Photodynamic nanomedicine in the treatment of solid tumors: perspectives and challenges

Abstract

Photodynamic therapy (PDT) is a promising treatment strategy where activation of photosensitizer drugs with specific wavelengths of light results in energy transfer cascades that ultimately yield cytotoxic reactive oxygen species which can render apoptotic and necrotic cell death. Without light the photosensitizer drugs are minimally toxic and the photoactivating light itself is non-ionizing. Therefore, harnessing this mechanism in tumors provides a safe and novel way to selectively eradicate tumor with reduced systemic toxicity and side effects on healthy tissues. For successful PDT of solid tumors, it is necessary to ensure tumor-selective delivery of the photosensitizers, as well as, the photoactivating light and to establish dosimetric correlation of light and drug parameters to PDT-induced tumor response. To this end, the nanomedicine approach provides a promising way towards enhanced control of photosensitizer biodistribution and tumor-selective delivery. In addition, refinement of nanoparticle designs can also allow incorporation of imaging agents, light delivery components and dosimetric components. This review aims at describing the current state-of-the-art regarding nanomedicine strategies in PDT, with a comprehensive narrative of the research that has been carried out in vitro and in vivo, with a discussion of the nanoformulation design aspects and a perspective on the promise and challenges of PDT regarding successful translation into clinical application.

Figure 1

Jablonski diagram depicting the electronic transition states and energy transfer phenomena between the photosensitizer molecule and oxygen in photodynamic therapy that ultimately leads to oxidative cell damage.

Figure 2. The history, development and current state-of-the-art for PDT

Figure 3

Representative images showing the feasibility of packaging photosensitizers in nanoparticle vehicles for delivery to cancer cells, in vitro; (A) percentage of breast cancer cell death caused by PDT with protoporphyrin IX loaded gold nanoparticles of different sizes compared to free drug; (B) intracellular uptake of porphyrin-derivative loaded silica nanoparticles after 4 hours incubation (ii) compared to cells alone (i); (C) F3 peptide-targeted polyacrylamide nanoparticles (i) loaded with 2-devinyl-2-(1- hexyloxyethyl) pyropheophorbide (HPPH), a chlorin-derivative, are taken up into 9L gliosarcoma cells faster than nontargeted analogs (ii), as corroborated by the quantitative fluorescence data (iii); (D) confocal microscopy of bladder carcinoma cells incubated with zinc (II) phthalocyanine loaded silica-coated upconversion nanoparticles, apoptotic cells are indicated by arrows; (E) increased percentage of cell death due to apoptosis and necrosis in breast cancer cells when treated with polymeric micelle-encapsulated silicon phthalocyanine photosensitizer Pc 4; (F) dose-response curve in breast cancer cells shows enhanced PDT efficacy when treated with nanoparticle encapsulated methylene blue compared to free drug; (G) cell death (red) following 2 hrs of incubation in glioma cells with nanoparticle-encapsulated methylene blue and irradiation compared to nonirradiated cells (green) and (H) decrease in ovarian cancer cell viability following treatment with free hypericin (circles) compared to nanoparticle-encapsulated hypericin (squares) at various drug dosages. Adapted with permission from [, , , –59]

Figure 4

Representative images of in vivo studies of nanoformulation-mediated PDT; (A) T2 weighted image of porphyrin derivative loaded magnetic chitosan NPs showing reduction in magnetically targeted tumor (left) compared to nontargeted tumor (right); (B) Tumor volume after treatment with chlorin-conjugated iron oxide NPs showing tumor stagnation in the group receiving magnetically localized NPs followed by subsequent PDT; (C) Tumor targeting ability of chlorin-loaded NPs compared to free drug as seen by fluorescence imaging of the tumor hotspot and (D) tumor growth suppression caused by phthalocyanine-loaded NPs in hepatoma xenografts. Adapted with permission from [35, 63, 99, 108].