Abstract
The concept of selective tumor targeting using nanomedicines has been around for decades; however, no targeted nanoparticle has yet reached the clinic. A key bottleneck is the non-selectivity of targeted nanomedicines in vivo, which is attributed to the lack of characterization of their surface properties, especially the ligand number, thereby calling for robust techniques that allow quantifiable outcomes for an optimal design. Multivalent interactions comprise multiple copies of ligands attached to scaffolds, allowing simultaneous binding to receptors, and they play an important role in targeting. As such, ‘multivalent’ nanoparticles facilitate simultaneous interaction of weak surface ligands with multiple target receptors resulting in higher avidity and enhanced cell selectivity. Therefore, the study of weak binding ligands for membrane-exposed biomarkers is crucial for the successful development of targeted nanomedicines. Here we carried out a study of a cell targeting peptide known as WQP having weak binding affinity for prostate specific membrane antigen, a known prostate cancer biomarker. We evaluated the effect of its multivalent targeting using polymeric NPs over its monomeric form on the cellular uptake in different prostate cancer cell lines. We developed a method of specific enzymatic digestion to quantify the number of WQPs on NPs having different surface valencies and observed that increasing valencies resulted in a higher cellular uptake of WQP-NPs over the peptide alone. We also found that WQP-NPs showed higher uptake in PSMA over-expressing cells, attributed to a stronger avidity for selective PSMA targeting. This kind of strategy can be useful for improving the binding affinity of a weak ligand as a means for selective tumor targeting.
| Original language | English |
|---|---|
| Pages (from-to) | 1378-1385 |
| Number of pages | 8 |
| Journal | Nanoscale Advances |
| Volume | 5 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 7 Mar 2023 |
Bibliographical note
Funding Information:S. P. and L. A. acknowledge the financial support by the Spanish Ministry of Science and Innovation (PID2019-109450RB-I00/AEI/10.13039/501100011033), the European Research Council/Horizon 2020 (ERC-StG-757397), the “la Caixa” Foundation (ID 100010434), and the Generalitat de Catalunya through the CERCA program. L. A. thanks NWO for support (VIDI grant no. 192.028) and the Barcelona Institute of Science and Technology for support (BIST-AOM). The authors would like to thank Dr Lina Ghibelli from the University of Rome Tor Vergata and Dr Xavier Salvatella from the Institute of Research on Biomedicine, Barcelona, Spain for providing us with RWPE-1 and 22Rv1 cell lines, respectively. They would also like to acknowledge the valuable inputs from Dr Francisco Cárdenas López, NMR facility, University of Barcelona, and Dr Jaume Comas, Cytometry unit, University of Barcelona, for technical support in NMR characterization and cellular uptake studies, respectively. M. M. is grateful for the FPI fellowship (BES-2017-079827) funded by the Spanish Ministry of Economy and Competitiveness (MINECO).
Funding
S. P. and L. A. acknowledge the financial support by the Spanish Ministry of Science and Innovation (PID2019-109450RB-I00/AEI/10.13039/501100011033), the European Research Council/Horizon 2020 (ERC-StG-757397), the “la Caixa” Foundation (ID 100010434), and the Generalitat de Catalunya through the CERCA program. L. A. thanks NWO for support (VIDI grant no. 192.028) and the Barcelona Institute of Science and Technology for support (BIST-AOM). The authors would like to thank Dr Lina Ghibelli from the University of Rome Tor Vergata and Dr Xavier Salvatella from the Institute of Research on Biomedicine, Barcelona, Spain for providing us with RWPE-1 and 22Rv1 cell lines, respectively. They would also like to acknowledge the valuable inputs from Dr Francisco Cárdenas López, NMR facility, University of Barcelona, and Dr Jaume Comas, Cytometry unit, University of Barcelona, for technical support in NMR characterization and cellular uptake studies, respectively. M. M. is grateful for the FPI fellowship (BES-2017-079827) funded by the Spanish Ministry of Economy and Competitiveness (MINECO).
