Maltotriose-conjugation to a fluorinated chlorin derivative generating a PDT photosensitizer with improved water-solubility

Narumi, Atsushi; Tsuji, Takeshi; Shinohara, Kosuke; Yamazaki, Hiromi; Kikuchi, Moriya; Kawaguchi, Seigou; Mae, Tomoya; Ikeda, Atsushi; Sakai, Y.; Kataoka, Hiromi; Inoue, Masahiro; Nomoto, Akihiro; Kikuchi, Jun‐ichi; Yano, Shigenobu

doi:10.1039/c6ob00276e

Cited by 27 publications

(32 citation statements)

References 25 publications

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“…Compared to G-chlorin, O-chlorin proved to be more highly water-soluble (Figure 1E, 1F) [23]. This high solubility enabled O-chlorin to be administered intravenously and to reach the whole body without addition of a toxic organic solvent.…”

Section: Resultsmentioning

confidence: 99%

A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis

et al. 2016

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Photodynamic therapy (PDT) exploits light interactions and photosensitizers to induce cytotoxic reactive oxygen species. Photodynamic diagnosis (PDD) uses the phenomenon of photosensitizer emitting fluorescence to distinguish some tumors from normal tissue. The standard photosensitizer used for PDD is 5-aminolevulinic acid (5-ALA), although it is not entirely satisfactory. We previously reported glucose-conjugated chlorin (G-chlorin) as a more effective photosensitizer than another widely used photosensitizer, talaporfin sodium (TS); however, G-chlorin is hydrophobic. We synthesized oligosaccharide-conjugated chlorin (O-chlorin) with improved water-solubility. We report herein on its accumulation and cytotoxicity. O-chlorin was synthesized and examined for solubility. Flow cytometric analysis was performed to evaluate O-chlorin accumulation in cancer cells. To evaluate the intracellular localization of photosensitizer, cells were stained with O-chlorin and organelle-specific fluorescent probes. We then measured the in vitro fluorescence of various photosensitizers and the half-maximal inhibitory concentrations to evaluate effects in PDD and PDT, respectively. Xenograft tumor models were established, and antitumor and visibility effects were analyzed. O-chlorin was first shown to be hydrophilic. Flow cytometry then revealed a 20- to 40-times higher accumulation of O-chlorin in cancer cells than of TS, and a 7- to 23-times greater fluorescence than 5-ALA. In vitro, the cytotoxicity of O-chlorin PDT was stronger than that of TS PDT, and O-chlorin tended to accumulate in lysosomes. In vivo, O-chlorin showed the best effect in PDT and PDD compared to other photosensitizers.O-chlorin was hydrophilic and showed excellent tumor accumulation and fluorescence. O-chlorin is promising as a next-generation bifunctional photosensitizer candidate for both PDT and PDD.

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Section: Resultsmentioning

confidence: 99%

A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis

et al. 2016

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“…As for the 1 O 2 generation efficiency and photocytotoxicity, Mal 3 -chlorin was proved to have a very high performance comparable to that of G-chlorin. In addition, the crucial water-soluble advantage of Mal 3 -chlorin allows its injection without the use of toxic organic solvents, with hydrophilicity similar to that of talaporfin (20). Talaporfin, a second-generation photosensitizer, shows improved efficacy compared with first-generation photosensitizers (12).…”

Section: Discussionmentioning

confidence: 99%

“…We have therefore developed a straightforward strategy to improve the water solubility of chlorin derivatives by using a oligosaccharide, such as maltotriose (Mal 3 ), called Mal 3 -chlorin and have reported its highly hydrophilicity and photocytotoxicity (20). In the present study, we investigated the efficacy of PDT with a novel photosensitizer, Mal 3 -chlorin, in culture and in a mouse model of disseminated peritoneal pancreatic cancer using in vivo fluorescence imaging to monitor sequentially.…”

