Antitumor effect of photodynamic therapy with chlorin‐based photosensitizer DH‐II‐24 in colorectal carcinoma

Abstract

While photodynamic therapy (PDT) has been recognized as a promising therapeutic modality for the treatment of various cancers and diseases, developments of effective photosensitizers are highly desired to improve the prospect for the use of PDT. In this study, we evaluated DH-II-24, a new photosensitizer, for antitumor PDT in vitro and in vivo. Loaded into human colorectal carcinoma cells (HCT116), DH-II-24 was primarily accumulated in mitochondria, lysosomes, and endoplasmic reticula. Administration of DH-II-24 followed by light exposure induced necrotic cell death in a dose-dependent manner, whereas DH-II-24 in the absence of light induced minimal cell death. In order to investigate the distribution and phamacokinetics of the photosensitizer in vivo, DH-II-24 was intravenously injected to female BALB ⁄ c nude mice. Fluorescence imaging in vivo showed that DH-II-24 was rapidly distributed across the entire body and then mostly eliminated at 24 h. Next, effectiveness of DH-II-24-mediated PDT was examined on colorectal carcinoma xenografts established subcutaneously in BALB ⁄ c nude mice. DH-II-24 (1 mg ⁄ kg, i.v. administration) followed by light exposure significantly suppressed growth of xenograft tumors, compared to light exposure or DH-II-24 alone. Histological examination revealed necrotic damage in PDT-treated tumors, concomitantly with severe damage of tumor vasculature. These results suggest that DH-II-24 is a potential photosensitizer of photodynamic therapy for cancer. (Cancer Sci 2009; 100: 2431-2436) P hotodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancer.(1-4) PDT involves an administration of a photosensitizer followed by illumination of tumor tissues with visible light of a suitable wavelength for excitation of the photosensitizer. (5,6) The activation of the photosensitizer leads to conversion of molecular oxygen to various highly reactive oxygen species (ROS), which kills tumor cells directly or damages the tumor-associated vasculature.(1,2,7)Tumor vascular damage subsequently deprives the oxygen and nutrients of tumor, resulting in tumor cell death. (2,4,8) In addition, PDT could have a significant stimulatory effect on the immune system. (1,8,9) These multifactorial mechanisms by which PDT mediates tumor destruction have been suggested to be beneficial for long-term tumor control. (7,9) PDT has several advantages over other conventional cancer treatments.(4) Since it requires mere illumination of the tumor site, the treatment is relatively non-invasive.(4) PDT does not induce systemic immunosupression that causes a variety of infections.(8) PDT displays low systemic toxicity and relatively selective destruction of tumors, which is known to be in part due to preferential localization of photosensitizer within tumor.(2,10,11) Thus, PDT has been widely employed to various tumors directly approachable to illumination, such as esophageal carcinoma, head and neck tumors, bladder, prostate, nonmelanoma skin cancers, and actinic keratosis. (7,(12)(13)(14)(15)(16) Compa...

Differential cytotoxic responses to low- and high-dose photodynamic therapy in human gastric and bladder cancer cells

“…Recently, we investigated the in vivo antitumor effects of PDT with DH-II-24, which exhibits several advantages such as strong absorption at relatively long wavelengths, minimal dark toxicity, and a shorter half-life in the body [Lim et al, 2009[Lim et al, , 2011]. Our results demonstrate that DH-II-24-mediated PDT could induce cell death through both apoptosis and necrosis in a PDT dose-dependent manner; intracellular ROS play a decisive role in the TG2-dependent apoptotic cell death induced by low-dose PDT (LDP), whereas high-dose PDT (HDP)-mediated necrotic cell death is controlled dominantly by intracellular Ca 2þ overload.…”

“…KEY WORDS: PHOTODYNAMIC THERAPY; CELL DEATH, TISSUE TRANSGLUTAMINASE; REACTIVE OXYGEN SPECIES; INTRACELLULAR Ca 2þ P hotodynamic therapy (PDT) has been increasingly recognized as a selective treatment modality for various cancers and diseases [Triesscheijn et al, 2006;Lim et al, 2009;O'Connor et al, 2009;Robertson et al, 2009;Bredell et al, 2010]. Although an enormous number of studies have reported that PDT can induce many cellular and molecular signaling events that ultimately result in cell death, we remain far from a definitive understanding of the mechanisms of tumor cell killing because the efficiency and specific mechanism(s) of cell death are largely determined by a variety of parameters such as the concentration and intracellular localization of the photosensitizer, dose of light, cell genotype, and oxygen availability [Sharman et al, 1999;Nowis et al, 2005;Triesscheijn et al, 2006;Robertson et al, 2009].…”

Molecular imaging of membrane proteins and microfilaments using atomic force microscopy

“…Recently, we reported a semi-in situ system through photodynamic therapy (PDT) to study the ultrastructure of microfilaments without additional treatment and under near-native conditions (Jung et al, 2009a). PDT is an anticancer modality that uses photosensitizers preferentially accumulated in cancer cells (Almeida et al, 2004;Ferreira et al, 2004;Tsai et al, 2005;Uzdensky et al, 2005;Lim et al, 2009). Subsequent activation of photosensitizer in target cells or tissues by light of an appropriate wavelength causes a cascade of biological events through various photophysical pathways, which induce production of reactive oxygen species, elevation of intracellular Ca 2+ , activation of caspases, and translocation of apoptosis-inducing factor, and ultimately result in cell death through apoptosis or necrosis (Almeida et al, 2004;Ferreira et al, 2004;Tsai et al, 2005;Yoo et al, 2009).…”

“…Optical microscopy has contributed greatly to various studies of biological materials, including cells and tissues (Yi et al, 2004;Lim et al, 2009). However, the resolution of optical microscopy, due to the diffraction limit of the light source, is not sufficient to visualize subcellular structures.…”

Synthesis and Photophysical Properties of S-Mannosylated Chlorins and Their Effect on Photocytotoxicity in HeLa Cells

“…25 Accordingly, developing photosensitizers with high specific accumulation properties is highly desired. 3 Carbohydrates are involved in various biological processes such as polyvalent interactions, 6 recognition, and some antibiotic agents. 7 Bound to a photosensitizer, they are able to improve solubility, decrease toxicity, and open the possibility of targeting saccharide-specific binding domains or metabolic pathways.…”