Specific Activation of Photosensitizer with Extrinsic Enzyme for Precisive Photodynamic Therapy

Junlong Xiong, Jacky C.H. Chu, Wing Ping Fong, Clarence T.T. Wong, Dennis K.P. Ng

Research output: Journal article publicationJournal articleAcademic researchpeer-review

8 Citations (Scopus)

Abstract

Delivery of functional proteins into the intracellular space has been a challenging task that could lead to a myriad of therapeutic applications. We report herein a novel bioconjugation strategy for enzyme modification and selective delivery into cancer cells for lock-and-key-type activation of photosensitizers. Using a bifunctional linker containing a bis(bromomethyl)phenyl group and an o-phthalaldehyde moiety, it could induce cyclization of the peptide sequence Ac-NH-CRGDfC-CONH2through site-specific dibenzylation with the two cysteine residues and further coupling with β-galactosidase via the phthalaldehyde-amine capture reaction. This facile two-step one-pot procedure enabled the preparation of cyclic RGD-modified β-galactosidase readily, which could be internalized selectively into αvβ3integrin-overexpressed cancer cells. Upon encountering an intrinsically quenched distyryl boron dipyrromethene-based photosensitizer conjugated with a galactose moiety through a self-immolative linker inside the cells, the extrinsic enzyme induced specific cleavage of the β-galactosidic bond followed by self-immolation to release an activated derivative, thereby restoring the photodynamic activities and causing cell death effectively. The high specificity of this extrinsic enzyme-activated photosensitizing system was also demonstrated in vivo using nude mice bearing an αvβ3integrin-positive U87-MG tumor. The specific activation at the tumor site resulted in lighting up and complete eradication of the tumor upon laser irradiation, while by using the native β-galactosidase, the effects were largely reduced. In contrast to the conventional activation using intrinsic enzymes, this extrinsic enzyme activatable approach can further minimize the nonspecific activation toward precisive photodynamic therapy.

Original languageEnglish
Pages (from-to)10647-10658
Number of pages12
JournalJournal of the American Chemical Society
Volume144
Issue number23
DOIs
Publication statusPublished - 15 Jun 2022

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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