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Kazuto Hoshi – 1st expert on this subject based on the ideXlab platform
bmp 2 embedded Atelocollagen scaffold for tissue engineered cartilage cultured in the medium containing insulin and triiodothyronine a new protocol for three dimensional in vitro culture of human chondrocytesTissue Engineering Part C-methods, 2012Co-Authors: Edward Chengchuan Ko, Yuko Fujihara, Toru Ogasawara, Yukiyo Asawa, Satoru Nishizawa, Satoru Nagata, Tsuyoshi Takato, Kazuto HoshiAbstract:
When the chondrocytes are isolated from the native cartilage and proliferate in vitro, they soon lose their original ability to express glycosaminoglycan (GAG) and type II collagen, which is termed dedifferentiation, or decrease cell viability. We first examined in vitro cartilage regeneration of tissue-engineered pellets that consisted of human auricular chondrocytes and Atelocollagen and that were incubated in vitro under stimulation with bone morphogenetic protein-2 (BMP-2), insulin, and T3. We then examined the administration of those growth factors into the scaffold or in the medium and explored the possibility that the Atelocollagen, the hydrogel scaffold of the chondrocytes, may function for drug delivery of the factors. BMP-2 in the Atelocollagen with the supplement of insulin and T3 in the medium could not only produce a greater GAG matrix in a shorter period but also sustain cell viability with lower mortality. The insulin in the medium could be better administered only for 2 weeks, rather than …
administration of the insulin into the scaffold Atelocollagen for tissue engineered cartilageJournal of Biomedical Materials Research Part A, 2011Co-Authors: Edward Chengchuan Ko, Yuko Fujihara, Toru Ogasawara, Yukiyo Asawa, Satoru Nishizawa, Satoru Nagata, Tsuyoshi Takato, Kazuto HoshiAbstract:
Three-dimensional culture of the tissue-engineered cartilage constructs may increase the matrix production, but central necrosis must occur if the construct becomes large. To increase the cell viability in the middle part of constructs and to enhance the in vivo cartilage regeneration, we attempted to administer the insulin into the scaffold. Insulin is known to strongly enhance the matrix production in the chondrocytes. The pellets of human auricular chondrocytes with Atelocollagen hydrogel were 3D-cultured in the medium. The comparison among three groups (insulin mixed in the Atelocollagen, insulin added to the medium, and control group, i.e.; insulin in neither Atelocollagen nor medium) revealed that both insulin mixed in the Atelocollagen and that in the medium could effectively promoted the cell viability and matrix synthesis of the chondrocytes. The daily assay also showed the gradual release of insulin from the Atelocollagen hydrogel, suggesting that this material may work as a control release of insulin. We actually transplanted the poly-L-lactide porous scaffolds carrying the chondrocytes and the Atelocollagen mixed with or without insulin, into the nude mice, showing that glycosaminoglycan accumulation was evident in the group with insulin although less without insulin. We thus showed the possibility to enhance the in vivo cartilage regeneration, when administered insulin into the Atelocollagen hydrogel. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 97A: 186―192, 2011.
