Ikumi Sugiyama
Iwate Medical University
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Featured researches published by Ikumi Sugiyama.
Toxicology Letters | 2008
Yasuyuki Sadzuka; Fumiaki Iwasaki; Ikumi Sugiyama; Kentaro Horiuchi; Toru Hirano; Hidechika Ozawa; Naohiro Kanayama; Naoto Oku
This study attempted the liposomalization of coproporphyrin I (CPI) with hydrophobic properties. Liposomalization of CPI was not successful at any pH when using lactate buffer. In contrast, when using 9% sucrose/10mM phosphate buffer (pH 7.8), CPI liposomes (Lipo-CPI) and polyethyleneglycol (PEG) modified liposomes (PEG-CPI) were prepared with a high entrapment ratio of CPI and small particle size. Plasma CPI concentration at 6h after PEG-CPI injection were 6.5-fold greater than that after the injection of Lipo-CPI. In tumors, the CPI concentration was higher after PEG-CPI injection than after Lipo-CPI or CPI solution. Therefore, PEG-CPI was likely to increase blood circulation and achieve greater accumulation of CPI in the tumor. When loaded into tumor cells, photosensitizers generate singlet oxygen during laser irradiation, resulting in the induction of necrosis in the cells. The order of magnitude of CPI tumor cells uptake was PEG-CPI>Lipo-CPI>CPI solution. Thus, the PEG modification of CPI liposomes improved its tumor cell uptake. Furthermore, it is likely that the order of the ability to produce singlet oxygen was PEG-CPI [symbol: see text] Lipo-CPI>CPI solution. The cytotoxicity of PEG-CPI was significantly greater than the other formulations, suggesting that the cytotoxicity reflected the CPI concentration in tumor cells. In conclusion, PEG-CPI was confirmed to show effective tissue distribution, elevated CPI concentration in the tumor cells, to produce singlet oxygen, and cytotoxicity by PDT.
International Journal of Pharmaceutics | 2013
Ikumi Sugiyama; Yasuyuki Sadzuka
The effect of polyethyleneglycol (PEG)-modified liposome as a drug carrier has been demonstrated clinically. We designed and synthesized a novel PEG-lipid, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG (different double arms PEG, DDA-PEG) which had two PEG chains of 500 and 2000 in one molecule to develop more useful PEG-modified liposome. DDA-PEG-modified liposomal doxorubicin (DDA-LDOX(7.5)) had the biggest fixed aqueous layer thickness (FALT) compared with other PEG-lipid-modified liposomes even if the added amount was a few. It was thought that FALT was the indication of blood circulation time. In DOX uptake in tumor cells, DDA-LDOX(7.5) group increased the DOX concentration in tumor cells because it had contact ability with tumor cells. Hence, DDA-LDOX(7.5) which has long circulation time in the bloodstream and contact ability with tumor cells, also had a strong antitumor effect on mice bearing M5076 ovarian sarcoma cells which were DOX low sensitive cells according to the expression of multidrug resistance protein. Furthermore, this liposome maintained a high DOX concentration in a tumor for a long time. These results indicated that the useful antitumor effect of DDA-LDOX(7.5) against M5076 ovarian sarcoma cells is a promising DDS carrier for therapies against drug resistant tumors.
International Journal of Pharmaceutics | 2009
Ikumi Sugiyama; Takashi Sonobe; Yasuyuki Sadzuka
This study is about hybridized liposome contained doxorubicin (Hy-LDOX) that has dual properties of stability in blood and incorporation in tumor cells. We used two kinds of polyethyleneglycol-lipids which are 1-monomethoxypolyethyleneglycol-2,3-distearoylglycerol (PEG-DSG) with an alkyl anchor and cholesterol-PEG (PEG-CHO) with a cholesterol anchor. Hy-LDOX was evaluated on antitumor activity (in vivo), DOX uptake into tumor cells, and DOX cytotoxicity (in vitro). Both tumor size and tumor weight in the Hy-LDOX group were decreased, compared with those in the control group. Hy-LDOX had increased DOX uptake into P388 leukemia cells, compared with the single PEG-DSG modified liposomes. Moreover, the IC(50) value, used as the index of the effect of cytotoxicity, significantly decreased in Hy-LDOX. We suggested that these results of DOX uptake and cytotoxicity contributed to PEG-CHO on liposomal membrane. The PEG modified liposome with only PEG-CHO cannot have a prolonged circulation time, but the Hy-LDOX which was modified with mixing PEG-lipids (PEG-DSG and PEG-CHO) showed stability in blood and incorporation in tumor cells. As the result of these experiments, Hy-LDOX were observed to be useful in terms of cell transition at target site, as shown by high DOX uptake into cell, and high cytotoxicity because PEG-CHO has good incorporated into tumor cell. Hence, it is expected that Hy-LDOX has novel functions.
