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Human Lipocalin-Type Prostaglandin D Synthase-Based Drug Delivery System for Poorly Water-Soluble Anti-Cancer Drug SN-38.

Nakatsuji M, Inoue H, Kohno M, Saito M, Tsuge S, Shimizu S, Ishida A, Ishibashi O, Inui T - PLoS ONE (2015)

Bottom Line: In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS.The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone.Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

ABSTRACT
Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily, which is composed of secretory transporter proteins, and binds a wide variety of small hydrophobic molecules. Using this function, we have reported the feasibility of using L-PGDS as a novel drug delivery vehicle for poorly water-soluble drugs. In this study, we show the development of a drug delivery system using L-PGDS, one that enables the direct clinical use of 7-ethyl-10-hydroxy-camptothecin (SN-38), a poorly water-soluble anti-cancer drug. In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS. Calorimetric experiments revealed that L-PGDS bound SN-38 at a molecular ratio of 1:3 with a dissociation constant value of 60 μM. The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone. The intravenous administration of SN-38/L-PGDS complexes to mice bearing Colo201 tumors showed a pronounced anti-tumor effect. Intestinal mucositis, which is one of the side effects of this drug, was not observed in mice administered SN-38/L-PGDS complexes. Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects.

No MeSH data available.


Related in: MedlinePlus

Effects of SN-38/L-PGDS complexes on the small intestines.(A) Histology of the ileal mucosa. Inset shows the villi architecture. Scale bar represents 100 μm. The left panel shows the ileal mucosa of the mice administered SN-38/L-PGDS complexes; and the right one, that of the mice administered PBS. The ileal mucosa in both groups was almost the same. (B) Expression levels of inflammatory cytokines in the ileal mucosa. Each bar represents the mean ± SD (n = 3).
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pone.0142206.g005: Effects of SN-38/L-PGDS complexes on the small intestines.(A) Histology of the ileal mucosa. Inset shows the villi architecture. Scale bar represents 100 μm. The left panel shows the ileal mucosa of the mice administered SN-38/L-PGDS complexes; and the right one, that of the mice administered PBS. The ileal mucosa in both groups was almost the same. (B) Expression levels of inflammatory cytokines in the ileal mucosa. Each bar represents the mean ± SD (n = 3).

Mentions: It is well known that one of the major clinical side effects of CPT-11 is severe diarrhea [24, 25]. Several reports have shown that the administration of CPT-11 induces intestinal mucositis characterized by the loss of crypt architecture and the production of inflammatory cytokines [26, 27]. Thus, we investigated by histopathological analysis and the measurement of the expression levels of various inflammatory cytokines in the small intestines whether or not these side effects of CPT-11 were manifested by the SN-38/L-PGDS complex (Fig 5). The mice intravenously administered SN-38/L-PGDS complexes at a dose of 2.8 mg/kg/d by using the same dose schedule as used for the growth inhibition assay did not show any diarrhea. The histological observations of the intestinal mucosa demonstrated the preservation of the villi and crypt architecture, which was similar to that seen in the PBS-administered group (Fig 5A), thus indicating that the SN-38/L-PGDS complex did not induce intestinal lesions. In addition, the expression levels of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the intestines of the mice administered SN-38/L-PGDS complexes were unchanged compared with those for the mice administered PBS (1.3- and 1.0-fold, respectively; Fig 5B). On the other hand, in the intestines of the mice administered lipopolysaccharide, as a positive control, the up-regulation of IL-6 and IL-1β was observed (data not shown). Thus, these results revealed that the administration of the SN-38/L-PGDS complex did not show any side effects such as intestinal mucositis.


Human Lipocalin-Type Prostaglandin D Synthase-Based Drug Delivery System for Poorly Water-Soluble Anti-Cancer Drug SN-38.

Nakatsuji M, Inoue H, Kohno M, Saito M, Tsuge S, Shimizu S, Ishida A, Ishibashi O, Inui T - PLoS ONE (2015)

Effects of SN-38/L-PGDS complexes on the small intestines.(A) Histology of the ileal mucosa. Inset shows the villi architecture. Scale bar represents 100 μm. The left panel shows the ileal mucosa of the mice administered SN-38/L-PGDS complexes; and the right one, that of the mice administered PBS. The ileal mucosa in both groups was almost the same. (B) Expression levels of inflammatory cytokines in the ileal mucosa. Each bar represents the mean ± SD (n = 3).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4631600&req=5

pone.0142206.g005: Effects of SN-38/L-PGDS complexes on the small intestines.(A) Histology of the ileal mucosa. Inset shows the villi architecture. Scale bar represents 100 μm. The left panel shows the ileal mucosa of the mice administered SN-38/L-PGDS complexes; and the right one, that of the mice administered PBS. The ileal mucosa in both groups was almost the same. (B) Expression levels of inflammatory cytokines in the ileal mucosa. Each bar represents the mean ± SD (n = 3).
Mentions: It is well known that one of the major clinical side effects of CPT-11 is severe diarrhea [24, 25]. Several reports have shown that the administration of CPT-11 induces intestinal mucositis characterized by the loss of crypt architecture and the production of inflammatory cytokines [26, 27]. Thus, we investigated by histopathological analysis and the measurement of the expression levels of various inflammatory cytokines in the small intestines whether or not these side effects of CPT-11 were manifested by the SN-38/L-PGDS complex (Fig 5). The mice intravenously administered SN-38/L-PGDS complexes at a dose of 2.8 mg/kg/d by using the same dose schedule as used for the growth inhibition assay did not show any diarrhea. The histological observations of the intestinal mucosa demonstrated the preservation of the villi and crypt architecture, which was similar to that seen in the PBS-administered group (Fig 5A), thus indicating that the SN-38/L-PGDS complex did not induce intestinal lesions. In addition, the expression levels of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the intestines of the mice administered SN-38/L-PGDS complexes were unchanged compared with those for the mice administered PBS (1.3- and 1.0-fold, respectively; Fig 5B). On the other hand, in the intestines of the mice administered lipopolysaccharide, as a positive control, the up-regulation of IL-6 and IL-1β was observed (data not shown). Thus, these results revealed that the administration of the SN-38/L-PGDS complex did not show any side effects such as intestinal mucositis.

Bottom Line: In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS.The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone.Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.

ABSTRACT
Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily, which is composed of secretory transporter proteins, and binds a wide variety of small hydrophobic molecules. Using this function, we have reported the feasibility of using L-PGDS as a novel drug delivery vehicle for poorly water-soluble drugs. In this study, we show the development of a drug delivery system using L-PGDS, one that enables the direct clinical use of 7-ethyl-10-hydroxy-camptothecin (SN-38), a poorly water-soluble anti-cancer drug. In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS. Calorimetric experiments revealed that L-PGDS bound SN-38 at a molecular ratio of 1:3 with a dissociation constant value of 60 μM. The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone. The intravenous administration of SN-38/L-PGDS complexes to mice bearing Colo201 tumors showed a pronounced anti-tumor effect. Intestinal mucositis, which is one of the side effects of this drug, was not observed in mice administered SN-38/L-PGDS complexes. Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects.

No MeSH data available.


Related in: MedlinePlus