ゾル−ゲル転移を示す生体適合ポリマー材料の開発と応用

本研究の⼀部は2016-2017年度関⻄⼤学研究拠点形成⽀援経費において，研究課題「ゾル−ゲル転移を⽰す⽣体適合ポリマー材料の開発と応⽤」として研究費を受け，その成果を公表するものである

LPD after RHC for ascending colon cancer

Laparoscopic pancreaticoduodenectomy (LPD) has been widely adopted in institutions with sufficiently skilled practitioners. This technique requires attentive dissection around the superior mesenteric vein (SMV) and artery. Dissection around the SMV and Henle’s trunk is one of the key aspects of right hemicolectomy (RHC) ; adhesions and fibrosis around these vessels may impede LPD in patients with a history of RHC. We encountered three cases of periampullary tumors in patients with a history of RHC who were successfully treated with LPD. Cases 1, 2, and 3 were of 60-, 73-, and 74-year-old men with periampullary tumors. The operative durations in cases 1, 2, and 3 were 316, 267, and 265 min, respectively. The estimated blood loss volumes in cases 1, 2, and 3 were 20, 50, and 720 mL, respectively. The postoperative hospital stay durations in cases 1, 2, and 3 were of 13, 35, and 15 days, respectively. In conclusion, LPD following RHC may be safely completed with laparoscopy

Cell-type-specific Augmentation of the Tumoricidal Activity of Polymeric Adriamycin Combined with Galactosamine

The optimization of drug delivery system with approaches to a target in structure has been implicated to play a role in cancer chemotherapy, because it can reduce the adverse effects. However, this system partly reduces the direct cytotoxicity of anticancer drugs against tumor cells, in comparison to its free form. In the present study, poly(ﾎｱ- malic acid) adriamycin (poly ADR) coated with saccharides including galactosamine which recognizes galactose-lectin specific to hepatocytes was prepared, and its cytotoxicities against Hep G2 cells (human hepatoblastoma), AZ521 cells (human gastric cancer) and KNS cells (human lung cancer) was evaluated using an in vitro cytotoxicity assay. In both AZ521 cells and KNS cells, poly ADR as well as poly ADR coated with glucosamine, glactosamine or mannosamine provided relatively lower cytotoxicities than the free form of ADR. In contrast, Hep G2 cells were to more efficiently sensitized, compared with the free form of ADR or poly ADR combined with or without glucosamine or mannosamine (P<0.01, respectively). These results indicate that poly ADR coated with galactosamine used as a cell recognition element is thus applicable for targeting cancer chemotherapy in the treatment of hepatocellular carcinoma

ゾル−ゲル転移を示す生体適合ポリマー材料の開発と応用 (2)

(1) Title: Bulk pH Responsive DNA Quadruplex Hydrogels Prepared by Liquid-Phase Large Scale DNA SynthesisJournal: ACS Macro Letters(2) Title: Communication—DNA Quadruplex Hydrogel Beads Showing Peroxidase ActivityJournal: Journal of The Electrochemical SocietyDOI: http://dx.doi.org/10.1149/2.0441909je

ゾルーゲル転移を示す生体適合ポリマー材料の開発と応用 (1)

We investigated the release behavior of glucagon-like peptide-1 (GLP-1) from a biodegradable injectable polymer (IP) hydrogel. This hydrogel shows temperature-responsive irreversible gelation due to the covalent bond formation through a thiol-ene reaction. In vitro sustained release of GLP-1 from an irreversible IP formulation (F(P1/D+PA40)) was observed compared with a reversible (physical gelation) IP formulation (F(P1)). Moreover, pharmaceutically active levels of GLP-1 were maintained in blood after subcutaneous injection of the irreversible IP formulation into rats. This system should be useful for the minimally invasive sustained drug release of peptide drugs and other water-soluble bioactive reagents.P.4~P.14Title: Peptide Drug Release Behavior from Biodegradable Temperature-Responsive Injectable Hydrogels Exhibiting Irreversible GelationJournal: Gels Doi:https://doi.org/10.3390/gels3040038本研究の⼀部は 2016-2017 年度関⻄⼤学研究拠点形成⽀援経費において，研究課題「ゾル−ゲル転移を⽰す⽣体適合ポリマー材料の開発と応⽤」として研究費を受け，その成果を公表するものである

