functionalization in improving the tumor accumulation of PEGylated gold nanoparticles (GNPs).
- To assess RGD-mediated nanoparticle targeting in an immunocompetent mouse model, accounting for immune system interactions.
- To compare in vitro cancer cell uptake with in vivo tumor accumulation of RGD-functionalized GNPs.
Main Methods:
- Functionalization of PEGylated gold nanoparticles (GNPs) with RGD peptides.
- In vitro assessment of GNP uptake by cancer cells.
- In vivo evaluation of GNP tumor accumulation and biodistribution in an immunocompetent mouse model.
- Analysis of off-target clearance mechanisms, including mononuclear phagocyte system involvement.
Main Results:
- RGD functionalization significantly increased GNP uptake in cancer cells in vitro.
- In vivo, RGD functionalization led to reduced tumor accumulation of GNPs.
- Enhanced off-target accumulation of RGD-GNPs was observed in the spleen and liver, indicating increased clearance by the mononuclear phagocyte system.
- The study identified immune-driven clearance as a significant factor affecting RGD-targeted nanoparticle efficacy in vivo.
Conclusions:
- RGD peptide functionalization can enhance nanoparticle uptake by cancer cells in vitro but may not translate to improved tumor accumulation in vivo.
- Immune system interactions, particularly clearance by the mononuclear phagocyte system, can counteract the intended targeting effects of RGD peptides.
- Assessing nanoparticle targeting strategies in immunocompetent models is crucial for obtaining physiologically relevant data and predicting in vivo performance.
- The findings underscore the importance of considering host immune responses when designing and evaluating targeted nanotherapeutics.
