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Unravelling Receptor and RGD Motif Dependence of Retargeted Adenoviral Vectors using Advanced Tumor Model Systems
M Chernyavska1, M Schmid2, P C Freitag2
1Department of Biochemistry, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Scientific Reports
|December 8, 2019
Summary
The RGD motif is crucial for efficient adenoviral gene delivery in complex 3D tumor models, regardless of the specific receptor used. This finding aids in designing better cancer therapies.
Area of Science:
- Biomedical Engineering
- Gene Therapy
- Oncology
Background:
- Adenoviral vectors are promising for cancer gene therapy.
- Understanding retargeting efficiency in complex tumor environments is crucial.
- The role of the RGD motif in adenoviral retargeting remains unclear.
Purpose of the Study:
- To investigate the impact of adenoviral retargeting on transduction efficiency in increasingly complex tumor models.
- To clarify the role of the RGD motif at the penton base in retargeting.
- To examine the interplay between tumor architecture, receptors, and adenoviral transduction.
Main Methods:
- Utilized tumor models of increasing complexity, including 2D co-cultures and 3D spheroids.
- Employed optical clearing techniques for enhanced visualization.
- Developed a custom microfluidic model simulating interstitial flow and extracellular matrix interactions.
- Analyzed adenoviral transduction efficiency via image analysis of cleared spheroids.
Main Results:
- The RGD motif is essential for efficient transduction in 2D models via EpCAM but not EGFR.
- In 3D tumor architectures, the RGD motif is required for transduction mediated by both EpCAM and EGFR.
- Microfluidic models confirmed the RGD motif's importance for on-chip adenoviral transduction.
- Demonstrated a clear interrelationship between receptor characteristics, RGD motif, 3D architecture, and transduction efficiency.
Conclusions:
- The RGD motif plays a critical role in adenoviral transduction efficiency within complex 3D tumor structures.
- Findings highlight the importance of considering tumor architecture and RGD motif for designing effective next-generation therapeutic adenoviruses.
- This research provides insights for the rational design of targeted adenoviral gene delivery systems in cancer therapy.
