Emissive Behavior, Cytotoxic Activity, Cellular Uptake, and PEGylation Properties of New Luminescent Rhenium(I) Polypyridine Poly(ethylene glycol) Complexes

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Alex Wing-Tat Choi
  • Man-Wai Louie
  • Steve Po-Yam Li
  • Hua-Wei Liu
  • Bruce Ting-Ngok Chan
  • Tonlex Chun-Ying Lam
  • Alex Chun-Chi Lin

Detail(s)

Original languageEnglish
Pages (from-to)13289-13302
Journal / PublicationInorganic Chemistry
Volume51
Issue number24
Online published30 Nov 2012
Publication statusPublished - 17 Dec 2012

Abstract

We report here a new class of biological reagents derived from luminescent rhenium(I) polypyridine complexes modified with a poly(ethylene glycol) (PEG) pendant. The PEG-amine complexes [Re(N^N)(CO)3(py-PEG-NH2)](PF6) (py-PEG-NH2 = 3-amino-5-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)aminocarbonyl)pyridine, MWPEG = 5000 Da, PDIPEG <1.08; N^N = 1,10-phenanthroline (phen) (1-PEG-NH2), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-phen) (2-PEG-NH2), 4,7-diphenyl-1,10-phenanthroline (Ph2-phen) (3-PEG-NH2)) and [Re(bpy-PEG)(CO) 3(py-NH2)](PF6) (bpy-PEG = 4-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)aminocarbonyl)-4′-methyl-2, 2′-bipyridine; py-NH2 = 3-aminopyridine) (4-PEG-NH2) have been synthesized and characterized. The photophysical properties, lipophilicity, water solubility, cytotoxic activity, and cellular uptake properties of these complexes have been compared to those of their PEG-free counterparts [Re(N^N)(CO)3(py-Et-NH2)](PF6) (py-Et-NH2 = 3-amino-5-(N-(ethyl)aminocarbonyl) pyridine; N^N = phen (1-Et-NH2), Me4-phen (2-Et-NH2), Ph2-phen (3-Et-NH2)) and [Re(bpy-Et)(CO)3(py-NH2)](PF6) (bpy-Et = 4-(N-(ethyl)aminocarbonyl)-4′-methyl-2,2′-bipyridine) (4-Et-NH2). The PEG complexes exhibited significantly higher water solubility and lower cytotoxicity (IC50 = 6.6 to 1152 μM) than their PEG-free counterparts (IC50 = 3.6 to 159 μM), indicating that the covalent attachment of a PEG pendant to rhenium(I) polypyridine complexes is an effective way to increase their biocompatibility. The amine complexes 1-PEG-NH2-4-PEG-NH2 have been activated with thiophosgene to yield the isothiocyanate complexes [Re(N^N)(CO) 3(py-PEG-NCS)](PF6) (py-PEG-NCS = 3-isothiocyanato-5-(N-(2-(ω-ethoxypoly(1-oxapropyl))ethyl)aminocarbonyl)pyridine; N^N = phen (1-PEG-NCS), Me4-phen (2-PEG-NCS), Ph2-phen (3-PEG-NCS)), and [Re(bpy-PEG)(CO)3(py-NCS)] (PF6) (py-NCS = 3-isothiocyanatopyridine) (4-PEG-NCS) as a new class of luminescent PEGylation reagents. To examine their PEGylation properties, these isothiocyanate complexes have been reacted with a model substrate n-butylamine, resulting in the formation of the thiourea complexes [Re(N^N)(CO)3(py-PEG-Bu)](PF6) (py-PEG-Bu = 3-n-butylthioureidyl-5-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl) aminocarbonyl)pyridine; N^N = phen (1-PEG-Bu), Me4-phen (2-PEG-Bu), Ph2-phen (3-PEG-Bu)), and [Re(bpy-PEG)(CO) 3(py-Bu)](PF6) (py-Bu = 3-n-butylthioureidylpyridine) (4-PEG-Bu). Additionally, bovine serum albumin (BSA) and poly(ethyleneimine) (PEI) have been PEGylated with the isothiocyanate complexes to yield bioconjugates 1-PEG-BSA-4-PEG-BSA and 1-PEG-PEI-4-PEG-PEI, respectively. Upon irradiation, all the PEGylated BSA and PEI conjugates exhibited intense and long-lived emission in aqueous buffer under ambient conditions. The DNA-binding and polyplex-formation properties of conjugate 3-PEG-PEI have been studied and compared with those of unmodified PEI. Furthermore, the in vivo toxicity of complex 3-PEG-NH2 and its PEG-free counterpart 3-Et-NH2 has been investigated using zebrafish embryos as an animal model. Embryos treated with the PEG complex at high concentrations revealed delayed hatching, which has been ascribed to hypoxia as a result of adhering of the complex to the external surface of the chorion.

Citation Format(s)

Emissive Behavior, Cytotoxic Activity, Cellular Uptake, and PEGylation Properties of New Luminescent Rhenium(I) Polypyridine Poly(ethylene glycol) Complexes. / Choi, Alex Wing-Tat; Louie, Man-Wai; Li, Steve Po-Yam; Liu, Hua-Wei; Chan, Bruce Ting-Ngok; Lam, Tonlex Chun-Ying; Lin, Alex Chun-Chi; Cheng, Shuk-Han; Lo, Kenneth Kam-Wing.

In: Inorganic Chemistry, Vol. 51, No. 24, 17.12.2012, p. 13289-13302.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review