Abstract
.Significance: The necessity to use exogenous probes for optical oxygen measurements in radiotherapy poses challenges for clinical applications. Options for implantable probe biotechnology need to be improved to alleviate toxicity concerns in human use and facilitate translation to clinical trial use.Aim: To develop an implantable oxygen sensor containing a phosphorescent oxygen probe such that the overall administered dose of the probe would be below the Federal Drug Administration (FDA)-prescribed microdose level, and the sensor would provide local high-intensity signal for longitudinal measurements of tissue .Approach: PtG4, an oxygen quenched dendritic molecule, was mixed into an agarose matrix at concentration, allowing for local injection into tumors at the total dose of 10 nmol per animal, forming a gel at the site of injection. Cherenkov-excited luminescence imaging (CELI) was used to acquire the phosphorescence and provide intratumoral .Results: Although PtG4 does not form covalent bonds with agarose and gradually leaches out into the surrounding tissue, its retention time within the gel was sufficiently long to demonstrate the capability to measure intratumoral with the implantable gel sensors. The sensor’s performance was first evaluated in vitro in tissue simulation phantoms, and then the sensor was used to measure changes in oxygen in MDA-MB-231 tumors during hypofractionated radiotherapy.Conclusions: Our study demonstrates that implantable oxygen sensors in combination with CELI present a promising approach for quantifying oxygen changes during the course of radiation therapy and thus for evaluating the tumor response to radiation. By improving the design of the gel–probe composition in order to prevent leaching of the probe into the tissue, biosensors can be created that should allow longitudinal oxygen measurements in tumors by means of CELI while using FDA-compliant microdose levels of the probe and thus lowering toxicity concerns.
Highlights
The effects of tumor oxygenation on the outcome of radiotherapy have been under investigation for decades.[1,2] A multitude of studies have suggested that oxygen levels in tumors influence radiosensitivity of cells
Attempts have been made in numerous clinical trials to improve treatment outcomes by modifying oxygenation and/or the radiation dose delivered to tumors.[10,11,12]
We reported tumor pO2 measurements using Cherenkov-excited luminescence imaging (CELI) with a systemically delivered phosphorescent oxygen-sensitive probe PtG4.18–20 This technique makes use of the Cherenkov light generated within tissues subjected to radiation beams to excite the phosphorescence of PtG4, and the phosphorescence decay time of the probe is used to quantify tissue pO2
Summary
The effects of tumor oxygenation on the outcome of radiotherapy have been under investigation for decades.[1,2] A multitude of studies have suggested that oxygen levels in tumors influence radiosensitivity of cells. Cancer cells in low-oxygen (hypoxic) environments can tolerate radiation doses 2 to 3 times higher than cells under normoxia.[3,4] Oxygen enhances the radiobiologic damage through the action of oxygen-derived radical species, while hypoxia induces signaling cascades leading to adaptation and resistance.[5,6,7] Oxygenation of tumors can serve as a prognostic factor for survival after radiotherapy, as patients with hypoxic tumors commonly exhibit poorer outcomes.[8,9] Attempts have been made in numerous clinical trials to improve treatment outcomes by modifying oxygenation and/or the radiation dose delivered to tumors.[10,11,12] To do that in an informed way, it is necessary to accurately quantify tumor oxygen levels, ideally periodically throughout the fractionation schedule. An approach to measuring oxygen during radiation delivery using small implantable sensors is examined that could be more deployed in clinics to aid radiotherapy verification and planning
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