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

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 required for a two-fold increase in radiation dose would be 300 times for 6MV photons as compared to I-125. It has been estimated with modeling studies that for Iridium-192, a 10% dose enhancement is achievable with a gold concentration of 7 mg Au/gm in tumors. Hence, the integration of nanoparticles with radiotherapy occurs best with brachytherapy rather than EBRT.[3] Light excitation of inorganic NPs like ZNO, TiO2, or Si also leads to Cherenkov radiation culminating into the production of electron/hole pairs generating reactive oxygen species (ROS). It has been found in the preclinical studies that the generation of ROS in the presence of AuNPs is approximately 3–4 times that without the presence of NPs.[4] Nano-BT also disrupts cell cycle resulting in the accumulation of cells in radiosensitive G2/M phase, thus producing a radiosensitization/radio-enhancement effect. It interferes with DNA repair, and the bystander effect extends the effect of radiation to non-irradiated cells. Delivery and uptake of nano-brachytherapy in the tissues Two mechanisms have been proposed for the preferential localization of NPs inside the tumor tissues. Passive targeting is based on the pretext of enhanced permeability and retention effect (EPR); the leaky vasculature of the tumor tissues allows the relatively large-sized NPs to get through in the tumor tissues preferentially as compared to the normal tissues, and these are retained inside because of the impaired and disrupted lymphatic drainage. Active targeting mechanism utilizes conjugation of biomolecules (monoclonal antibodies or peptides) to NPs to specifically bind tumor-associated receptors or other cell surface proteins.[4] Intravenously administered NPs lead to the loss of a significant proportion owing to uptake by the mononuclear phagocytic system, renal filtration, and blood protein interaction. Hence, a higher local concentration can only be achieved by intratumoral administration of the NPs through various methods. Intratumoral delivery may also pose challenges with leakage of the NPs outside from the local tumor milieu and heterogeneous distribution of the NPs. Depot systems for the controlled release of AuNPs with precise intratumoral placement using interstitial methods have been devised and described.[5] Pre-clinical studies: Nano-brachytherapy A plethora of pre-clinical studies have been done focusing on the utilization of nano-brachytherapy. Chattopadhyay et al.[6] designed a pegylated AuNPs with trastuzumab and demonstrated enhanced radiosensitivity with radiation in breast cancer cell lines. Yook et al.[7] reported the application of Lu-177 labeled AuNPs coated with panitumumab (anti-epidermal growth factor receptor antibody) injected intratumorally in the locally advanced breast cancers of CD-1 athymic mice and found this to be highly effective in regression of the tumor potentially implicating the role of such treatments in neo-adjuvant setting. Recently, Salvanou et al.[8] demonstrated the durable therapeutic efficacy of Lu-177 labeled iron oxide NPs functionalized with doxorubicin and bevacizumab in a triple-negative breast cancer cell line. Several other pre-clinical studies in prostate cancer and osteosarcoma cell lines have been found to be effective and have been summarized nicely by Seniwal et al.[2] Clinical studies: Nano-brachytherapy Dr R.H. Flocks from the University of Iowa, USA, initially pioneered the technique of interstitial radiation with radioactive gold in the management of carcinoma prostate in the 1950s. Colloidal Au-198 was prepared with saline and hyaluronidase and injected into the interstitium of prostate using a pressure injector in the operating room.[9] Growing on the experience of initial 100 patients, Dr Flocks went on to treat 1515 men with colloidal gold over a period of 25 years and the local recurrence rates observed in his series were less as compared to contemporary treatment of prostate cancer in the same era (17% vs 28-34%) with a rectal complication rate ranging from 10 to 20%.[10] The closest encounter of nano-brachytherapy in a human prostate cancer was reported in a case who was destined to receive transperineal focal therapy after intravenous administration of AuroShell particles. However, since the planned treatment could not be delivered due to unforeseen equipment limitations, the patient went on to receive low-dose rate salvage brachytherapy with Pd-103 seeds (125 Gray to the periphery of the prostate gland). The authors reported no increased toxicity with this concurrent administration with preserved health-related quality of life indices at a follow-up of 1 year.[11] Rastinehad et al.[12] from Mount Sinai, New York, USA, reported on the clinical data of 16 patients of prostate cancers treated with laser excitation of intravenously delivered gold silica nano-shells with a 94% ablation rate and no clinically significant adverse effects. An ongoing clinical trial is evaluating the safety and efficacy of rhenium nanoliposomes in recurrent glioma patients.[13] Challenges of nano-brachytherapy Despite a significant development, there are several challenges which precludes routine clinical use of Nano-BT. The first and foremost challenge is in the design and construction of the NPs including its stability, effectiveness, and biological activity. Delivery methods (intravenous versus intratumoral), calculation of appropriate/adequate dose and concentration of NPs to be infused/injected, timing of sequencing with radiation (concurrent or with some gap), and toxicity concerns (immunological and physiological) are among the other limitations which need to be overcome. Lastly, several regulatory guidelines like radiochemical purity, radionuclide purity, stability of NPs against loss in body tissues, dosimetric parameters, etc., need to be met before use in human patients under clinical trial setting. Nano-BT application is also met with stiff competition from other focal therapies which have evolved over the last few decades like MR-guided laser interstitial thermotherapy, vascular photodynamic therapy, high-intensity focused ultrasound therapy, nano-knife/irreversible electroporation, cryotherapy, thermal ablation, RFA, etc. SUMMARY AND CONCLUSION In summary, great strides have been achieved in the design and construction of NPs leading to the realization of the use of Nano-BT. Nano-BT has unique mechanisms of action which have proven to be often synergistic or supra-additive to radiation therapy. Integration of NPs with brachytherapy is more effective as compared to EBRT. Intratumoral delivery of NPs has edge over intravenous delivery and may be more efficacious and safe. There is huge untapped potential for multi-functional tumor killing and minimal side effects with Nano-BT. Human clinical trials are earnestly needed and the days when nano-robots [Figure 1] would usher in a new era of cancer treatment may not be far away.Figure 1: Artificial intellegence generated image of futuristic nano-robotic brachytherapy (Source: https://www.microsoft.com/en-us/ai)