Abstract
The rationale for application of nanotechnology in targeted alpha therapy (TAT) is sound. However, the translational strategy requires attention. Formulation of TAT in nanoparticulate drug delivery systems has the potential to resolve many of the issues currently experienced. As α-particle emitters are more cytotoxic compared to beta-minus-emitting agents, the results of poor biodistribution are more dangerous. Formulation in nanotechnology is also suggested to be the ideal solution for containing the recoil daughters emitted by actinium-225, radium-223, and thorium-227. Nanoparticle-based TAT is likely to increase stability, enhance radiation dosimetry profiles, and increase therapeutic efficacy. Unfortunately, nanoparticles have their own unique barriers towards clinical translation. A major obstacle is accumulation in critical organs such as the spleen, liver, and lungs. Furthermore, inflammation, necrosis, reactive oxidative species, and apoptosis are key mechanisms through which nanoparticle-mediated toxicity takes place. It is important at this stage of the technology’s readiness level that focus is shifted to clinical translation. The relative scarcity of α-particle emitters also contributes to slow-moving research in the field of TAT nanotechnology. This review describes approaches and solutions which may overcome obstacles impeding nanoparticle-based TAT and enhance clinical translation. In addition, an in-depth discussion of relevant issues and a view on technical and regulatory barriers are presented.
Highlights
Whilst a considerable number of published preclinical evaluations demonstrate the positive influence of the formulation of α-particle emitters in connection with nanoparticles, their successful clinical translation is lacking
This review describes strategies which may be employed to diminish impediments to nanoparticle-based targeted alpha therapy (TAT) and thereby enhance clinical translation
Certain α-generators are referred to as in vivo atomic nanogenerators [4] in their own right, this review focuses on the application of nanotechnology on α-particle emitters and not in vivo atomic nanogenerators
Summary
Whilst a considerable number of published preclinical evaluations demonstrate the positive influence of the formulation of α-particle emitters in connection with nanoparticles, their successful clinical translation is lacking. Most of the early research on therapeutic radiopharmaceuticals was aimed at β-minus particle-emitting radionuclides, and some was successfully translated into the clinic. The physical limitation of β-particle-emitting radiopharmaceuticals is their long energy emission range, that can often lead to damage or death in healthy cells within the vicinity of the targeted pathologic tissue. These types of therapies are less appropriate for smaller (micro-metastatic) cancerous foci. The main α-particle-emitting radionuclides used for TAT are radium-223, radium224, astatine-211, actinium-225, lead-212, thorium-227, thorium-227, bismuth-212, and bismuth-213 Their main nuclear properties have been summarized in several reviews by Majokwska-Pilip et al [1] and Farzin et al [2]. Certain α-generators are referred to as in vivo atomic nanogenerators [4] in their own right (actinium-225, thorium-227, and radium-223), this review focuses on the application of nanotechnology on α-particle emitters and not in vivo atomic nanogenerators
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