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Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet-Hydrogel Frameworks.

ABSTRACT: The promising potential of bioorthogonal catalysis in biomedicine is inspiring incremental efforts to design strategies that regulate drug activity in living systems. To achieve this, it is not only essential to develop customized inactive prodrugs and biocompatible metal catalysts but also the right physical environment for them to interact and enable drug production under spatial and/or temporal control. Toward this goal, here, we report the first inactive precursor of the potent broad-spectrum anticancer drug paclitaxel (a.k.a. Taxol) that is stable in cell culture and labile to Pd catalysts. This new prodrug is effectively uncaged in cancer cell culture by Pd nanosheets captured within agarose and alginate hydrogels, providing a biodegradable catalytic framework to achieve controlled release of one of the most important chemotherapy drugs in medical practice. The compatibility of bioorthogonal catalysis and physical hydrogels opens up new opportunities to administer and modulate the mobility of transition metal catalysts in living environs.

SUBMITTER: Perez-Lopez AM

PROVIDER: S-EPMC7497487 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet-Hydrogel Frameworks.

Pérez-López Ana M AM Rubio-Ruiz Belén B Valero Teresa T Contreras-Montoya Rafael R Álvarez de Cienfuegos Luis L Sebastián Víctor V Santamaría Jesús J Unciti-Broceta Asier A

Journal of medicinal chemistry 20200817 17

The promising potential of bioorthogonal catalysis in biomedicine is inspiring incremental efforts to design strategies that regulate drug activity in living systems. To achieve this, it is not only essential to develop customized inactive prodrugs and biocompatible metal catalysts but also the right physical environment for them to interact and enable drug production under spatial and/or temporal control. Toward this goal, here, we report the first inactive precursor of the potent broad-spectru ...[more]

PMID: 32787091

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Project description:Click chemistry has proved a valuable tool in biocompatible hydrogel formation for 3D cell culture, owing to its bioorthogonal nature and high efficiency under physiological conditions. While traditional click reactions can be readily employed to create uniform functional materials about living cells, their spontaneity prohibits spatiotemporal control of material properties, thereby limiting their utility in recapitulating the dynamic heterogeneity characteristic of the in vivo microenvironment. Photopolymerization-based techniques gain this desired level of 4D programmability, but often at the expense of introducing propagating free radicals that are prone to non-specific reactions with biological systems. Here we present a strategy for bioorthogonal hydrogel formation and modification that does not rely on propagating free radicals, proceeding through oxime ligation moderated by a photocaged alkoxyamine. Upon mild near UV light exposure, the photocage is cleaved, liberating the alkoxyamine and permitting localized condensation with an aldehyde. Multi-arm crosslinkers, functionalized with either benzaldehydes or photocaged alkoxyamines, formed oxime-based hydrogels within minutes of light exposure in the presence of live cells. Polymerization rates and final mechanical properties of these gels could be systematically tuned by varying crosslinker concentrations, light intensity, aniline catalyst equivalents, and pH. Moreover, hydrogel geometry and final mechanical properties were controlled by the location and extent of UV exposure, respectively. Photomediated oxime ligation was then translated to the biochemical modification of hydrogels, where full-length proteins containing photocaged alkoxyamines were immobilized in user-defined regions exposed to UV light. The programmability afforded by photomediated oxime ligation can recapitulate dynamically anisotropic mechanical and biochemical aspects of the native extracellular matrix. Consequently, photopolymerized oxime-based hydrogels are expected to enable an enhanced understanding of cell-matrix interactions by serving as improved 4D cell culture platforms.

Dataset Information

Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet-Hydrogel Frameworks.

Publications

Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet-Hydrogel Frameworks.

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