Dual Targeting of Hypoxic and Acidic Tumor Environments with a Cobalt(III) Chaperone Complex

Abstract

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. Protonation or deprotonation of the complexes over a physiologically relevant pH range resulted in pH dependent accumulation of the fluorophore in colon cancer cells. Furthermore, in a spheroid solid tumor model, the anionic complexes exhibited preferential release of the fluorophore in the acidic/hypoxic region. By fine-tuning the physicochemical properties of the cobalt-chaperone moiety, we have demonstrated selective drug release in the acidic and hypoxic tumor microenvironment.

Comparison Between Polypyridyl and Cyclometalated Ruthenium(II) Complexes: Anticancer Activities Against 2D and 3D Cancer Models

“…Moreover, MCTSs can mimic therapeutic problems associated with the metabolic and proliferative gradients found in solid tumors, such as the altered responsiveness of chronically hypoxic tumor cells, as well as multidrug resistance to apoptosis-inducing agents. [43,44] In this respect, MCTSs serve as a useful tool for negative anticancer drug selection and reduce the need for animal testing. Several methods have been designed to generate tumor spheroids, among which agarose-coated liquid-overlay 96-well plate culture provides an easy-to-handle protocol for generating single MCTSs.…”

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

“…Octahedral cobalt(III) complexes containing cytotoxic ligands can be utilized for this purpose, as the oxidized form is inert, but upon one-electron reduction to the labile Co(II) form, the coordinated cytotoxic ligands can be released [35][36][37]. A number of Co(III) complexes containing tetradentate nitrogen ligands such as cyclam (1,4,8,11-tetraazacyclotetradecane), cyclen (1,4,7,10-tetraazacyclododecane), and TPA (tris(2-pyridylmethyl)amine), have been used to deliver therapeutic and imaging agents to hypoxic tumor microenvironments [38][39][40][41][42]. The reduction potential of these complexes range from 0 to −1400 mV (vs normal hydrogen electrode, NHE), therefore, in theory they can be fine-tuned by ligand modification to coincide with the CSC microenvironment.…”

Prodrug Applications for Targeted Cancer Therapy

“…Reduction by intracellular thiols rapidly generates cisplatin. A reversed role for the metal center is found in cobalt(III) coordination complexes which act as prodrug "chaperones" by releasing their therapeutic ligands upon reduction to cobalt(II) (32). Targeting can be additionally refined by manipulating the net charge on a prodrug, to take advantage of the relatively acidic (0.5 to 1 pH unit lower than physiologic) of the tumor microenvironment.…”