Severe Aortic Stenosis in Dialysis Patients

Background: Characteristics and prognosis of hemodialysis patients with severe aortic stenosis have not yet been well defined. Methods and Results: The CURRENT AS (contemporary outcomes after surgery and medical treatment in patients with severe aortic stenosis) registry, a Japanese multicenter registry, enrolled 3815 consecutive patients with severe aortic stenosis. There were 405 hemodialysis patients (initial aortic valve replacement [AVR] group: N=135 [33.3%], and conservative group: N=270) and 3410 nonhemodialysis patients (initial AVR group: N=1062 [31.1%], and conservative group: N=2348). The median follow‐up duration after the index echocardiography was 1361 days, with 90% follow‐up rate at 2 years. The cumulative 5‐year incidence of all‐cause death was significantly higher in hemodialysis patients than in nonhemodialysis patients in both the entire cohort (71% versus 40%, P<0.001) and in the initial AVR group (63.2% versus 17.9%, P<0.001). Among hemodialysis patients, the initial AVR group as compared with the conservative group was associated with significantly lower cumulative 5‐year incidences of all‐cause death (60.6% versus 75.5%, P<0.001) and sudden death (10.2% versus 31.7%, P<0.001). Nevertheless, the rate of aortic valve procedure–related death, which predominantly occurred within 6 months of the AVR procedure, was markedly higher in the hemodialysis patients than in the nonhemodialysis patients (21.2% and 2.3%, P<0.001). Conclusions: Among hemodialysis patients with severe aortic stenosis, the initial AVR strategy as compared with the conservative strategy was associated with significantly lower long‐term mortality risk, particularly the risk for sudden death, although the effect size for the survival benefit of the initial AVR strategy was smaller than that in the nonhemodialysis patients

Preparation of Biodegradable Oligo(lactide)s-Grafted Dextran Nanogels for Efficient Drug Delivery by Controlling Intracellular Traffic

Nanogels, nanometer-sized hydrogel particles, have great potential as drug delivery carriers. To achieve effective drug delivery to the active sites in a cell, control of intracellular traffic is important. In this study, we prepared nanogels composed of dextran with oligolactide (OLA) chains attached via disulfide bonds (Dex-g-SS-OLA) that collapse under the reductive conditions of the cytosol to achieve efficient drug delivery. In addition, we introduced galactose (Gal) residues on the nanogels, to enhance cellular uptake by receptor-mediated endocytosis, and secondary oligo-amine (tetraethylenepentamine) groups, to aid in escape from endosomes via proton sponge effects. The obtained Dex-g-SS-OLA with attached Gal residues and tetraethylenepentamine (EI4) groups, EI4/Gal-Dex-g-SS-OLA, formed a nanogel with a hydrodynamic diameter of ca. 203 nm in phosphate-buffered solution. The collapse of the EI4/Gal-Dex-g-SS-OLA nanogels under reductive conditions was confirmed by a decrease in the hydrodynamic diameter in the presence of reductive agents. The specific uptake of the hydrogels into HepG2 cells and their intercellular behavior were investigated by flow cytometry and confocal laser scanning microscopy using fluorescence dye-labeled nanogels. Escape from the endosome and subsequent collapse in the cytosol of the EI4/Gal-Dex-g-SS-OLA were observed. These biodegradable nanogels that collapse under reductive conditions in the cytosol should have great potential as efficient drug carriers in, for example, cancer chemotherapy

Gelation upon the Mixing of Amphiphilic Graft and Triblock Copolymers Containing Enantiomeric Polylactide Segments through Stereocomplex Formation

Biodegradable injectable polymer (IP) systems that form hydrogels in situ when injected into the body have considerable potential as medical materials. In this paper, we report a new two-solution mixed biodegradable IP system that utilizes the stereocomplex (SC) formation of poly(l-lactide) (PLLA) and poly(d-lactide) (PDLA). We synthesized triblock copolymers of PLLA and poly(ethylene glycol), PLLA-b-PEG-b-PLLA (tri-L), and a graft copolymer of dextran (Dex) attached to a PDLA-b-PEG diblock copolymer, Dex-g-(PDLA-b-PEG) (gb-D). We found that a hydrogel can be obtained by mixing gb-D solution and tri-L solution via SC formation. Although it is already known that graft copolymers attached to enantiomeric PLLA and PDLA chains can form an SC hydrogel upon mixing, we revealed that hydrogels can also be formed by a combination of graft and triblock copolymers. In this system (graft vs. triblock), the gelation time was shorter, within 1 min, and the physical strength of the resulting hydrogel (G′ > 100 Pa) was higher than when graft copolymers were mixed. Triblock copolymers form micelles (16 nm in diameter) in aqueous solutions and hydrophobic drugs can be easily encapsulated in micelles. In contrast, graft copolymers have the advantage that their molecular weight can be set high, contributing to improved mechanical strength of the obtained hydrogel. Various biologically active polymers can be used as the main chains of graft copolymers, and chemical modification using the remaining functional side chain groups is also easy. Therefore, the developed mixing system with a graft vs. triblock combination can be applied to medical materials as a highly convenient, physically cross-linked IP system