Focused Ultrasound and Ultrasound Stimulated Microbubbles in Radiotherapy Enhancement for Cancer Treatment

Abstract

Radiation therapy (RT) has been the standard of care for treating a multitude of cancer types. However, ionizing radiation has adverse short and long-term side effects which have resulted in treatment complications for decades. Thus, advances in enhancing the effects of RT have been the primary focus of research in radiation oncology. To avoid the usage of high radiation doses, treatment modalities such as high-intensity focused ultrasound can be implemented to reduce the radiation doses required to destroy cancer cells. In the past few years, the use of focused ultrasound (FUS) has demonstrated immense success in a number of applications as it capitalizes on spatial specificity. It allows ultrasound energy to be delivered to a targeted focal area without harming the surrounding tissue. FUS combined with RT has specifically demonstrated experimental evidence in its application resulting in enhanced cell death and tumor cure. Ultrasound-stimulated microbubbles have recently proved to be a novel way of enhancing RT as a radioenhancing agent on its own, or as a delivery vector for radiosensitizing agents such as oxygen. In this mini-review article, we discuss the bio-effects of FUS and RT in various preclinical models and highlight the applicability of this combined therapy in clinical settings.

Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial

“…Furthermore, Webb and colleagues [ 26 ] observed an objective response rate of 87% (10% complete and 77% partial responses), but a lower 2-year LC rate of 44% following treatment with 30 to 36 Gy in 5 to 6 fractions. Taken together, our results align with the radioenhancement potential of MRgFUS-MB, as supported by extensive preclinical studies [ 8 – 14 , 20 ].…”

“…Our research addresses a critical unmet need-the development of radiosensitizers capable of selectively enhancing radiation efficacy without increasing toxicity, thereby improving the therapeutic ratio. Our treatment approach is based on mechanical perturbation of the endothelial cells lining the tumour vasculature, which was shown in preclinical data to up-regulate proapoptotic pathways, ultimately enhancing tumour cell death [8][9][10][11][12][13][14]20]. To our knowledge, this…”

“…Furthermore, other recent extensive studies have revealed that the disruption of endothelial cells activates specific pro-apoptotic pathways, such as the acid sphingomyelinase (ASMase)ceramide pathway, which are typically activated by ablative radiation doses (>8-10 Gy per fraction) [8,10]. Preclinical studies have demonstrated a synergistic interaction between radiation and ultrasound-stimulated microbubbles, resulting in a 10-to 40-fold increase in tumour cell death when these treatments are combined [8][9][10][11][12][13][14]20]. The rationale is that when a microbubble-sensitised tumour is subsequently treated with radiation, there is increased apoptosis of endothelial cells, a consequent reduced microvascular density, and enhanced anoxic tumour cell death.…”

“…Based on promising outcomes observed in preclinical studies [12][13][14]20,21], we conducted the first Phase I clinical trial to evaluate the safety and effectiveness of utilising magnetic resonance (MR)-guided focussed ultrasound-stimulated microbubble (MRgFUS-MB) treatment for breast cancer patients with in situ tumours. We previously published preliminary data on the first 8 treated patients [22] and now report the mature outcomes of this innovative radioenhancement therapy.…”

Engineering tumor-oxygenated nanomaterials: advancing photodynamic therapy for cancer treatment

“…Another strategy for tumor vasculature normalization involves the use of physical interventions, such as radiation therapy or focused ultrasound ( Chen K. T. et al, 2023 ; Leong et al, 2023 ). These techniques can selectively damage the abnormal blood vessels, leading to their regression and subsequent normalization.…”