New paper in Nanomaterials – Photoactivable Ruthenium-Based CPNs for Light-Induced Chemotherapy

New paper in Nanomaterials – Photoactivable Ruthenium-Based CPNs for Light-Induced Chemotherapy

16 Nov 2021

New publication in Nanomaterials journal entitled “Photoactivable Ruthenium-Based Coordination Polymer Nanoparticles for Light-Induced Chemotherapy” authored by our PhD student Junda Zhang as first author and led by Dr. Claudio Roscini and Dr. Fernando Novio. The work is a result of a fruitful collaboration with Prof. Sylvestre Bonnet from Leiden Institute of Chemistry (Universiteit Leiden, The Netherlands).

In this work, the authors hypothesize that coordination polymer nanoparticles (CPNs) bearing Ru-active complexes as constitutive building blocks and a photocleavable bridging ligand may represent a step forward for photoactivated chemotherapy (PACT) applications. The use of CPNs has demonstrated efficient success to achieve smart NPs with high payloads and high performing as biocompatible contrast agents and antitumoral application, including Pt (IV)-based CPNs.

Scheme of synthesis and photoactivation process of Ru-based coordination polymer nanoparticles (RuBIS CPNs).

These nanoformulations offer good colloidal stability, scalability, cellular internalization, and even more noticeably high payloads, as the prodrug constitutes the backbone of the nanoparticles polymer itself. All these advantages turn out to be really helpful to reduce the dose, the irradiation intensity required to activate the anticancer drug diffusion, and therefore any side effect. Though, as far as we know, the number of ruthenium-based coordination polymers with antitumor applications is rather limited, none of them being photoactivable. The authors achieved this challenge with the synthesis of CPNs containing [Ru(biqbpy)(dmso)Cl]Cl monomer(complex 1, where biqbpy = stands for 6,6′-bis[N-(isoquinolyl)- 1-amino]-2,2′-bipyridine), which is known to form cytotoxic aqueous active species [Ru(biqbpy)(H2O)2]2+upon blue or green light activation. The polymerization process was performed using the photocleavable bis(imidazol-1-yl)-hexane (BIS) ligand and following a methodology previously described for the synthesis of non-photoactive CPNs of relevance in biological applications.

ABSTRACT: Green light photoactive Ru-based coordination polymer nanoparticles (CPNs), with chemical formula [[Ru(biqbpy)]1.5(bis)](PF6)3 (biqbpy = 6,6′-bis[N-(isoquinolyl)-1-amino]-2,2′-bipyridine; bis = bis(imidazol-1-yl)-hexane), were obtained through polymerization of the trans-[Ru(biqbpy)(dmso)Cl]Cl complex (Complex 1) and bis bridging ligands. The as-synthesized CPNs (50 ± 12 nm diameter) showed high colloidal and chemical stability in physiological solutions. The axial bis(imidazole) ligands coordinated to the ruthenium center were photosubstituted by water upon light irradiation in aqueous medium to generate the aqueous substituted and active ruthenium complexes. The UV-Vis spectral variations observed for the suspension upon irradiation corroborated the photoactivation of the CPNs, while High Performance Liquid Chromatography (HPLC) of irradiated particles in physiological media allowed for the first time precisely quantifying the amount of photoreleased complex from the polymeric material. In vitro studies with A431 and A549 cancer cell lines revealed an 11-fold increased uptake for the nanoparticles compared to the monomeric complex [Ru(biqbpy)(N-methylimidazole)2](PF6)2 (Complex 2). After irradiation (520 nm, 39.3 J/cm2), the CPNs yielded up to a two-fold increase in cytotoxicity compared to the same CPNs kept in the dark, indicating a selective effect by light irradiation. Meanwhile, the absence of 1O2 production from both nanostructured and monomeric prodrugs concluded that light-induced cell death is not caused by a photodynamic effect but rather by photoactivated chemotherapy.

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Funding: This work was supported by grant RTI2018-098027-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe. With the support from “Metalfármacos multifuncionales para el diagnóstico y la terapia” with grant RED2018-102471-T funded by MCIN/AEI/10.13039/501100011033. The ICN2 is funded by the CERCA programme/Generalitat de Catalunya. The ICN2 is supported by the Severo Ochoa Centres of Excellence programme, grant SEV-2017-0706 funded by MCIN/AEI/10.13039/501100011033. J.D. Zhang thanks the BIST PhD Fellowship Programme (This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 754558). NWO is kindly acknowledged for financial support to SB via a VICI grant. COST is kindly acknowledged for stimulating scientific discussion and financial support via the Cost Action CA 17140 “Cancer nanomedicine from the bench to the bedside”.