Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study

Abstract

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic) of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [64Cu]CuCl2. To evaluate the potential theranostic role of [64Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [64Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.

Biodistribution and radiation dosimetry of [64Cu]copper dichloride: first-in-human study in healthy volunteers

“…Preclinical studies using [ 64 Cu]CuCl 2 as a theranostic agent in selected human cancer xenograft models in mice, such as glioblastoma multiforme (U-87MG) and malignant melanoma (B16F10, A375M), demonstrated its potential as a therapeutic agent [5, 6]. A case report study of Valentini et al evaluated the potential of [ 64 Cu]CuCl 2 as a therapeutic agent in two patients with metastatic prostate and uterine cancer, respectively [7].…”

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

“…For its elusive response to standard treatments, the development of novel therapeutic approaches for GBM remains indeed a pivotal step in the modern oncologic research. Protocols based on radionuclide therapy appear to be particularly promising for the GBM treatment [2,[4][5][6][7]. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the cytoplasmic and nuclear fraction compared to normal cells.…”

“…Several positron-emitting radionuclides with a high atomic number and/ or a long half-life have been proposed both for imaging and therapeutic approach. Among these, Cu radioisotopes seem to be significantly interesting [1,4,11,12]. Cu radioisotopes, as a group, comprise radioisotopes which, due to their emission properties, may be applied both for diagnostic studies ( Cu) [13].…”

Calculations of dose point kernels of 64Cu in different media with PENELOPE Monte Carlo code

“…In addition, its particulate emissions coupled with an intermediate physical half‐life of 12.7 h also makes 64 Cu a potential agent for internal radionuclide therapy. In its chemical form, copper dichloride: [ 64 Cu] CuCl 2 has demonstrated potentials for imaging and treating glioblastoma and malignant melanoma in preclinical studies, based on its affinity toward human copper transporters . Preliminary human studies have also been performed with positive outcomes, as measured by tumor volume reduction, for treating prostate cancer and uterine cancer in two patients using 3,700 MBq of [ 64 Cu] CuCl 2 .…”

“…In its chemical form, copper dichloride: [ 64 Cu] CuCl 2 has demonstrated potentials for imaging and treating glioblastoma and malignant melanoma in preclinical studies, based on its affinity toward human copper transporters. 2,3 Preliminary human studies have also been performed with positive outcomes, as measured by tumor volume reduction, for treating prostate cancer and uterine cancer in two patients using 3,700 MBq of [ 64 Cu] CuCl 2 . 4 64 Cu can also be labeled with chelators which can be linked to monoclonal antibodies, proteins, peptides, and nanoparticles to image and treat a variety of clinical conditions and diseases.…”