2. Academic Validation
  3. The BASHY Platform Enables the Assembly of a Fluorescent Bortezomib-GV1001 Conjugate

The BASHY Platform Enables the Assembly of a Fluorescent Bortezomib-GV1001 Conjugate

  • ACS Med Chem Lett. 2021 Dec 30;13(1):128-133. doi: 10.1021/acsmedchemlett.1c00615.
Silvia Baldo 1,  Patrícia Antunes 2 3,  João Falcão Felicidade 1,  Fábio M F Santos 1,  Jesús F Arteaga 4,  Fábio Fernandes 2 3,  Uwe Pischel 1 4,  Sandra N Pinto 2 3,  Pedro M P Gois 1
Affiliations

Affiliations

  • 1 Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa 1649-003, Portugal.
  • 2 Institute for Bioengineering and Biosciences (IBB) and Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon 1049-001, Portugal.
  • 3 Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisbon 1049-001, Portugal.
  • 4 CIQSO-Centre for Research in Sustainable Chemistry and Department of Chemistry, University of Huelva, Campus de El Carmen s/n, 21071 Huelva, Spain.
PMID: 35059132 DOI: 10.1021/acsmedchemlett.1c00615
Abstract

In this study, we show that fluorescent boronic-acid derived salicylidenehydrazone complexes (BASHY) can function as fluorescent linkers for bioconjugates that were used to monitor the delivery of the Proteasome Inhibitor bortezomib (Btz) to HT-29 Cancer cells. BASHY complexes were structurally optimized to improve the stability of the complex in buffered conditions (ammonium acetate, pH 7 up to t 1/2 = 40 h), photophysically characterized regarding their fluorescence properties and used in confocal microscopy colocalization studies that revealed their intracellular sequestration by lipid droplets. The accumulation in these hydrophobic organelles limited the hydrolysis of the complex and consequently the drug release, a problem that was circumvented by the conjugation of the BASHY-Btz complex with a cell-penetrating peptide GV1001-C. The conjugate exhibited an improved cytoplasmic availability as confirmed by confocal fluorescence microscopy studies and an improved potency against HT-29 Cancer cells (IC50 = 100 nM) as compared to the nontargeted complex (IC50 = 450 nM).

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