Activatable Photodynamic Therapy Research Articles

Targeting‐Triggered Porphysome Nanostructure Disruption for Activatable Photodynamic Therapy

Photodynamic therapy (PDT) and photothermal therapy (PTT) possess advantages over the conventional therapies with additional treatment selectivity achieved with local laser irradiation. Comparing to PTT that ablates target tissue via thermal necrosis, PDT induces target cell death via singlet oxygen without damaging the underling connective tissue, thus preserving its biological function. Activatable photosensitizers provide an additional level of treatment selectivity via the disease-associated activation mechanism. In this study, folate-conjugated porphysomes are introduced as targeting-triggered activatable nano-sized beacons for PDT. Porphysomes are reported previously as the most stable and efficient delivery system of porphyrin, but their nanostructure converts the singlet oxygen generation mechanism to thermal ablation mechanism. By folate-receptor-mediated endocytosis, folate-porphysomes are internalized into cells rapidly and resulted in efficient disruption of nanostructures, thus switching back on the photodynamic activity of the densely packed porphyrins for effective PDT. In both in vitro and in vivo studies, folate-porphysomes can achieve folate receptor-selective PDT efficacy, which proves the robustness of targeting-triggered PDT activation of porphysome nanostructure for highly selective tumor ablation. The formulation of porphysomes can be modified with other targeting ligands as activatable photosensitizers for personalized treatment in future.

Morphology dependent photosensitization and formation of singlet oxygen (1Δg) by gold and silver nanoparticles and its application in cancer treatment.

Singlet oxygen is a very important reactive oxygen species (ROS) involved in peroxidation of olefins and polymers, as well as in clinical photodynamic therapy treatments of tumors. Previously, it was reported that singlet oxygen can be formed via sensitization by spherical metal nanoparticles upon photo-excitation of the surface plasmon resonance (SPR) bands. In this paper, we report that sensitization and formation of singlet O2 is strongly dependent on the morphologies of gold and silver nanostructures. For example, singlet O2 can be generated via photo-irradiation and sensitization of silver decahedrons and silver triangular nanoplates, but not by silver nanocubes and gold decahedrons. The sensitization patterns of silver and gold nanoparticles are the reverse of each other. In the case of gold nanorods, singlet O2 can be generated via photo-excitation at the longitudinal SPR band, but not by excitation at the transverse SPR band. The controlling factors for such a morphology dependent singlet O2 sensitization will be discussed. Furthermore, we also demonstrate in vitro morphology dependent sensitization behaviour of silver nanoparticles in the photodynamic cancer treatment. Our results indicate that metal nanoparticles with certain morphologies are potentially very promising dual functional nanomaterials with capabilities of simultaneously serving as near infrared (NIR) activatable photodynamic therapy and photothermal therapy reagents for cancer treatments.

FRET Quenching of Photosensitizer Singlet Oxygen Generation

The development of activatable photodynamic therapy (PDT) has demonstrated a utility for effective photosensitizer quenchers. However, little is known quantitatively about Forster resonance energy transfer (FRET) quenching of photosensitizers, even though these quenchers are versatile and readily available. To characterize FRET deactivation of singlet oxygen generation, we attached various quenchers to the photosensitizer pyropheophorbide-alpha (Pyro) using a lysine linker. The linker did not induce major changes in the properties of the photosensitizer. Absorbance and emission wavelength maxima of the quenched constructs remained constant, suggesting that quenching by ground-state complex formation was minimal. All quenchers sharing moderate spectral overlap with the fluorescence emission of Pyro (J > or = 5.1 x 10(13) M(-1) cm(-1) nm4) quenched over 90% of the singlet oxygen, and quenchers with weaker spectral overlap displayed minimal quenching. A self-quenched double Pyro construct exhibited intermediate quenching. Consistent with a FRET deactivation mechanism, extension of the linker to a 10 residue polyproline peptide resulted in only the quenchers with spectral overlap almost 2 orders of magnitude higher (J > or = 3.7 x 10(15) M(-1) cm(-1) nm4) maintaining high quenching efficiency. Overall, there was good correlation (0.98) between fluorescence quenching and singlet oxygen quenching, implying that fluorescence intensity can be a convenient indicator for the singlet oxygen production status of activatable photosensitizers. Uniform singlet oxygen luminescence lifetimes of the compounds, along with minimal triplet state transient absorption were consistent with quenchers primarily deactivating the photosensitizer excited singlet state. In vitro, cells treated with well-quenched constructs demonstrated greatly reduced PDT induced toxicity, indicating that FRET-based quenchers can provide a level of quenching useful for future biological applications. The presented findings show that FRET-based quenchers can potently decrease singlet oxygen production and therefore be used to facilitate the rational design of activatable photosensitizers.