Samenvatting
Novel approaches to targeted cancer therapy that combine improved efficacy of current chemotherapies while minimising side effects are highly sought after. The development of single-chain polymeric nanoparticles (SCPNs) as bio-orthogonal catalysts for targeted site-specific pro-drug activation is a promising avenue to achieve this. Currently, the application of SCPNs as bio-orthogonal catalysts is in its early stages due to reduced performance when increasing the medium's complexity. Herein, we present a systematic approach to identify the various aspects of SCPN-based catalytic systems, to improve their efficiency in future in vitro/in vivo studies. We developed amphiphilic polymers with a polyacrylamide backbone and functionalised with the Pd(ii)-binding ligands triphenylphosphine and bipyridine. The resulting polymers collapse into small-sized nanoparticles (5-6 nm) with an inner hydrophobic domain that comprises the Pd(ii) catalyst. We systematically evaluated the effect of polymer microstructure, ligand-metal complex, and substrate hydrophobicity on the catalytic activity of the nanoparticles for depropargylation reactions in water, PBS or DMEM. The results show that the catalytic activity of nanoparticles is primarily impacted by the ligand-metal complex while polymer microstructure has a minor influence. Moreover, the rate of reaction is increased for hydrophobic substrates. In addition, Pd(ii) leaching studies confirmed little to no loss of Pd(ii) from the hydrophobic interior which can reduce off-target toxicities in future applications. Careful deconstruction of the catalytic system revealed that covalent attachment of the ligand to the polymer backbone is necessary to retain its catalytic activity in cell culture medium while not in water. Finally, we activated anti-cancer pro-drugs based on 5-FU, paclitaxel, and doxorubicin using the best-performing catalytic SCPNs. We found that the rate of pro-drug activation in water was accelerated efficiently by catalytic SCPNs, whereas in cell culture medium the results depended on the type of protecting group and hydrophobicity of the prodrug. We believe our findings will aid in the development of suitable catalytic systems and pro-drugs for future in vivo applications.
Originele taal-2 | Engels |
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Pagina's (van-tot) | 1736–1748 |
Aantal pagina's | 13 |
Tijdschrift | Molecular Systems Design & Engineering |
Volume | 7 |
Nummer van het tijdschrift | 12 |
DOI's | |
Status | Gepubliceerd - 1 dec. 2022 |
Bibliografische nota
Funding Information:This work is financed by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement no. 765497 (THERACAT). AMPL and AUB thank EPSRC (EP/N021134/1) for funding. We would like to acknowledge Vishnu Sureshkumar and Alperen Uslu for help with MP-AES measurements, Dr. Gijs ter Huurne for BTA–NH, and ICMS animation studio for artwork. Xianwen Lou is acknowledged for help with LC–MS. 2
Publisher Copyright:
© 2022 The Royal Society of Chemistry.
Financiering
This work is financed by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement no. 765497 (THERACAT). AMPL and AUB thank EPSRC (EP/N021134/1) for funding. We would like to acknowledge Vishnu Sureshkumar and Alperen Uslu for help with MP-AES measurements, Dr. Gijs ter Huurne for BTA–NH, and ICMS animation studio for artwork. Xianwen Lou is acknowledged for help with LC–MS. 2
Financiers | Financiernummer |
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European Union’s Horizon Europe research and innovation programme | |
Engineering and Physical Sciences Research Council | EP/N021134/1 |
Horizon 2020 | 765497 |