Scandinavian Journal of Immunology | 2018
Naoto Yoshino; Ryosuke Takeshita; Hanae Kawamura; Kazuyuki Murakami; Yutaka Sasaki; Ikumi Sugiyama; Yasuyuki Sadzuka; Masahiro Kagabu; Toru Sugiyama; Yasushi Muraki; Shigehiro Sato
Cyclic lipopeptides such as surfactin and polymyxin have potent mucosal adjuvant properties. Cyclic lipopeptides are tensioactive compounds, but the relationship between adjuvanticity and surface activity is unknown. Here, we show that the critical micelle concentration (cmc) of surfactant and particle size of the surfactant‐protein complex are important determinants of cyclic lipopeptide adjuvanticity. We found that the diameter of cyclic lipopeptide‐ovalbumin (OVA) complex particles was significantly larger than that in the solutions of OVA alone at cyclic lipopeptide concentrations above the cmc. OVA‐specific antibody titres in mice immunized intranasally with OVA and a cyclic lipopeptide at concentrations above its cmc were significantly higher than those in mice immunized with OVA plus the same dose of the cyclic lipopeptide but administered with formulations in which cyclic lipopeptide concentration was below the cmc. Thus, the concentration of the cyclic lipopeptide in the formulation at immunization, but not its overall dose, was critical for its adjuvanticity. Furthermore, two types of aggregates, the cyclic lipopeptide simplex micelles and the cyclic lipopeptide‐OVA complex micelles, were found in formulations with SF concentrations above its cmc. Degranulation of mast cells exposed to SF simplex micelles was more pronounced when SF concentration was above the cmc. In conclusion, our study showed that surface activity properties, such as the cmc and the size of surfactant‐protein complex, contribute to the adjuvanticity of cyclic lipopeptides. Our study proposes a novel idea that cmc is a key parameter for tensioactive adjuvants.
International Journal of Pharmaceutics | 2018
Ikumi Sugiyama; Kunihiro Kaihatsu; Yukako Soma; Nobuo Kato; Yasuyuki Sadzuka
This study sought to evaluate the antitumor effects of and elucidate the mechanisms underlying (-)-epigallocatechin-3-O-gallate (EGCG) and polyethyleneglycol (PEG)-modified liposomes. EGCG functions as a target ligand of the 67-kDa laminin receptor (67LR), which is expressed on high-grade tumor cells. An EGCG derivative was synthesized for binding to the end of PEG. Doxorubicin (DOX)-loaded EGCG-PEG-modified liposome (EPL) significantly decreased tumor size in mice bearing high 67LR-high-expressing tumors. Caspase-3 activity, which indicates induction of apoptosis, was also elevated only in the EPL group. The importance of PEG for the antitumor effects of EGCG was noted, as soluble EGCG did not accumulate at a sufficient concentration to exert an apoptotic effect. Moreover, EPL significantly increased caspase-8 activity, suggesting that EPL-induced apoptosis occurred due to caspase-8 activity induced following the binding of EGCG to 67LR as a cell-death ligand. In conclusion, EPL appear to have superior antitumor activity against high 67LR-expressing tumor cells, as the liposomes had dual effects, namely antitumor effects due to the loaded DOX and apoptosis induced by the bound EGCG.
