X-Ray Psoralen Activated Cancer Therapy (X-PACT)

Abstract

This work investigates X-PACT (X-ray Psoralen Activated Cancer Therapy): a new approach for the treatment of solid cancer. X-PACT utilizes psoralen, a potent anti-cancer therapeutic with current application to proliferative disease and extracorporeal photopheresis (ECP) of cutaneous T Cell Lymphoma. An immunogenic role for light-activated psoralen has been reported, contributing to long-term clinical responses. Psoralen therapies have to-date been limited to superficial or extracorporeal scenarios due to the requirement for psoralen activation by UVA light, which has limited penetration in tissue. X-PACT solves this challenge by activating psoralen with UV light emitted from novel non-tethered phosphors (co-incubated with psoralen) that absorb x-rays and re-radiate (phosphoresce) at UV wavelengths. The efficacy of X-PACT was evaluated in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP-B) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (psoralen and phosphor) and radiation parameters (energy, dose, and dose rate) were varied. Efficacy was evaluated primarily using flow cell cytometry in combination with complimentary assays, and the in-vivo mouse study. In an in-vitro study, we show that X-PACT induces significant tumor cell apoptosis and cytotoxicity, unlike psoralen or phosphor alone (p<0.0001). We also show that apoptosis increases as doses of phosphor, psoralen, or radiation increase. Finally, in an in-vivo pilot study of BALBc mice with syngeneic 4T1 tumors, we show that the rate of tumor growth is slower with X-PACT than with saline or AMT + X-ray (p<0.0001). Overall these studies demonstrate a potential therapeutic effect for X-PACT, and provide a foundation and rationale for future studies. In summary, X-PACT represents a novel treatment approach in which well-tolerated low doses of x-ray radiation are delivered to a specific tumor site to generate UVA light which in-turn unleashes both short- and potentially long-term antitumor activity of photo-active therapeutics like psoralen.

Psoralen Derivatives with Enhanced Potency

“…Nonetheless, it will be interesting to follow whether these more potent derivatives have a better therapeutic window than prior psoralens in preclinical models. AMT was recently implemented in a novel therapy for solid tumors termed X-PACT (X-ray Psoralen Activated Cancer Therapy) (41). 1F and 6E may be attractive alternatives to AMT in X-PACT if the same therapeutic effect can be induced at lower drug concentrations and X-ray doses.…”

Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects

“…PUVA is ideal for superficial applications only, due to low penetration into deep tissues. Therefore, X-PACT has been introduced, which at low X-ray doses photoactivates psoralens and hence mitigates the low penetration problem and adverse effects of PUVA [133].…”

Optical and x-ray technology synergies enabling diagnostic and therapeutic applications in medicine

“…Mediated by the Cherenkov light generated by MV x-rays, psoralens have recently shown radiosensitizing properties for low-dose fractionated radiotherapy, both in vitro and in preclinical tumor models in vivo. 60,61 This novel approach is thought to be based on fundamentally different mechanisms of action than conventional physical or chemical radiosensitizers. There are also potential synergistic interactions in x-ray-induced photosensitization using nanoparticles, as discussed below.…”