Development of a Potential Gallium-68-Labelled Radiotracer Based on DOTA-Curcumin for Colon-Rectal Carcinoma: From Synthesis to In Vivo Studies

Abstract

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative (68Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. 68Ga-DOTA-C21 exhibits decent stability (57 ± 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 ± 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of 68Ga-DOTA-C21 is 3.57 ± 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 ± 0.2. High amount of activity (12.73 ± 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 ± 3.3% ID/g), lungs (8.42 ± 0.8% ID/g), liver (5.81 ± 0.5% ID/g) and heart (4.70 ± 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, 68Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer.

Metal–Curcumin Complexes in Therapeutics: An Approach to Enhance Pharmacological Effects of Curcumin

“…It was found that the Mn 2+ -curcumin complex is stable in physiological buffers and media, as opposed to curcumin, even under reducing conditions [32]. The gallium complexed curcumin increases the stability, cellular uptake, and bioavailability of curcumin in both in vitro and in vivo cancer models [110]. In a study, a gallium-curcumin complex and gallium-diacetylcurcumin showed a higher uptake by colorectal carcinoma (HT29) and lymphoma (K562) cell lines than in lymphocytes [111].…”

Applications of Radiolabelled Curcumin and Its Derivatives in Medicinal Chemistry

“…Based on these findings, a new series of compounds in which gallium-68 was stably coordinated by several bifunctional chelators (namely, DOTA, NODAGA and AAZTA) tethered to a curcumin-based molecular vector was developed [ 51 , 73 ]. Synthesis of these derivatives generally entailed a first step in which the curcuminoid was functionalised with a protected spacer able to bind the chelator upon cleavage of the protecting group.…”

“… In vivo PET images at 65 min of [ 18 F]FEE-PCur ( A ) and [ 18 F]FEEM-PCur ( B ) in C6 glioma-bearing mice, and at 60 min of [ 68 Ga]Ga-DOTA-C21 in a HT29 colorectal tumour-bearing mouse ( C ). Figure has been obtained by merging and elaborating images from references [ 50 , 51 ]. Reprinted with permission from [ 50 , 51 ].…”

“…Figure has been obtained by merging and elaborating images from references [ 50 , 51 ]. Reprinted with permission from [ 50 , 51 ]. Copyright 2011 RSC Publishing.…”

The Pharmaceutical Technology Approach on Imaging Innovations from Italian Research

“…Exploiting the promising tumor-targeting ability of curcumin and its derivatives, Orteca and her group synthesized a new 68 Ga-labeled curcumin derivative for PET imaging of colorectal cancer [31]. Indeed, in previous studies [115,116], the authors synthesized and characterized 68 Ga-labeled complexes with curcumin, diacetyl-curcumin, and bis(dehydroxy)curcumin, but these compounds underwent rapid degradation in whole human blood.…”