Cancer Research | 2018
Ikumi Sugiyama; Yasuyuki Sadzuka
[Purpose] In chemotherapy for cancer, liposomes as drug delivery system (DDS) carriers are expected to have a useful effect. The aim of this study was, therefore to evaluate the antitumor effects of, and elucidate the mechanisms underlying, (-)-epigallocatechin-3-O-gallate (EGCG) and polyethyleneglycol (PEG)-modified liposomes. EGCG functions as a target ligand of the 67 kDa laminin receptor (67LR), which is expressed on high-grade tumor cells. An EGCG derivative was synthesized for binding to the end site of PEG structure. In this study, the antitumor effects of EGCG-modified liposomes as active-targeting liposome were evaluated. [Methods] Liposome was loaded with doxorubicin (DOX) as an antitumor agent. C57BL/6 mice were subcutaneously inoculated with B16F10 mouse melanoma cells (5x10 5 cells/animal). Each sample was administered intravenously with 2.5 mg/kg DOX. EGCG solution (EGCG sol.) was also administered intravenously at 11.3 mg/kg, based on the amount of EGCG modification in DOX-loaded EGCG-PEG-modified liposomes (EPL). Caspase-3 was evaluated as 7-amino-4-trifluoromethyl coumarin (Ex: 400 nm, Em: 505 nm), following a reaction with the fluorescent substrate DEVD-AFC. Caspase-8 was determined reacted with DEVD-pNA and detected as chromophore p-nitroanilin (λ: 400nm). [Results and Discussion] EPL significantly decreased tumor size against B16F10 mouse melanoma cells, in mice bearing 67LR-high-expression tumors. The tumor weight of the EPL group was significantly lower than that of the control (p Citation Format: Ikumi Sugiyama, Yasuyuki Sadzuka. Antitumor effect against 67 kDa laminin receptor expressed on high-grade tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2678.
Cancer Research | 2015
Ikumi Sugiyama; Kunihiro Kaihatsu; Nobuo Kato; Yasuyuki Sadzuka
Purpose: The aim of this study is increase of antitumor effect and decrease of adverse effect by liposomes which have high affinity with 67 kDa laminin receptor (67LR). It was reported that 67LR is expression specifically on tumor cell membrane. When (-)-epigallocatechin-3-gallate (EGCG) as one of the green tea polyphenol are connected with 67LR, apoptosis is induced on tumor cells. On the other hand, liposome is often used for cancer chemotherapy. Then we have studied about EGCG modified liposome containing antitumor agent as drug delivery system. In this study, important strategies are 3 points. The first point is targets to 67LR on tumor cell by EGCG modification around liposomal membrane. The second point is to induce apoptosis mediated by 67LR. Last point is to increase antitumor effect by antitumor agent loaded into liposome. Based on these strategies, EGCG modified liposome was evaluated in vivo distribution. Methods: Three derivatives were synthesized for EGCG modification on liposomal membrane. The liposome with each EGCG derivative were prepared and assessed by measuring particle sizes and zeta potentials. EGCG was only modified liposome (EL) and both EGCG and polyethyleneglycol (PEG) were modified liposome (EPL). On P388 leukemia cells, cytotoxicity was evaluated by WST-8 assay and shown IC50. In the distribution study, C57BL/6 mice were injected (i.v.) each liposome, and collected blood and removed organs with definite time after injection. Results and Discussion: Synthesized EGCG derivatives with di-palmitoyl base were inserted directly into liposomal membrane. Two structures of other derivatives obtained PEG or is able to connect with PEG. In all liposomes, the particle sizes were from 100 to 200 nm and zeta potentials were negative charge. The cytotoxicity of EL was stronger than EGCG unmodified liposome. Moreover, 50% inhibitory concentration of EPL was smaller than EL, namely the cytotoxicity of EPL was strong. It was suggested that this effect was mediated with 67LR needed gallate base in the structure of EGCG because EPL showed strong effect compared with EL. The EGCG derivative in EL had di-palmitoyl base at gallate base, and its bind was not free. In mice experiment, EL rapidly disappeared from the blood circulation after injection. This concentration was one sixteenth of common PEG modified liposome at 15 min after injection. On the other hand, accumulation levels into liver and spleen as reticuloendothelial system (RES) reached high level immediately after injection. This phenomenon indicated that disappearance of EL depends on RES trap. EPL which had EGCG-PEG was significantly improved blood circulating time. In conclusion, it was expected that EGCG-PEG modified liposome (EPL) maintains long circulation time in blood, and increases targeted ability to tumor cells and antitumor activity. Citation Format: Ikumi Sugiyama, Kunihiro Kaihatsu, Nobuo Kato, Yasuyuki Sadzuka. The advanced strategy for novel EGCG derivative modified liposome with high targeting ability to tumor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5529. doi:10.1158/1538-7445.AM2015-5529
