Periodic Reporting for period 1 - DELCAT (Catalysis toward platinum substrates for drug delivery)
Berichtszeitraum: 2021-09-20 bis 2023-09-19
Flavins can act as efficient photocatalysts for the conversion of Pt(IV) complexes into Pt(II) anticancer drugs such as cisplatin and carboplatin (Chem. Sci., 2017, 8, 4619; Angew. Chem. Int. Ed., 2018, 57, 3143; ACS Catal., 2020, 10, 187). These unconventional catalytic reactions are bioorthogonal. Thus, they occur with high selectivity in biological environments, with minimal off-target reactions. Nevertheless, advancing the application of this original chemistry in chemotherapy requires an optimal co-localization of the flavin catalyst and Pt(IV) substrate in cells or tissues in order to control the release of active Pt(II) drugs upon photocatalytic activation.
To this end, DELCAT proposes the covalent entrapment of Pt(IV) anticancer complexes and flavins, such as riboflavin and its functionalized derivatives, into biocompatible agarose (AG) and polyglycerol (PG) hydrogels. The functionalization versatility of these polymers is ideal for the development of drug delivery platforms that could display various loading capacities, pharmacokinetics and drug release profiles. Hence, the project will engineer AG and PG of different structures for loading flavins and Pt(IV) prodrugs, and then assess the drug delivery capacity of these materials in skin tissues. Ultimately, the project will provide innovative photocatalytic polymeric biomaterials for the efficient administration of platinum-based anticancer drugs.
To this end, DELCAT proposes the covalent entrapment of Pt(IV) anticancer complexes and flavins, such as riboflavin and its functionalized derivatives, into biocompatible agarose (AG) and polyglycerol (PG) hydrogels. The functionalization versatility of these polymers is ideal for the development of drug delivery platforms that could display various loading capacities, pharmacokinetics and drug release profiles. Hence, the project will engineer AG and PG of different structures for loading flavins and Pt(IV) prodrugs, and then assess the drug delivery capacity of these materials in skin tissues. Ultimately, the project will provide innovative photocatalytic polymeric biomaterials for the efficient administration of platinum-based anticancer drugs.
Research objectives and work plan were organized into four Work Packages (WPs). Here below a summary of the results obtained for each WP is reported.
WP1: Within this WP, I prepared and characterized four Pt(IV) prodrugs and two modified flavins that were needed for assembling DELCAT photodelivery platforms. Moreover, new flavins were designed to shift their absorption toward the red and enable photoactivation at longer wavelengths. The compounds that exhibited the most favorable combination of yield and stability in aqueous media were synthesized in larger quantities to facilitate the subsequent anchoring onto polymeric platforms.
WP2: Loading of flavin catalysts and Pt(IV) complexes was pursued on two activated polymeric supports, agarose (AG) and polyglycerol (PG), in collaboration with the groups Profs. López-Gallego and F. Barroso, respectively. A riboflavin derivative featuring an NH2 group has been effectively covalently tethered to agarose beads, and subsequently employed in the chemoenzymatic oxidation of diols (1). Furthermore, riboflavin and a Pt(IV) prodrug were covalently loaded onto cyclic (cPg) and hyperbranched (hPg) polyols. A low yield of anchoring has been observed in the case of Pg polymers, prompting ongoing research to explore and address the underlying factors.
WP3: The dark stability of the synthesized compounds and their polymeric derivatives was examined in buffers, revealing moderate to high stability. Subsequently, the photochemistry of these derivatives in buffer was investigated using spectroscopic methods. Successful photoactivation of the polymer was demonstrated at 365 nm without the need for any photosensitizer. However, irradiation experiments conducted at 456 nm confirmed the requirement for the photocatalyst (riboflavin) when activation is carried out at longer wavelengths which are more relevant for application in biology.
WP4: We conducted initial tests to determine the ability of PG conjugates to penetrate skin tissues (pig ear) compared to Rf and a Pt(IV) prodrug. This study aimed at exploiting the capability of Pg to enhance the penetration of small drugs into different types of tissues. Experiments were carried out in collaboration with Professor Marcelo Calderón's group. The data showed that after 5 hours of incubation, Pt conjugates could penetrate the skin tissue, though not significantly more than the individual components. We are continuing to optimize the incubation protocol and polymer formulation to improve the applicability of these systems.
List of publications
(1) “Chemoenzymatic oxidation of diols catalyzed by coimmobilized flavins and
dehydrogenases”, S. F. Castillo Pacheco, M. J. Moran*, J. I. Santos, L. Salassa and F.
López Gallego, ChemCatChem, e202300140, 2023
List of Conferences, workshops and and seminars in international institutes
Oral presentations
1) 1. 9th Symposium on Theoretical Biophysics (TheoBio2023). Cetraro, Italy, 16-20 July 2023.
2) 2. Second International Conference on Unconventional Catalysis, Reactors and Applications (UCRA 2022). Warwickshire (UK), 21-23 September 2022.
3) 3. XII Reunión Científica de Bioinorgánica (BioMadrid2022). Madrid, Spain, 11-13 July 2022.
4) 4. Gordon Research Conference on Metals in Medicine. Andover, New Hampshire, United States, 26 June 2022 – 01 July 2022.
Poster presentations
5) 1. XXXIX Reunión Bienal de la Sociedad Española de Química (Bienal23). Zaragoza, Spain, 25-29 June 2023.
6) 2. XIII Reunión Científica de Bioinorgánica (BioGranada23). Granada, Spain, 5-7 June 2023. (Best Poster Award).
