Cancer Brachytherapy at the Nanoscale: An Emerging Paradigm

Brachytherapy is an established treatment modality that has been globally utilized for the therapy of malignant solid tumors. However, classic therapeutic sealed sources used in brachytherapy must be surgically implanted directly into the tumor site and removed after the requisite period of treatment. In order to avoid the trauma involved in the surgical procedures and prevent undesirable radioactive distribution at the cancerous site, well-dispersed radiolabeled nanomaterials are now being explored for brachytherapy applications. This emerging field has been coined "nanoscale brachytherapy". Despite present-day advancements, an ongoing challenge is obtaining an advanced, functional nanomaterial that concurrently incorporates features of high radiolabeling yield, short labeling time, good radiolabeling stability, and long tumor retention time without leakage of radioactivity to the nontargeted organs. Further, attachment of suitable targeting ligands to the nanoplatforms would widen the nanoscale brachytherapy approach to tumors expressing various phenotypes. Molecular imaging using radiolabeled nanoplatforms enables noninvasive visualization of cellular functions and biological processes in vivo. In vivo imaging also aids in visualizing the localization and retention of the radiolabeled nanoplatforms at the tumor site for the requisite time period to render safe and effective therapy. Herein, we review the advancements over the last several years in the synthesis and use of functionalized radiolabeled nanoplatforms as a noninvasive substitute to standard brachytherapy sources. The limitations of present-day brachytherapy sealed sources are analyzed, while highlighting the advantages of using radiolabeled nanoparticles (NPs) for this purpose. The recent progress in the development of different radiolabeling methods, delivery techniques and nanoparticle internalization mechanisms are discussed. The preclinical studies performed to date are summarized with an emphasis on the current challenges toward the future translation of nanoscale brachytherapy in routine clinical practices.