the application of Atelocollagen gel in combination with porous scaffolds for cartilage tissue engineering and its suitable conditionsJournal of Biomedical Materials Research Part A, 2009Co-Authors: Hisayo Yamaoka, Kazuto Hoshi, Yukiyo Asawa, Satoru Nishizawa, Tsuyoshi Takato, Yoko TanakaAbstract:
For improving the quality of tissue-engineered cartilage, we examined the in vivo usefulness of porous bodies as scaffolds combined with an Atelocollagen hydrogel, and investigated the suitable conditions for Atelocollagen and seeding cells within the engineered tissues. We made tissue-engineered constructs using a collagen sponge (CS) or porous poly(L-lactide) (PLLA) with human chondrocytes and 1% hydrogel, the concentration of which maximized the accumulation of cartilage matrices. The CS was soft with a Young’s modulus of less than 1 MPa, whereas the porous PLLA was very rigid with a Young’s modulus of 10 MPa. Although the constructs with the CS shrank to 50% in size after a 2-month subcutaneous transplantation in nude mice, the PLLA constructs maintained their original sizes. Both of the porous scaffolds contained some cartilage regeneration in the presence of the chondrocytes and hydrogel, but the PLLA counterpart significantly accumulated abundant matrices in vivo. Regarding the conditions of the chondrocytes, the cartilage regeneration was improved in inverse proportion to the passage numbers among passages 3–8, and was linear with the cell densities (106 to 108 cells/mL). Thus, the rigid porous scaffold can maintain the size of the tissue-engineered cartilage and realize fair cartilage regeneration in vivo when combined with 1% Atelocollagen and some conditioned chondrocytes. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res 2010
Shunji Nagahara – 2nd expert on this subject based on the ideXlab platform
Atelocollagen mediated systemic delivery prevents immunostimulatory adverse effects of sirna in mammalsMolecular Therapy, 2012Co-Authors: Shinichiro Inaba, Shunji Nagahara, Naoki Makita, Yuzo Tarumi, Kenji Kadomatsu, Takuji Ishimoto, Seiichi Matsuo, Yoshifumi TakeiAbstract:
Short interfering RNA (siRNA) is a potent activator of the mammalian innate immune system. When considering possible clinical applications of siRNA for humans, the adverse immunostimulatory effects must also be taken into account. Here, we show that Atelocollagen-mediated systemic delivery of siRNA without chemical modifications did not cause any immunostimulation in both animals and human peripheral blood mononuclear cells (PBMCs), even if the siRNA harbored an interferon (IFN)-inducible sequence. In contrast, systemic delivery of immunostimulatory RNA (isRNA)-mediated by a cationic lipid (such as Invivofectamine) induced potent type-I IFNs and inflammatory cytokines. Regarding the mechanism by which the isRNA/Atelocollagen complex avoided adverse effects on immunostimulation, we revealed that this complex was not incorporated into PBMCs. On the other hand, Invivofectamine delivered isRNA into PBMCs. The use of either Atelocollagen or Invivofectamine as a vehicle elicited significant and undistinguishable therapeutic effects in a contact hypersensitivity (CHS) inflammatory model mouse, when we intravenously injected the siRNA targeting monocyte chemoattractant protein-1 as the complex. For the goal of realizing siRNA-based medicines for humans, Atelocollagen is an excellent and promising delivery vehicle, and it has the useful advantage of evading detection by the “radar” of innate immunity.
systemic delivery of sirna specific to tumor mediated by Atelocollagen combined therapy using sirna targeting bcl xl and cisplatin against prostate cancerInternational Journal of Cancer, 2009Co-Authors: Ping Mu, Shunji Nagahara, Naoki Makita, Yuzo Tarumi, Kenji Kadomatsu, Yoshifumi TakeiAbstract:
The largest obstacle to the effective use of short interfering RNA (siRNA) in an animal body is the ability to deliver it to the target tissue. Here we showed a systemic delivery method of siRNA specific to pregrown solid tumors via Atelocollagen. Atelocollagen facilitated the selective uptake of siRNA into the tumors when an siRNA/Atelocollagen complex was administered intravenously to mice. We chose a Bcl-xL protein as a model target to prove the therapeutic efficacy of the Atelocollagen-mediated method. Bcl-xL acts as an anti-apoptotic factor, which is overexpressed in many cancers, including prostate cancer. One of the four designed siRNAs to human Bcl-xL potently inhibited the expression of Bcl-xL by the PC-3 human prostate cancer cell line in vitro, leading to cell apoptosis. Intravenous injections for3 consecutive days (siRNA, 100 μg/injection per day as a complex with Atelocollagen) effectively downregulated Bcl-xL expression in the PC-3 xenograft. We administered four series of 3 consecutive days of intravenous injections each, for a total of 12 injections, which significantly inhibited tumor growth when the treatment was combined with cisplatin (2 mg/kg). Local injection of Bcl-xL siRNA also potently inhibited tumor growth. All of the tumors treated with Bcl-xL siRNA/Atelocollagen complex via both intravenous and intratumoral injection showed terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptosis. There were no severe side effects such as interferon-α induction and liver or renal damage in mice. Our results indicate that systemic delivery of siRNA via Atelocollagen, which specifically targets tumors, is safe and feasible for cancer therapy. © 2009 UICC
single injection ornithine decarboxylase directed antisense therapy using Atelocollagen to suppress human cancer growthCancer, 2007Co-Authors: Kunihiko Nakazawa, Shunji Nagahara, Akihiko Sano, Takahiro Nemoto, Tomoko Hata, Yousuke Seyama, Hiroshi Itoh, Yutaka Nagai, Shunichiro KubotaAbstract:
Substantial evidence supports a direct role of ornithine decarboxylase (ODC) in the development and maintenance of human tumors. Although antisense oligonucleotide therapy targeting various genes are useful for cancer treatment, 1 of the major limitations is the problem of delivery. A novel antisense oligonucleotide delivery method is described that allows prolonged sustainment and release of ODC antisense oligonucleotides in vivo using Atelocollagen.
