The use of nanomaterials in advancing photodynamic therapy (PDT) for deep-seated tumors and synergy with radiotherapy

Abstract

Photodynamic therapy (PDT) has been under development for at least 40 years. Multiple studies have demonstrated significant anti-tumor efficacy with limited toxicity concerns. PDT was expected to become a major new therapeutic option in treating localized cancer. However, despite a shifting focus in oncology to aggressive local therapies, PDT has not to date gained widespread acceptance as a standard-of-care option. A major factor is the technical challenge of treating deep-seated and large tumors, due to the limited penetration and variability of the activating light in tissue. Poor tumor selectivity of PDT sensitizers has been problematic for many applications. Attempts to mitigate these limitations with the use of multiple interstitial fiberoptic catheters to deliver the light, new generations of photosensitizer with longer-wavelength activation, oxygen independence and better tumor specificity, as well as improved dosimetry and treatment planning are starting to show encouraging results. Nanomaterials used either as photosensitizers per se or to improve delivery of molecular photosensitizers is an emerging area of research. PDT can also benefit radiotherapy patients due to its complementary and potentially synergistic mechanisms-of-action, ability to treat radioresistant tumors and upregulation of anti-tumoral immune effects. Furthermore, recent advances may allow ionizing radiation energy, including high-energy X-rays, to replace external light sources, opening a novel therapeutic strategy (radioPDT), which is facilitated by novel nanomaterials. This may provide the best of both worlds by combining the precise targeting and treatment depth/volume capabilities of radiation therapy with the high therapeutic index and biological advantages of PDT, without increasing toxicities. Achieving this, however, will require novel agents, primarily developed with nanomaterials. This is under active investigation by many research groups using different approaches.

Keywords: X-ray PDT; XPDT; immune activation; photodynamic therapy (PDT); radiation; radioPDT.

FIGURE 1

Simplified Jablonski energy diagram of photodynamic activation. Radiative transitions are shown as colored arrows and non-radiative transitions as black/dashed arrows.

FIGURE 2

Methods of interstitial light delivery combined with spatial and temporal fractionation for optimizing PDT effect. A Dunning R3327 rat prostate cancer model was implanted with fiberoptics for light delivery in a standardized icosahedral layout (A), adopted for ease of light dosimetry calculation and geometric expansion to larger tumors (B). The fibers were activated sequentially in a specific geometric pattern (C) to allow fractionated therapy (D). This deposits light (measured in arbitrary units, a.u., by the detecting light catheter/photodiode arrangement) in short bursts (each blue point) at regular intervals either continuously (top) or with pauses to allow for recovery of the photosensitizer (middle). This allows more homogenously and controls the rate of photobleaching and oxygen depletion in the treatment field, which leads to higher therapeutic yield. Image adapted from Xiao et al. (2007) with permission. a.u. = arbitrary units.