Cancer Research | 2014
Ikumi Sugiyama; Kunihiro Kaihatsu; Nobuo Kato; Yasuyuki Sadzuka
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Purpose: The aim of this study is increase of antitumor activity using novel liposome with (-)-epigallocatechin-3-gallate (EGCG) as one of the green tea components. Liposome has been known as a one of useful drug carriers for delivering drug into targeting site. Moreover, some ligand is able to modify around liposomal membrane by a simple method. On the other hand, it was reported that surface of high grade tumor cell expresses 67kDa laminin receptor (67LR) which intermediates of cytostatic effect of EGCG, and EGCG is able to induce apoptosis selectively. Our strategy was to prepare liposomal doxorubicin with EGCG as carrier ligand for getting antitumor activity by both apoptosis and doxorubicin at tumor site. In this study, we tried to prepare EGCG-modified liposome and evaluated the antitumor activity in vitro. Methods: The liposomal doxorubicin was prepared by L-α-distearoylphosphatidylcholine, cholesterol, L-α-distearoylphosphatidyl-DL-glycerol and doxorubicin (100:100:60:18 μmol). Doxorubicin included EGCG-modified liposome (EL-DOX) was prepared to add EGCG-dipalmitate. Amount of EGCG modification on liposomal membrane was determined using DPPH assay. On P388 leukemia cells and M5076 ovarian sarcoma cells, cytotoxicity was evaluated by WST-8 assay and shown IC50. DOX uptake into tumor cells was evaluated in vitro. The concentration of doxorubicin into tumor cells was determined with a fluorescence spectrophotometer at an excitation wavelength of 500 nm and an emission wavelength of 550 nm. Results and Discussion: Particle sizes of EL-DOX were 147 nm on average, zeta potential was -33.1 mV and encapsulated ratio of doxorubicin was 96.5 %. These data of sizes and zeta potentials were better for intravenous administration of liposomes. EGCG ratio on liposomal membrane (71.0 %) was enough to show its ability. In the study of doxorubicin uptake into tumor cells, EL-DOX group was increased amount of doxorubicin for 30 min. The doxorubicin level of EL-DOX was significantly higher compared with that of unmodified liposomal doxorubicin (p<0.05). At cytotoxicity, EL-DOX was stronger than unmodified liposomal doxorubicin. It was provided that IC50 of EL-DOX was also 125 times higher than EGCG solution which was reported to have been antitumor activity. Furthermore, co-incubation of EGCG solution and liposomal doxorubicin was not shown the enhancement effect both doxorubicin uptake into cells and the cytotoxicity. It was suggested that superior effect were shown in modification of EGCG around liposomal membrane, not mixture of EGCG and liposome. In conclusion, EL-DOX exhibited strong antitumor activity efficiently. Citation Format: Ikumi Sugiyama, Kunihiro Kaihatsu, Nobuo Kato, Yasuyuki Sadzuka. Liposomal doxorubicin with modified EGCG increased antitumor activity by topical targeting efficiency into tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5408. doi:10.1158/1538-7445.AM2014-5408
Cancer Research | 2013
Ikumi Sugiyama; Yasuyuki Sadzuka
[Purpose] Metastasis is responsible for most mortality in cancer therapy. Important things of metastatic treatment are not only prevention but also therapy of metastatic tumor. It was indicated that usability of liposomal doxorubicin (DOX) as drug delivery system formulation which were modified with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine dipolyethyleneglycol(different double arms PEG; DDA-PEG) (DDA-LDOX). DDA-PEG had two different PEG lengths, 2000 and 500, in one molecule. In this study, the effect of DDA-LDOX was examined on pulmonary metastasis compared with 1-monomethoxy-PEG(2000)-2,3-distearoylglycerol (PEG2000-DSG) modified liposomal DOX (2000-LDOX).