Abstract
Abstract Photodynamic therapy (PDT), a non-invasive and alternative method for the treatment of cancer, is a light-activated treatment modality for breast cancer. Destruction of cancerous cells by PDT is achieved by a combination of photosensitizer and light of an appropriate wavelength for the photosensitizer. Methylene blue (MB) is a blue dye clinically being used and is known to show efficient photosensitizing activity with a very high yield of singlet oxygen generation (65%), where singlet oxygen is the actual therapeutic agent for PDT. However MB shows low cell uptake efficiency by itself and thus a low PDT efficacy. In this regard, we developed a nanoformulation of MB (nanoMB) to improve cancer cell uptake efficiency while keeping the high efficiency of singlet oxygen generation. NanoMB is composed of ternary components that are physically assembled in an aqueous milieu. In this study, we investigated the cellular uptake of nanoMB and cancer cell apoptosis induced by nanoMB PDT in MDA-MB-231 human breast cancer cells in vitro and in vivo. In vitro, nanoMB was indeed avidly taken up by MDA-MB231 cells, unlike free MB showing negligible cellular uptake. NanoMB formulation preserved the photosensitization activity of MB under laser irradiation at 655 nm. Taken together, it was revealed from the in vitro microscopic observation that nanoMB can efficiently destroy live MDA-MB231 cells even under red lamp illumination. In the control group, cells were treated with free MB and did not show phototoxic influence under the same light. In vivo phototoxicity evaluation, the locally injected nanoMB was internalized into cancer cells. Upon annexin V treatment after laser irradiation at 655 nm, apoptosis of cancer cells was clearly observed from the spot where nanoMB and laser were applied together. The PDT-induced cell apoptosis was visualized in a simple mouse model by using fluorescently labeled annexinV that has high affinity toward apoptotic cells. Briefly, cancer cells were inoculated in muscle on opposite sides and nanoMB was applied to both the inoculation sites. After some time, only one side was laser-treated and fluorescent annexinV was injected to both. Only the dual-treated side (nanoMB + laser) showed retention of annexinV after 1 hour, indicating the occurrence of apoptosis by the PDT treatment. Free MB and nanoMB were applied by subcutaneous injection around an early tumor tissue (not intratumoral injection). After 1 hour, free MB signals disappeared whereas nanoMB was retained at the tumor, implying that nanoMB penetrated into the tumor through the basement membrane. Laser irradiation was done one hour after sample injection for both free MB and nanoMB. This treatment (sample + laser) was repeated seven times. According to the results, only nanoMB showed the tumor growth suppression effect, demonstrating the potential of nanoMB as a local injectable PDT agent. In this study, nanoMB (MBOF) presented avid internalization into live cancer cells while keeping the high photosensitizing efficiency of MB. Consequently, highly efficient PDT of cancer cells was demonstrated in vitro and in vivo. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-17-02.
Published Version
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