Emissive Behavior, Cytotoxic Activity, Cellular Uptake, and PEGylation Properties of New Luminescent Rhenium(I) Polypyridine Poly(ethylene glycol) Complexes
- Authors
- Choi, A.W., Louie, M.W., Li, S.P., Liu, H.W., Chan, B.T., Lam, T.C., Lin, A.C., Cheng, S.H., and Lo, K.K.
- ID
- ZDB-PUB-121206-23
- Date
- 2012
- Source
- Inorganic chemistry 51(24): 13289-13302 (Journal)
- Registered Authors
- Cheng, Shuk Han
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacokinetics
- Antineoplastic Agents/pharmacology
- Cisplatin/pharmacology
- Coordination Complexes/chemical synthesis*
- Coordination Complexes/chemistry
- Coordination Complexes/pharmacokinetics
- Embryo, Nonmammalian/drug effects
- HeLa Cells
- Humans
- Inhibitory Concentration 50
- Luminescence
- Microscopy, Confocal
- Models, Animal
- Molecular Structure
- Photochemistry
- Polyethylene Glycols/chemistry*
- Rhenium/chemistry*
- Solubility
- Water/chemistry*
- Zebrafish
- PubMed
- 23198846 Full text @ Inorg. Chem.
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(NN)(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; NN = 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)-42-methyl-2,22-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(NN)(CO)3(py-Et-NH2)](PF6) (py-Et-NH2 = 3-amino-5-(N-(ethyl)aminocarbonyl)pyridine; NN = 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)-42-methyl-2,22-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(NN)(CO)3(py-PEG-NCS)](PF6) (py-PEG-NCS = 3-isothiocyanato-5-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)aminocarbonyl)pyridine; NN = 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(NN)(CO)3(py-PEG-Bu)](PF6) (py-PEG-Bu = 3-n-butylthioureidyl-5-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)aminocarbonyl)pyridine; NN = 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.