[Methods] The liposomal DOX was prepared by L-α-distearoylphosphatidylcholine, cholesterol, L-α-distearoylphosphatidyl-DL-glycerol and DOX (100:100:60:18 μmol). Liposomal DOX was added 7.5 μmol DDA-PEG or 15 μmol PEG2000-DSG. In anti-metastasis experiment, BDF 1 mice were transplanted B16F10 melanoma cells by intravenous inoculation and each liposome (2.5 mg/kg, DOX) was injected at 20, 23 and 26 day after tumor transplantation. After 48 hr from last administration, the mice were dissected and score of pulmonary metastasis was recorded (0∼10, 0: normal). Removed tissues were determined DOX concentration by fluorescence method. In vitro, it was examined DOX uptake into B16F10 melanoma cells from each liposome. [Results and Discussion] Pulmonary metastasis scores of control and 2000-LDOX were 6.5 and 2.6, respectively. In contrast, that of DDA-LDOX was 1.0. Relative pulmonary weight (%) was correlation with metastatic score (R 2 =0.954) and supported pulmonary metastasis score. DOX concentration of DDA-LDOX was twice higher than that of 2000-LDOX in the lung, namely, it was proved that DDA-LDOX was easy to accumulate in the lung. Especially, it was suggested that DDA-LDOX accumulated into pulmonary metastatic site because DOX concentrations of heart, spleen and kidney were equal level in other group. In the examination of DOX uptake into tumor cells, DOX level in DDA-LDOX group was significantly higher than that in 2000-LDOX group. The data had supported high accumulation into pulmonary metastasis in vivo. In conclusion, it was suggested that DDA-LDOX was useful drug carrier for suppressed pulmonary metastasis since it could have target ability to pulmonary metastasis. Citation Format: Ikumi Sugiyama, Yasuyuki Sadzuka. Therapeutic efficacy of different double arms polyethyleneglycol-modified liposome containing doxorubicin on pulmonary metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4343. doi:10.1158/1538-7445.AM2013-4343
Cancer Research | 2013
Mai Yagi; Ikumi Sugiyama; Yasuyuki Sadzuka
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC [Purpose] Polyethyleneglycol (PEG) modification on liposomal membrane increases therapeutic index by improvement of targeting based on prolonged blood stream circulation. In contrast, some accumulation of drug after liposome treatment has also been observed in normal tissues, it is necessary to improve liposomal composition on the decrease of adverse reactions. Particularly, doxorubicin (DOX) encapsulated liposome has some adverse reactions as cardiac toxicity or hand-foot syndrome,etc. To contribute superior liposome formulation, different double arms PEG in a molecule(DDA-PEG) was synthesized and was clarified effectiveness in our previous reports. In this study, we examined physical properties of novel synthesized DDA-PEG, and the tissue distribution of the DOX encapsulated liposome with modification of these DDA-PEGs. [Methods] Two DDA-PEGs with (PEG1000 and PEG500) or (PEG2000 and PEG500) were synthesized. Critical micelle concentration (cmc) in 10 mM Tris-HCl buffer (pH7.4) and 10 mM lactate buffer (pH4.0) was measured by the method of florescent probe using the 8-anilinonaphthalene-1-sulfonate (ANS). Octanol-buffer partitioning value was determined. DOX encapsulated liposomes with the modification of each DDA-PEGs were prepared by DSPC/cholesterol/DSPG-Na/DOX/PEG-lipid =100:100:60:18:7.5 μmol according to the method of Bangham. M5076 ovarian sarcoma cells were transplanted into the backs of BDF1 mice, and each liposome was injected intravenously at a dose of 2.5 mg DOX/kg on 15, 18 and 21 day after tumor inoculation. The mice were sacrificed after 2 day from last administration, and the tumor was removed and weighted. Moreover, DOX concentrations in each tissue were determined. [Results and discussion] The cmc of all PEG-lipids were same level. In PEG(2000, 500)-modified liposome, DOX concentrations in tumors were equal to that in PEG2000-modified liposome. On the other hand, DOX concentration in the heart after PEG(2000, 500) modified liposome and PEG(1000,500)-modified liposome treatments were one second and one sixth compared with DOX solution group, respectively. According to these results, it was expected that novel DDA-PEG-modified liposome was able to reduce the cardiac toxicity which is adverse reaction by DOX. The DOX concentration in the liver was showed a low level by PEG (1000, 500) modified liposome. It was suggested that novel DDA- PEG-modified liposome had the effect of avoiding the uptake into the liver. In conclusion, it was suggested that PEG(1000,500) modified liposome could decrease the DOX level in heart, and had ability of accumulation into tumor and avoidance from reticuloendothelial cells as same as PEG2000-modified liposome as known liposome. Citation Format: Mai Yagi, Ikumi Sugiyama, Yasuyuki Sadzuka. Improvement of tissue distribution by the treatment of novel different double-arms polyethyleneglycol modified liposome encapsulating doxorubicin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4515. doi:10.1158/1538-7445.AM2013-4515