Unlocking the “Golden” potential of brachytherapy at the nanoscale: Is the era of nano-brachytherapy near?

Abstract

Radiotherapy is an integral component of the multimodality treatment approach in cancers and approximately 50–60% of patients need radiation therapy at any point of their cancer treatment trajectory. The holy grail has always been to maximize cure and limit acute and late toxicities preserving the quality of life of patients at the same time, essentially widening the gap between tumor control probability and normal tissue complication probability. The past few decades have witnessed tremendous advancements in the delivery of external beam radiotherapy (EBRT), although the conformality achieved by brachytherapy has yet not been surpassed and it has been emphasized time and again that brachytherapy is superior to EBRT in several clinical scenarios and it is not interchangeable.[1] Brachytherapy in modern parlance essentially entails the delivery of high-dose rate radiation in several forms like intracavitary, interstitial, surface mold, etc. In the majority of these advanced and complex cases, large diameter needle needs to be placed in the interstitium of the tissues and is invasive requiring expertise and skills. Another form of more conformal brachytherapy is low-dose rate seed brachytherapy; however, issues like seed migration, availability of sources, issues with dosimetry, etc., impede widespread application to several clinical sites. Radionuclide therapy (wherein the radionuclide is delivered to the tumor with specific targeting) has been currently applied to limited and specific indications like Samarium-153 for bone metastasis, I-131 tositumomab, and Y-90 Ibritumomab tiuxetan for non-Hodgkin lymphoma, etc. Brachytherapy innovations in the conventionally delivered treatment have thus reached saturation, and there is an earnest need for a novel form of brachytherapy that has enhanced conformality, and versatility to act as carriers for other cytotoxic payloads and pave the way for a new era of treatment. There has been a consistent effort towards the development of nano-brachytherapy (Nano-BT), and significant strides have been made in the last couple of years. We intend to briefly introduce “Nano-brachytherapy” in this editorial. Definition and construction of the nano-brachytherapy A “nanomaterial” is defined as a natural, incidental, or manufactured material with one or more external dimensions in the size range of 1 nm to 100 nm. The advantage of a nanomaterial because of a large surface area is that it can be functionalized with not only radionuclides but also additional chemotherapeutic agents and/or imaging molecules and can have active multivalent binding of targeting moieties to the cancer-specific receptors. Several of the terminologies, nano-brachytherapy, nanoscale brachytherapy, and radiation nanomedicine, have been used to refer to the nanoparticles (NPs) designed for the delivery of brachytherapy. A typical toolbox for the construct of Nano-BT is 1) NPs like gold NPs, iron oxide NPs, carbon nanotubes, and polymeric NPs. 2) NPs coating agents like polyethylene glycol to minimize uptake by the lympho-reticular system. 3) Chelators or metal chelating polymers to complex radiometals. 4) Radiometal emitting beta particles (Lu-177, Au-198, Re-186, etc.) or alpha particles (Ac-225, Pb-212, etc.) or auger electrons (I-125, Pd-103, etc.). 5) Incorporation of other agents like cytotoxic chemotherapy, antibodies, peptide ligands, and imaging agents.[2] Mechanism of action of nano-brachytherapy In addition to the traditional mechanism of indirect cell killing by generation of ROS from the secondary electrons, Nano-BT may exhibit additional cell killing by another mechanism of action. Dose partitioning effect leads to increased fractional dose deposition close to NPs due to high Z material of the NPs as compared to low Z material of the body tissues. Strongest absorption of X-ray energy for gold nanoparticles (AuNPs) occurs in the range of 2–80 Kev. Monte Carlo simulation suggested that the concentration of gold require