Modulating the Cellular Uptake of Fluorescently Tagged Substrates of Prostate-Specific Antigen before and after Enzymatic Activation.

A series of peptides based on the prostate-specific antigen (PSA)-specific sequence histidine-serine-serine-lysine-leucine-glutamine were functionalized with an anthraquinone fluorophore at the C-terminal residue side chain using the copper(I)-catalyzed azide-alkyne cycloaddition reaction. The effect of incorporating a negatively charged N-terminal tetra-glutamic acid group into the substrate and the effect of masking the negatively charged C-terminal carboxylic acid functionality of the substrate were investigated using confocal fluorescence microscopy in two cell lines, DLD-1 and LnCaP. The addition of a tetra-glutamic acid group to the N-terminus of the intact sequence was shown to reduce cellular uptake of the intact substrate prior to activation by PSA.

Targeted Inhibition of Snail Activity in Breast Cancer Cells by Using a Co(III) -Ebox Conjugate.

The transition from a non-invasive to an invasive phenotype is an essential step in tumor metastasis. The Snail family of transcription factors (TFs) is known to play a significant role in this transition. These TFs are zinc fingers that bind to the CAGGTG Ebox consensus sequence.

Cobalt derivatives as promising therapeutic agents.

Inorganic complexes are versatile platforms for the development of potent and selective pharmaceutical agents. Cobalt possesses a diverse array of properties that can be manipulated to yield promising drug candidates. Investigations into the mechanism of cobalt therapeutic agents can provide valuable insight into the physicochemical properties that can be harnessed for drug development.

Dual targeting of hypoxic and acidic tumor environments with a cobalt(III) chaperone complex.

The rational design of prodrugs for selective accumulation and activation in tumor microenvironments is one of the most promising strategies for minimizing the toxicity of anticancer drugs. Manipulation of the charge of the prodrug represents a potential mechanism to selectively deliver the prodrug to the acidic tumor microenvironment. Here we present delivery of a fluorescent coumarin using a cobalt(III) chaperone to target hypoxic regions, and charged ligands for pH selectivity.

Effects of enzymatic activation on the distribution of fluorescently tagged MMP-2 cleavable peptides in cancer cells and spheroids.

A peptide tagged at the N-terminus with FITC, at the C-terminus with coumarin-343, and incorporating a sequence selectively cleaved by the matrix metalloproteinase, MMP-2, was synthesized to investigate the effect of peptide cleavage on both cellular accumulation and distribution in cancer cell spheroids. The peptide was shown by HPLC and mass spectroscopy to be cleaved in the presence of MMP-2 at the expected site. The cellular and spheroid distribution of each of the fragments was monitored using confocal fluorescence microscopy.

Iron(III) complexes of fluorescent hydroxamate ligands: preparation, properties, and cellular processing.

Iron(III) complexes containing hydroxamic acid fluorophores were investigated as models of hypoxia selective prodrugs in vitro. Two complexes were synthesised, [Fe(c343haH)(3)] and [Fe(salen)(c343haH)]. The fluorescence of the hydroxamate coumarin fluorophore was almost completely quenched on coordination to the iron(III) centre in [Fe(c343haH)(3)].

Accumulation of an anthraquinone and its platinum complexes in cancer cell spheroids: the effect of charge on drug distribution in solid tumour models.

The penetration of anthraquinones and their platinum complexes into cancer cell spheroids reveals that they model well the distribution of such compounds in solid tumours and that the proportion of the compound that accumulates deep in the spheroid is inversely related to the rate of cellular uptake which is affected by the charge of the compound.

Cellular uptake and distribution of cobalt complexes of fluorescent ligands.

The development of complexes that allow the monitoring of the release and distribution of fluorescent models of anticancer drugs initially bound to cobalt(III) moieties is reported. Strong quenching of fluorescence upon ligation to cobalt(III) was observed for both the carboxylate- and the hydroximate-bound fluorophores as was the partial return of fluorescence following addition of ascorbate and cysteine. The extent of the increase in the fluorescence intensity observed following addition of these potential reductants is indicative of the fluorophore being displaced from the complex by the action of ascorbate or cysteine, by ligand exchange.

Bioreductive activation and drug chaperoning in cobalt pharmaceuticals.

The potential for cobalt(III) complexes in medicine, as chaperones of bioactive ligands, and to target tumours through bioreductive activation, has been examined over the past 20 years. Despite this, chemical properties such as reduction potential and carrier ligands required for optimal tumour targeting and drug delivery have not been optimised. Here we review the chemistry of cobalt(III) drug design, and recent developments in the understanding of the cellular fate of these drugs.

Studies of a cobalt(III) complex of the MMP inhibitor marimastat: a potential hypoxia-activated prodrug.

We report a potential means of selectively delivering matrix metalloproteinase (MMP) inhibitors to target tumour sites by use of a bioreductively activated Co(III) carrier system. The carrier, comprising a Co(III) complex of the tripodal ligand tris(methylpyridyl)amine (tpa), was investigated with the antimetastatic MMP inhibitor marimastat (mmstH(2)). The X-ray crystal structure of [Co(mmst)(tpa)]ClO(4) x 4H(2)O was determined and two-dimensional NMR revealed the existence of two isomeric forms of the complex in solution.