Abstract
Near-infrared photoimmunotherapy (NIR-PIT), a promising cancer therapy utilizing an antibody-photoabsorber conjugate (APC) and NIR light, which induces rapid necrotic cell death only in APC-bound cells. Effective NIR-PIT in mouse models has been achieved using superficial light illumination (SLI) with light emitting diodes (LEDs) or lasers, but in the clinical setting, fiber optic diffusers have been employed to deliver light to deeper tumors. However, the performance of NIR light in tissue delivered by fiber optic diffusers is poorly understood. Here, we investigated NIR-PIT using a cylindrical fiber optic diffuser in a mouse model of A431 tumors. NIR-PIT with 100 J/cm, the same light dose used in clinical trials of NIR-PIT, was applied after insertion of the diffuser within the tumor bed, and then both bioluminescence and fluorescence imaging were analyzed to assess the therapeutic efficacy. The diffuser can deliver adequate NIR light dose for effective NIR-PIT to the A431 tumor at a distance of approximately 1 cm around the light source at 100 J/cm. At 50 J/cm NIR light effective NIR-PIT was reduced to a distance of 5 – 7 mm diameter around the light source. These results indicate that the energy of interstitial light (measured in Joules/cm) administered via a fiber diffuser determines the depth of effective NIR-PIT around the diffuser and determines the spacing at which such diffusers should be placed to entirely cover the tumor. Thermal measurements demonstrate that interstitial light for NIR-PIT does not cause damage to the skin overlying the diffuser.
Highlights
Near-infrared photoimmunotherapy (NIR-PIT) is a promising new cancer therapy, which utilizes a monoclonal antibody-photoabsorber conjugate (APC)
near infrared (NIR) light illumination resulted in decreased IRDye700DX NHS ester (IR700) fluorescence in a light dose dependent fashion due to photobleaching, whereas no apparent changes in IR700 fluorescence were shown in the control group (Figure 1D)
All NIR-PIT-treated mice exhibited increased IR700 fluorescence at 1 day after NIR-PIT (due to refreshing of circulating panitumumab - IR700 conjugate (Pan-IR700) into the tumor) the signal continued to decrease 2 days after NIR-PIT as well as in the control group (Figure 4D, 4E). These results suggested that 25 J/ cm ILI was not enough for successful NIR-PIT, but 50 J/ cm or more NIR light can successfully result in cell killing at a distance of 5 - 7 mm size from the fiber optic diffuser
Summary
Near-infrared photoimmunotherapy (NIR-PIT) is a promising new cancer therapy, which utilizes a monoclonal antibody (mAb)-photoabsorber conjugate (APC). Subsequent local illumination with NIR light activates the photoabsorber, IRDye700DX (IR700, silicaphthalocyanine dye), and induces cell rupture only in cells where the APC has bound. Since NIR light is totally harmless for living tissues and penetrates 1 – 2 cm into living tissues, NIR-PIT is easyto-use for thin surface tumors. Human tumors often project more deeply below the skin surface and alternate solutions to delivering light via fiber optic diffusers are needed. In Phase 1 and 2 trials of NIR-PIT in patients with recurrent head and neck cancer where the APC targeted epidermal growth factor receptor (EGFR), interstitial fiber optic diffusers were used to treat larger tumors with good success (https://clinicaltrials.gov/ct2/ show/NCT02422979)
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