Abstract
Radiotherapy (RT) is a standard treatment strategy for many cancer types, but the need to frequently apply high doses of ionizing radiation in order to achieve therapeutic efficacy can cause severe harm to healthy tissues, leading to adverse patient outcomes. In an effort to minimize these toxic side effects, we herein sought to design a novel approach to the low-dose RT treatment of hypoxic tumors using a Tirapazamine (TPZ)-loaded exosome (EXO) nanoplatform (MT). This MT platform was synthesized via loading EXOs with TPZ, which is a prodrug that is activated when exposed to hypoxic conditions. MT application was able to achieve effective tumor inhibition at a relatively low RT dose (2 Gy) that was superior to standard high-dose (6 Gy) RT treatment with specific targeting to the hypoxic region of tumor. RT-mediated oxygen consumption further aggravated hypoxic conditions to improve TPZ activation and treatment efficacy. Together, our findings demonstrate the clinical promise of this MT platform as a novel tool for the efficient radiosensitization and treatment of cancer patients.
Highlights
As a leading cause of death throughout the world despite intensive research efforts, cancer represents a major public health threat (Begg et al, 2011; Munaweera et al, 2015; Jin et al, 2020; Yang et al, 2020)
While often a valuable treatment tool, RT is linked to many potentially severe side effects and its efficacy is often hampered by intratumoral hypoxia, with low levels of oxygen being sufficient to render tumor cells significantly more radioresistant (Huang et al, 2018; Zhou et al, 2018; Wang et al, 2021)
Hyperbaric oxygen therapy (HBO) has previously been studied as a potential approach to overcoming hypoxia within the tumor microenvironment (TME) in order to enhance the efficacy of RT (Lu et al, 2016; Zheng et al, 2016), but HBO can cause dangerous complications including barotrauma and hypoxic seizures, profoundly limiting its potential for routine clinical use (Zheng et al, 2016)
Summary
As a leading cause of death throughout the world despite intensive research efforts, cancer represents a major public health threat (Begg et al, 2011; Munaweera et al, 2015; Jin et al, 2020; Yang et al, 2020). Owing to their ability to readily penetrate tumors, we hypothesized that tumor cell-derived EXOs would be ideal tools for targeting hypoxic regions within tumors Developing such an EXO-based drug delivery platform would offer the potential to improve RT efficacy for the treatment of cancer patients. We were able to confirm the synergistic activity of our MT system in vitro and in vivo without any concomitant adverse events, and determined that MT was able to achieve superior therapeutic efficacy to high-dose RT (6 Gy) under lower doses of radiation (2 Gy), given that RT-mediated oxygen consumption drove the aggravation of intratumoral hypoxia and thereby promoted TPZ activation to achieve enhanced bio-reductive chemotherapy outcomes Together, these data highlight a novel approach to the simple and potent treatment of a variety of solid tumors
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