The effect of ODC antisense oligonucleotides in the Atelocollagen on cell growth of gastrointestinal cancer (MKN 45 and COLO201) and rhabdomyosarcoma (RD) was studied in vitro using a cell-counting method with a hemocytometer. In vivo, the effect of intratumoral, intramuscular, and intraperitoneal single administration of ODC antisense oligonucleotides in the Atelocollagen on tumor growth of MKN45, COLO201, and RD cells was studied. ODC activity and polyamine contents were measured.
In vitro, ODC antisense oligonucleotides in the Atelocollagen remarkably suppressed MKN45, COLO201, and RD cell growth. A single administration of antisense oligonucleotides in the Atelocollagen via 3 routes remarkably suppressed the growth of MKN45, COLO201, and RD tumor over a period of 35–42 days.
As various human cancers significantly express ODC, the results strongly suggest that this new antisense method may be of considerable value for treatment of human cancers. Cancer 2007;109:993–1002. © 2007 American Cancer Society.
Koji Hanai – 3rd expert on this subject based on the ideXlab platform
effects of Atelocollagen formulation containing oligonucleotide on endothelial permeabilityJournal of drug delivery, 2012Co-Authors: Koji Hanai, Takashi Kojima, Jun Onodera, Norimasa SawadaAbstract:
Atelocollagen is a major animal protein that is used as a highly biocompatible biomaterial. To date, Atelocollagen has been used as an effective drug delivery technology to sustain the release of antitumor proteins and to enhance the antitumor activity of oligonucleotides in in vivo models. However, the biological effects of this technology are not fully understood. In the present study, we investigated the effects of Atelocollagen on endothelial paracellular barrier function. An Atelocollagen formulation containing oligonucleotides specifically increased the permeability of two types of endothelial cells, and the change was dependent on the molecular size, structure of the oligonucleotides used and the concentrations of the oligonucleotide and Atelocollagen in the formulation. An immunohistochemical examination revealed that the formulation had effects on the cellular skeleton and intercellular structure although it did not affect the expression of adherens junction or tight junction proteins. These changes were induced through p38 MAP kinase signaling. It is important to elucidate the biological functions of Atelocollagen in order to be able to exploit its drug delivery properties.
Atelocollagen mediated systemic dds for nucleic acid medicinesAnnals of the New York Academy of Sciences, 2006Co-Authors: Koji Hanai, Shunji Nagahara, Yoshiko Minakuchi, Fumitaka Takeshita, Kimi Honma, Akihiko Sano, Miho Maeda, Takahiro OchiyaAbstract:
: The goal of our research is to provide a practical platform for drug delivery in oligonucleotide therapy. We report here the efficacy of an Atelocollagen-mediated oligonucleotide delivery system applied to systemic siRNA and antisense oligonucleotide treatments in animal disease models. Atelocollagen and oligonucleotides formed a complex of nanosized particles, which was highly stable against nucleases. The complex allowed oligonucleotides to be delivered efficiently into several organs and tissues via intravenous administration. In a tumor metastasis model, the complex successfully delivered siRNA to metastasized tumors in bone tissue and inhibited their growth. We also demonstrated that a single intravenous treatment of the antisense oligodeoxynucleotide complex suppressed ear dermatitis in a contact hypersensitivity model. These results indicate the strong potential of the Atelocollagen-mediated drug delivery system for practical therapeutic technology.
efficient delivery of small interfering rna to bone metastatic tumors by using Atelocollagen in vivoProceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Fumitaka Takeshita, Shunji Nagahara, Yoshiko Minakuchi, Kimi Honma, Hideo Sasaki, Yusuke Yamamoto, Kotaro Hirai, Takumi Teratani, Nachi Namatame, Koji HanaiAbstract:
Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with Atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and/or legs. We also show that the siRNA/Atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, Atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3′-hydroxykinase p110-α-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-α levels was not associated with the in vivo administration of the siRNA/Atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an Atelocollagen-mediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA.