Organically Modified Silica Nanoparticles Co-encapsulating Photosensitizing Drug and Aggregation-Enhanced Two-Photon Absorbing Fluorescent Dye Aggregates for Two-Photon Photodynamic Therapy

Abstract

We report energy-transferring organically modified silica nanoparticles for two-photon photodynamic therapy. These nanoparticles co-encapsulate two-photon fluorescent dye nanoaggregates as an energy up-converting donor and a photosensitizing PDT drug as an acceptor. They combine two features: i) aggregation-enhanced two-photon absorption and emission properties of a novel two-photon dye, and ii) nanoscopic fluorescence resonance energy transfer between this nanoaggregate and a photosensitizer, 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide. Stable aqueous dispersions of the co-encapsulating nanoparticles (diameter≤30 nm) have been prepared in the nonpolar interior of micelles by co-precipitating an organically modified silica sol with the photosensitizer and an excess amount of the two-photon dye which forms fluorescent aggregates by phase separation from the particle matrix. Using a multidisciplinary nanophotonic approach, we show: i) indirect excitation of the photosensitizer through efficient two-photon excited intraparticle energy transfer from the dye aggregates in the intracellular environment of tumor cells, and ii) generation of singlet oxygen and in-vitro cytotoxic effect in tumor cells by photosensitization under two-photon irradiation.

Nanodrug applications in photodynamic therapy

“…Protoporphyrin IX has also been encapsulated into silica nanoparticles [98]. Appropriately modified, such nanoparticles show promise in newer developments such as two-photon absorption PDT [99]. Other nanoparticles modified with (phthalocyaninato)zinc(II) have been used to develop upconverting nanotransducers [100].…”

Multi-photon excitation in uncaging the small molecule bioregulator nitric oxide

“…Applications of TPE to PDT again have been directed towards taking advantage of the tissue transmission properties of NIR light and the spatial resolution provided by the quadratic dependence on the intensity of the exciting light [27,39,41]. The latter has been demonstrated in vivo by using TPE and PDT dyes to seal blood vessels in mice [42].…”

Blood-vessel closure using photosensitizers engineered for two-photon excitation

“…The majority of chromophores possess low two-photon cross-sections, of the order of 1-100 Goeppert-Mayer units (1 GM = 10 -50 cm 4 s photon -1 ). For example, the two FDA-approved PDT photosensitisers, verteporfin and Photofrin (cross sections 50 GM and 10 GM respectively) 17 , are unlikely to be suitable for TPE-PDT, as the high light intensities needed to achieve a therapeutic effect are close to the thresholds for photothermal or photomechanical damage 18 .Several design strategies for TPE-PDT photosensitisers have been reported recently [11][12][13][14][15][16] , but few of these compounds have yet been studied in vitro 15 , and, to date, none have progressed to in vivo testing. Porphyrin derivatives are often effective PDT agents, as exemplified by verteporfin and Photofrin 4 .…”

“…Several design strategies for TPE-PDT photosensitisers have been reported recently [11][12][13][14][15][16] , but few of these compounds have yet been studied in vitro 15 , and, to date, none have progressed to in vivo testing. Porphyrin derivatives are often effective PDT agents, as exemplified by verteporfin and Photofrin 4 .…”