Photodynamic Therapy

In photodynamic therapy (PDT), light is used to activate the drug (a photosensitizer) at diseased sites. Initially, PDT was used for the treatment of superficial tumors such as skin cancer. Recent improvements in the technology have allowed for the treatment of deep tumors such as lung cancers.159 The tumor area is exposed to light of a specific wavelength that activates the drug, leading to the destruction of tumor cells and proximal tumor vasculature via the production of reactive oxygen species or by other mechanisms.160,161 In order for the PDT agents to be effective in destroying tumor cells, it is necessary that there is no aggregation of the drug. However, in aqueous media, the hydrophobic photosensitizers tend to aggregate, resulting in reduced potency. Pluronic® micelles were reported to be able to solubilize benzoporphyrin while avoiding drug aggregation in the micelle core, implying that the potency of the photosensitizer was maintained.162 In this way, polymeric micelles become an attractive alternative for the solubilization and delivery of photosensitizers.

Kataoka's group has developed polyion complex (PIC) micelles based on anionic copolymers (PEG-b-poly(L-lysine) or PEG-b-PAsp) for the encapsulation of a polycationic photosensitizer. These micelles are stabilized by electrostatic interactions, and the micelles are pH-responsive, allowing intratumoral drug release or intracellular endosomal escape.160,162,163 The photosensi-tizer-loaded PIC micelles showed no skin phototoxicity in rats upon exposure to broadband visible light, and severe skin phototoxicity was observed with the administration of Photofrin® (a currently approved PDT drug formulated in 0.9% sodium chloride).164 The photosensitizer-loaded PIC micelles were also shown to exhibit enhanced efficacy and reduced toxicity in the Lewis lung carcinoma (LLC) cell line in comparison to free photosensitizer.160

It has also been reported that the subcellular localization of the photosensitizer influences its efficacy. Leroux's group has developed pH-sensitive aluminum chloride pthalocyanine (AICIPc)-loaded N-isopropylacrylamide copolymer micelles for treatment against EMT-6 tumors in vivo. The tumor accumulation of the micelle-formulated drug is lower than that of AICIPc dissolved in Cremophor EL. However, the copolymer micelle formulation has been shown to have enhanced therapeutic efficacy that is most likely attributed to an increase in the cytoplasmic accumulation of the drug.165,166 In many cases, the accumulation of photosensitizer at the mitochondria has been found to be the most efficacious.161,167 Therefore, the use of pH-responsive polymeric micelles for PDT could enhance drug accumulation in the mitochondria following endosomal/lysosomal escape of the micelles. In the future, the design of polymeric micelles for use in PDT will likely be aimed at improving tumor and subcellular localization by fine-tuning the copolymer composition in order to achieve active targeting.

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