2. Academic Validation
  3. Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy

Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy

  • J Am Chem Soc. 2018 Nov 21;140(46):15764-15773. doi: 10.1021/jacs.8b08249.
Carlo Matera 1 2,  Alexandre M J Gomila 1 2,  Núria Camarero 1 2,  Michela Libergoli 1,  Concepció Soler 3,  Pau Gorostiza 1 2 4
Affiliations

Affiliations

  • 1 Institute for Bioengineering of Catalonia (IBEC) , Barcelona Institute for Science and Technology , Barcelona 08028 , Spain.
  • 2 Biomedical Research Networking Center in Bioengineering , Biomaterials and Nanomedicine (CIBER-BBN) , Madrid 28029 , Spain.
  • 3 Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL , Universitat de Barcelona , L'Hospitalet de Llobregat 08908 , Barcelona , Spain.
  • 4 Catalan Institution for Research and Advanced Studies (ICREA) , Barcelona 08010 , Spain.
PMID: 30346152 DOI: 10.1021/jacs.8b08249
Abstract

The efficacy and tolerability of systemically administered Anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analogue of methotrexate, a widely prescribed chemotherapeutic drug to treat Cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent Antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules and a step forward to develop targeted Anticancer photochemotherapies with localized efficacy and reduced adverse effects.

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