Cellular Uptake and Photo-Cytotoxicity of a Gadolinium(III)-DOTA-Naphthalimide Complex "Clicked" to a Lipidated Tat Peptide

William I O'Malley; Riccardo Rubbiani; Margaret L Aulsebrook; Michael R Grace; Leone Spiccia; Kellie L Tuck; Gilles Gasser; Bim Graham

doi:10.3390/molecules21020194

Cellular Uptake and Photo-Cytotoxicity of a Gadolinium(III)-DOTA-Naphthalimide Complex "Clicked" to a Lipidated Tat Peptide

Molecules. 2016 Feb 5;21(2):194. doi: 10.3390/molecules21020194.

Authors

William I O'Malley¹, Riccardo Rubbiani², Margaret L Aulsebrook³, Michael R Grace⁴, Leone Spiccia⁵, Kellie L Tuck⁶, Gilles Gasser⁷, Bim Graham⁸

Affiliations

¹ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville VIC 3163, Australia. william.o'malley@monash.edu.
² Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland. riccardo.rubbiani@chem.uzh.ch.
³ School of Chemistry, Monash University, Clayton VIC 3800, Australia. margaret.aulsebrook@monash.edu.
⁴ School of Chemistry, Monash University, Clayton VIC 3800, Australia. mike.grace@monash.edu.
⁵ School of Chemistry, Monash University, Clayton VIC 3800, Australia. leone.spiccia@monash.edu.
⁶ School of Chemistry, Monash University, Clayton VIC 3800, Australia. kellie.tuck@monash.edu.
⁷ Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland. gilles.gasser@chem.uzh.ch.
⁸ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville VIC 3163, Australia. bim.graham@monash.edu.

Abstract

A new bifunctional macrocyclic chelator featuring a conjugatable alkynyl-naphthalimide fluorophore pendant group has been prepared and its Gd(III) complex coupled to a cell-penetrating lipidated azido-Tat peptide derivative using Cu(I)-catalysed "click" chemistry. The resulting fluorescent conjugate is able to enter CAL-33 tongue squamous carcinoma cells, as revealed by confocal microscopy, producing a very modest anti-proliferative effect (IC50 = 93 µM). Due to the photo-reactivity of the naphthalimide moiety, however, the conjugate's cytotoxicity is significantly enhanced (IC50 = 16 µM) upon brief low-power UV-A irradiation.

Keywords: cell-penetrating peptide; fluorescence; gadolinium complex; photo-cytotoxicity; theranostic.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / metabolism*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Chelating Agents / metabolism
Chelating Agents / pharmacology
Click Chemistry
Coordination Complexes / metabolism*
Coordination Complexes / pharmacology
Gadolinium / chemistry
Heterocyclic Compounds, 1-Ring / chemistry
Humans
Naphthalimides / metabolism*
Naphthalimides / pharmacology
Photosensitizing Agents / metabolism*
Photosensitizing Agents / pharmacology
tat Gene Products, Human Immunodeficiency Virus / chemistry

Substances

Antineoplastic Agents
Chelating Agents
Coordination Complexes
Heterocyclic Compounds, 1-Ring
Naphthalimides
Photosensitizing Agents
tat Gene Products, Human Immunodeficiency Virus
1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
Gadolinium