7) 3. International Conference on Coordination Chemistry (ICCC22). Rimini, Italy, 28 August – 2 September 2022.
Outreach activities
1) Química para tí 2021-2022 (Donostia, May 2022) – Practical lab activities for high school students.
2) Eureka! Zienzia Museoa “A Life in Science” (Donostia, 17 October 2022)
3) STEAM Sare Orientiación Profesional (Donostia, 18 October 2022)
WP1: Within this WP, I prepared and characterized four Pt(IV) prodrugs and two modified flavins that were needed for assembling DELCAT photodelivery platforms. Moreover, new flavins were designed to shift their absorption toward the red and enable photoactivation at longer wavelengths. The compounds that exhibited the most favorable combination of yield and stability in aqueous media were synthesized in larger quantities to facilitate the subsequent anchoring onto polymeric platforms.
WP2: Loading of flavin catalysts and Pt(IV) complexes was pursued on two activated polymeric supports, agarose (AG) and polyglycerol (PG), in collaboration with the groups Profs. López-Gallego and F. Barroso, respectively. A riboflavin derivative featuring an NH2 group has been effectively covalently tethered to agarose beads, and subsequently employed in the chemoenzymatic oxidation of diols (1). Furthermore, riboflavin and a Pt(IV) prodrug were covalently loaded onto cyclic (cPg) and hyperbranched (hPg) polyols. A low yield of anchoring has been observed in the case of Pg polymers, prompting ongoing research to explore and address the underlying factors.
WP3: The dark stability of the synthesized compounds and their polymeric derivatives was examined in buffers, revealing moderate to high stability. Subsequently, the photochemistry of these derivatives in buffer was investigated using spectroscopic methods. Successful photoactivation of the polymer was demonstrated at 365 nm without the need for any photosensitizer. However, irradiation experiments conducted at 456 nm confirmed the requirement for the photocatalyst (riboflavin) when activation is carried out at longer wavelengths which are more relevant for application in biology.
WP4: We conducted initial tests to determine the ability of PG conjugates to penetrate skin tissues (pig ear) compared to Rf and a Pt(IV) prodrug. This study aimed at exploiting the capability of Pg to enhance the penetration of small drugs into different types of tissues. Experiments were carried out in collaboration with Professor Marcelo Calderón's group. The data showed that after 5 hours of incubation, Pt conjugates could penetrate the skin tissue, though not significantly more than the individual components. We are continuing to optimize the incubation protocol and polymer formulation to improve the applicability of these systems.
List of publications
(1) “Chemoenzymatic oxidation of diols catalyzed by coimmobilized flavins and
dehydrogenases”, S. F. Castillo Pacheco, M. J. Moran*, J. I. Santos, L. Salassa and F.
López Gallego, ChemCatChem, e202300140, 2023
List of Conferences, workshops and and seminars in international institutes
Oral presentations
1) 1. 9th Symposium on Theoretical Biophysics (TheoBio2023). Cetraro, Italy, 16-20 July 2023.
2) 2. Second International Conference on Unconventional Catalysis, Reactors and Applications (UCRA 2022). Warwickshire (UK), 21-23 September 2022.
3) 3. XII Reunión Científica de Bioinorgánica (BioMadrid2022). Madrid, Spain, 11-13 July 2022.
4) 4. Gordon Research Conference on Metals in Medicine. Andover, New Hampshire, United States, 26 June 2022 – 01 July 2022.
Poster presentations
5) 1. XXXIX Reunión Bienal de la Sociedad Española de Química (Bienal23). Zaragoza, Spain, 25-29 June 2023.
6) 2. XIII Reunión Científica de Bioinorgánica (BioGranada23). Granada, Spain, 5-7 June 2023. (Best Poster Award).
7) 3. International Conference on Coordination Chemistry (ICCC22). Rimini, Italy, 28 August – 2 September 2022.
Outreach activities
1) Química para tí 2021-2022 (Donostia, May 2022) – Practical lab activities for high school students.
2) Eureka! Zienzia Museoa “A Life in Science” (Donostia, 17 October 2022)
3) STEAM Sare Orientiación Profesional (Donostia, 18 October 2022)
DELCAT pursued and achieved significant innovative elements in fundamental disciplines such as inorganic chemistry, and photochemistry, as well as in the application of metal-based chemotherapy. These can be summarized as follows:
1. We have prepared a functionalized riboflavin derivative which is a useful synthetic building block to link this biomolecule directly to anticancer metal complexes and polymeric platforms. Several metal complexes and materials are currently being designed in our laboratory. This work may lead to the development of a novel type of anticancer agents with improved redox properties. Our society is in need of new drugs are for fighting against cancer and its social burden.
2. We have prepared a biocompatibile polymer loaded with a Pt(IV) prodrug that is not toxic unless activated. If optimized, this material may lead to the generation of new agents capable of reducing the side-effect associated to Pt chemotherapeutics, which are still among the most used drugs in the clinics.
1. We have prepared a functionalized riboflavin derivative which is a useful synthetic building block to link this biomolecule directly to anticancer metal complexes and polymeric platforms. Several metal complexes and materials are currently being designed in our laboratory. This work may lead to the development of a novel type of anticancer agents with improved redox properties. Our society is in need of new drugs are for fighting against cancer and its social burden.
2. We have prepared a biocompatibile polymer loaded with a Pt(IV) prodrug that is not toxic unless activated. If optimized, this material may lead to the generation of new agents capable of reducing the side-effect associated to Pt chemotherapeutics, which are still among the most used drugs in the clinics.