Synthesis, characterization, and relaxation studies of Gd‐DO3A conjugate of chlorambucil as a potential theranostic agent

Abstract

DO3A‐based macrocycles serve as attractive templates from which clinically useful theranostic agents can be obtained after coupling with molecular targeted therapeutic drugs. In this study, we describe the chemical synthesis, relaxation, and cytotoxicity studies of a new DO3A conjugate of chlorambucil (CHL) as a magnetic resonance imaging (MRI) theranostic agent. A convenient route of synthesis is reported, which allowed conjugation of the macrocyclic ligand (DO3A) to the chemotherapeutic drug (CHL) via tyrosine for the preparation of an attractive chelate‐drug ensemble (DO3A‐TR‐CHL). The structures of all intermediates and final compound have been determined by 1H, 13C NMR, and MS. The efficacy of DO3A‐TR‐CHL as a non‐ionic magnetic contrast agent was tested by performing relaxometric studies on its gadolinium complex. The complex exhibited relaxivities (7.11 mm−1/s) higher than that of currently used MR contrast agents and showed enhanced contrast in T1‐weighted images. MTT assays revealed that both DO3A‐TR‐CHL and Gd(III)‐DO3A‐TR‐CHL conjugates exhibited dose‐dependent toxicity and an enhanced antiproliferative activity against tumor (A549 and HeLa) cell lines compared to that of parent drug (CHL), thereby demonstrating their potential to be used as a magnetic resonance imaging theranostic for improved molecular imaging and therapy of human cancers.

Synthesis, Luminescence and Relaxometric Properties of Macrocyclic Lanthanide Complexes Appended with an Imidazothiadiazole, a Heterocyclic Bioactive Scaffold

“…Only few examples of Gd 3 + -complexes appended with a drug have been described in the literature. GdDOTA monoamide complexes have been covalently linked to anticancer drugs such as colchicine, [11] chlorambucil, [12] benzothiazole, [13] camptothecin, [14] or anti-inflammatory conjugates. [15] Despite the fact that many drugs have a heterocyclic scaffold, very few examples have been described and none of them focus on the potential beneficial properties of the heterocyclic scaffold for diagnosis.…”

Fluorinated MRI Contrast Agents and Their Versatile Applications in the Biomedical Field

“…Most of the clinically available MRI CAs are based on gadolinium ion (Gd 3+ ) because of its paramagnetic properties provided by its seven unpaired electrons, its long electronic relaxation time (around 10 -9 s) and its large magnetic moment (7,9 BM) [23], [26]- [28]. Nevertheless, Gd 3+ has a high toxicity for the tissues in its free state.…”

Macrocycles, the edge of drug‐likeness chemical space or Goldilocks zone?

“…This series completes with two original articles, and in the first, Kaur [ ] and co‐workers outline the synthesis of a DO3A‐based macrocycle 14 for MRI imaging and potential theranostic use (Figure ). The compound demonstrated high relaxivity 7.1 m m −1 s −1 superior to some standard agents.…”