Section: Introductionmentioning

confidence: 99%

Maltotriose Conjugation to a Chlorin Derivative Enhances the Antitumor Effects of Photodynamic Therapy in Peritoneal Dissemination of Pancreatic Cancer

Kato

Kataoka

Yano

et al. 2017

Molecular Cancer Therapeutics

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Peritoneal dissemination is a major clinical issue associated with dismal prognosis and poor quality of life for patients with pancreatic cancer; however, no effective treatment strategies have been established. Herein, we evaluated the effects of photodynamic therapy (PDT) with maltotriose-conjugated chlorin (Mal-chlorin) in culture and in a peritoneal disseminated mice model of pancreatic cancer. The Mal-chlorin was prepared as a water-soluble chlorin derivative conjugated with four Mal molecules to improve cancer selectivity. , Mal-chlorin showed superior uptake into pancreatic cancer cells compared with talaporfin, which is clinically used. Moreover, the strong cytotoxic effects of PDT with Mal-chlorin occurred via apoptosis and reactive oxygen species generation, whereas Mal-chlorin alone did not cause any cytotoxicity in pancreatic cancer cells. Notably, using a peritoneal disseminated mice model, we demonstrated that Mal-chlorin accumulated in xenograft tumors and suppressed both tumor growth and ascites formation with PDT. Furthermore, PDT with Mal-chlorin induced robust apoptosis in peritoneal disseminated tumors, as indicated by immunohistochemistry. Taken together, these findings implicate Mal-chlorin as a potential next-generation photosensitizer for PDT and the basis of a new strategy for managing peritoneal dissemination of pancreatic cancer. .

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“…Although G-chlorin and M-chlorin are not hydrophilic, we recently developed maltotriose-conjugated chlorin ( Figure 2B) which selectively accumulates in cancer cells and has a hydrophilic nature (25,26).…”

Section: Future Trendsmentioning

confidence: 99%

New photodynamic therapy with next-generation photosensitizers

Kataoka¹,

Nishie²,

Hayashi³

et al. 2017

Ann. Transl. Med.

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Photodynamic therapy (PDT) is a non-invasive antitumor treatment that uses the combination of a photosensitizer, tissue oxygen, and visible light irradiation to produce cytotoxic reactive oxygen species, predominantly singlet oxygen. Currently, first-generation PDT using porfimer sodium with an excimer dye laser, and second-generation PDT using talaporfin sodium PDT with a semiconductor laser are approved by health insurance for use in Japan. However, the cancer cell specificity and selectivity of these treatments are inadequate.Cancer cells consume higher levels of glucose than normal cells and this phenomenon is known as the Warburg effect. Thus, we developed a third-generation PDT, based on the Warburg effect, by synthesizing a novel photosensitizer, sugar-conjugated chlorin, with increased cancer cell-selective accumulation. Glucose-conjugated chlorin (G-chlorin) PDT showed significantly stronger antitumor effects than second-generation talaporfin PDT.We also found that PDT with G-chlorin induced immunogenic cell death which is characterized by the secretion, release, or surface exposure of damage-associated molecular patterns (DAMPs), including calreticulin (CRT) and the high-mobility group box 1 (HMGB1) protein. Mannose-conjugated chlorin (M-chlorin) PDT which targets the mannose receptors on the surface of cancer cells and tumor-associated macrophages (TAMs) in cancer tissue stroma also showed very strong antitumor effects. These novel PDTs using glucose or M-chlorins stand as new candidates for very effective, next-generation PDTs.

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Maltotriose-conjugation to a fluorinated chlorin derivative generating a PDT photosensitizer with improved water-solubility

Cited by 27 publications

References 25 publications

A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis

A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis

Maltotriose Conjugation to a Chlorin Derivative Enhances the Antitumor Effects of Photodynamic Therapy in Peritoneal Dissemination of Pancreatic Cancer

New photodynamic therapy with next-generation photosensitizers

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