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Tumor Discovery Mg-28-A theoretical novel strategy in cancer therapy

systemic side effects, and the persistent issue of tumor Mg levels far exceeding those of healthy tissues. Following
relapses due to incomplete eradication of cancer cells. 2 intravenous administration, Mg-28 is hypothesized
The advent of targeted therapies, including nanoparticle to selectively accumulate within these tumor cells,
2+
delivery systems, monoclonal antibodies, peptides, competitively replacing stable Mg in crucial enzymes.
5
4
3
clustered regularly interspaced short palindromic-Cas9, The subsequent decay of Mg-28 emits beta particles, Auger
6
and chimeric antigen receptor-T cells, has improved electrons, and recoil ions that directly target intracellular
7
the precision of cancer cell targeting. However, these structures, such as the nucleus and mitochondria. This
approaches predominantly focus on extracellular dual mechanism aims to overcome therapeutic resistance,
targets and often require complex delivery mechanisms. minimize off-target effects, and enable self-theranostic
A critical gap persists in our ability to effectively target key applications by integrating both therapy and diagnostics
intracellular processes, particularly the enzymes essential within a single agent.
for cancer cell metabolism and replication. The overarching objective of this work is to
While radioisotopes, such as iodine-131, phosphorus-32, comprehensively analyze the Mg-28 approach and
lutetium-177, holmium-166, and yttrium-90 have advanced demonstrate its feasibility as a groundbreaking strategy
the field of extracorporeal radiotherapy, including that combines the precision of targeted intracellular
techniques, such as brachytherapy, these methods chemotherapy with radiotherapy, while minimizing
2,8
typically rely on carriers to deliver isotopes to the vicinity damage to healthy tissues and enabling early diagnosis and
of tumors and primarily exert their effects extracellularly. dynamic monitoring of therapeutic progress. This research
As a result, their impact on the intracellular machinery seeks to unlock the transformative potential of Mg-28 as
a next-generation theranostic platform in the ongoing
9
of cancer cells remains limited. For instance, although fight against cancer. In fact, this approach may serve as a
iodine-131 is effective in treating thyroid cancer, its use foundation for pre-clinical and clinical evaluation in the
carries the risk of inducing secondary malignancies. 10
future.
A fundamental challenge in current cancer treatment is
the failure to comprehensively disrupt the core processes 2. Methodology
that drive cancer progression, namely, uncontrolled This theoretical study evaluates the feasibility of Mg-28 as a
proliferation, limitless replicative potential (immortality), precision cancer therapy through a comprehensive analysis
invasion, metastasis, and the sustained energy supply encompassing five key aspects: (1) The fundamental
required to support these processes. Intriguingly, all these principles of metalloenzyme inactivation; (2) the
critical functions are heavily reliant on magnesium ions mechanism of Mg-dependent multienzyme disruption
(Mg ), which serve as an essential cofactor for numerous due to changes in cofactor valence and ionic radius; (3) the
2+
Mg-dependent enzymes. Tumor cells characterized by calculation of linear energy transfer (LET) and the range of
11
rapid proliferation and heightened metabolic demands, emitted radiation particles, including recoil effects; (4) the
exhibit a significantly elevated requirement for Mg quantification of absorbed dose in tumors of varying
2+
compared to normal cells. This metabolic vulnerability volumes and the assessment of systemic dose; and (5) the
presents a unique and underexplored therapeutic tumor-specific uptake of Mg ions driven by the metabolic
opportunity. demands of cancer cells. This approach builds upon the
Historically, magnesium-28 (Mg-28) has been utilized basic principles of metalloenzyme inactivation detailed in
as a valuable tracer in metabolic studies, particularly in our previous publications. 15,16
plant biology and in investigations into the pathophysiology
of diabetes. 12-14 However, it’s potential as a therapeutic 2.1. Principles of metalloenzyme inactivation
agent for cancer remains largely unexplored. This study The strategy is based on the substitution of stable metal ion
introduces Mg-28 as a dual-action agent that combines cofactors in metalloenzymes with suitable radioisotopes
targeted intracellular irradiation with the direct inactivation to induce enzyme inactivation. Ideal radioisotopes for this
of Mg-dependent enzymes. A potential concern regarding purpose should emit beta particles or Auger electrons and
2+
the use of Mg-28 stems from the fact that Mg is a cofactor possess a half-life (T₁/₂) that is neither excessively long (to
for over 300 enzymes, raising questions about potential minimize prolonged radiation exposure) nor too short (to
off-target effects in vital organs, such as the lungs, liver, allow for clinical utility). Furthermore, their decay products
and brain. However, this research demonstrates the should be isotopes of elements that do not function as
contrary: Mg-28 exhibits a strong propensity to selectively cofactors at the enzyme’s active site. Mg-28 (T₁/₂ ≈ 21 h)
concentrate on malignant tumors—the very sites where meets these criteria for targeting Mg-dependent enzymes,
cell survival, proliferation, invasion, and metastasis require decaying into Aluminum-28 (Al-28) and subsequently

Volume 4 Issue 3 (2025) 71 doi: 10.36922/TD025070010