Proton boron capture therapy (PBCT) induces cell death and mitophagy in a heterotopic glioblastoma model

Abstract

Despite aggressive therapeutic regimens, glioblastoma (GBM) represents a deadly brain tumor with significant aggressiveness, radioresistance and chemoresistance, leading to dismal prognosis. Hypoxic microenvironment, which characterizes GBM, is associated with reduced therapeutic effectiveness. Moreover, current irradiation approaches are limited by uncertain tumor delineation and severe side effects that comprehensively lead to unsuccessful treatment and to a worsening of the quality of life of GBM patients. Proton beam offers the opportunity of reduced side effects and a depth-dose profile, which, unfortunately, are coupled with low relative biological effectiveness (RBE). The use of radiosensitizing agents, such as boron-containing molecules, enhances proton RBE and increases the effectiveness on proton beam-hit targets. We report a first preclinical evaluation of proton boron capture therapy (PBCT) in a preclinical model of GBM analyzed via μ-positron emission tomography/computed tomography (μPET-CT) assisted live imaging, finding a significant increased therapeutic effectiveness of PBCT versus proton coupled with an increased cell death and mitophagy. Our work supports PBCT and radiosensitizing agents as a scalable strategy to treat GBM exploiting ballistic advances of proton beam and increasing therapeutic effectiveness and quality of life in GBM patients.

Microglia and glioblastoma heterocellular interplay sustains tumour growth and proliferation as an off‐target effect of radiotherapy

“… 29 Mitochondria‐related morphology, metabolism, respiration and ROS production are largely involved in RT‐mediated alterations. 30 Therefore, we assume that microglia prevent and protect directly RT‐mediated effects, as bystander mechanisms promoted by RT on tumour mass. This assumption correlates with evidence that RT mediates direct effects on GBM cells, and also off‐target bystander effects, modifying both TME cell composition and tumour.…”

A ternary model of proton therapy based on boron medium radiosensitization and enhancement paths: a Monte Carlo simulation

“…Although there is a current dispute regarding the theoretical and experimental outcomes, the notion of utilizing boron-based nuclear reactions to improve proton therapy has sparked numerous subsequent investigations ( 5 , 6 , 14 - 17 ). However, further exploration is necessary to resolve the controversy surrounding its physical feasibility and practical biological implications.…”

A novel boron-conjugated SRC inhibitor for Proton Boron Capture Therapy in glioblastoma treatment

“…Previously, the relative biological efficacy increase by applying a proton beam to tumor cells exposed with sodium borocaptate (BSH) has been investigated in vitro [1]. The encouraging results stimulated further preclinical investigations to evaluate the benefits of Proton Boron Capture Therapy (PBCT) approach in a glioblastoma (GBM) mouse model [2]. The results of the study demonstrated that the synergistic treatment with protons and BoronoPhenylAlanine (BPA) leads to a lower metabolic activity and increased tumor cell death [2].…”

“…The encouraging results stimulated further preclinical investigations to evaluate the benefits of Proton Boron Capture Therapy (PBCT) approach in a glioblastoma (GBM) mouse model [2]. The results of the study demonstrated that the synergistic treatment with protons and BoronoPhenylAlanine (BPA) leads to a lower metabolic activity and increased tumor cell death [2]. Nonetheless, one of the primary drawbacks of the PBCT strategy is an effective delivery of boron atoms into tumor cells, particularly regarding brain tumors.…”