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    Please use this identifier to cite or link to this item: http://nthur.lib.nthu.edu.tw/dspace/handle/987654321/86861


    Title: 以細胞穿透胜?發展新穎抗癌生醫材料
    Authors: 韓聞
    Han Wen
    Description: GH02102080605
    碩士
    分子與細胞生物研究所
    Date: 2015
    Keywords: 微脂體藥物 細胞穿透胜? 醣胺多醣 生醫材料 腫瘤標靶
    liposomal drug cell penetrating peptide glycosaminoglycan biomaterial tumor targeting
    Abstract: 上皮癌細胞的治療方法受限於內吞作用及被動運輸,傳統化學治療藥物非專一性的藥物生物分布會導致嚴重的副作用,因此開發專一性辨認腫瘤細胞表面配體(ligand)為目前改良癌症治療的轉譯研究趨勢。本實驗室於人類嗜酸性白血球陽離子蛋白(human eosinophil cationic protein、hECP)中核心硫酸乙醯肝素(heparan sulfate、HS)結合區域發展具有醣胺多醣(glycosaminoglycan、GAG)結合、表皮細胞結合、細胞穿透、及載物傳遞能力的新穎細胞穿透胜?(cell penetrating peptide、CPPecp)。細胞表面的GAG在受體(receptor)與生長因子之間扮演複合受體(coreceptor)的角色,調控細胞的生長、黏附、移行、訊號傳遞、並調控癌症進程。本研究成功將含有磷脂質的交聯劑和CPPecp結合成為生醫材料,進一步發展以CPPecp為基礎修飾之新穎微脂體藥物,並證實其於人類肺癌上皮細胞之攝入效率高於未修飾的微脂體藥物,故可提升抗癌活性。本研究利用3D細胞培養技術模擬立體腫瘤微組織,發現CPPecp修飾微脂體藥物穿透3D癌細胞球體之能力高於未修飾微脂體藥物,顯示其具備較強的抑制固體癌組織能力。進一步利用皮下異種移植之腫瘤小鼠模式進行藥物療效研究,初步結果顯示相較於未修飾微脂體藥物治療之腫瘤小鼠,CPPecp修飾微脂體藥物不會造成受試動物體重減輕、顯著改善藥物之副作用、且此新穎配方明顯抑制腫瘤的生長。基於現今尚未被滿足的醫療需求甚高,本研究發展之合成策略可提供替代的解決方案以減低微脂體藥物之劑量及癌症化療藥物的副作用,具備轉譯醫學發展潛力。
    Therapeutic treatment on epithelial cancer is still limited by low internalization activity and passive transportation. Traditional chemotherapeutic agents usually accompany with severe side effects due to nonspecific drug biodistribution. The development of new methods for improving translational research for cancer therapy is contingent on specific recognition of ligands on the surface of cancer cells. Here, a novel cell penetrating peptide derived from core heparan sulfate binding motif of human eosinophil cationic protein (hECP), CPPecp, possesses cell surface glycosaminoglycan (GAG) binding, epithelial cell binding, cell penetrating, and cargo delivery activities. Cell surface GAGs are important co-receptors between cell surface receptor and growth factors, and regulate cell proliferation, adhesion, migration and signaling, especially during cancer progression. In this study we have successfully conjugated CPPecp to a phospholipid containing linker and developed a novel CPPecp-based modification methodology of liposomal drug. As expected, in vitro cellular uptake efficiency of CPPecp-modified liposomal drug toward lung epithelial cancer cells is evidently higher than that of unmodified liposomal drug, leading to enhancement of anti-tumor activity. In addition, 3D culture of epithelial cancer spheroid mimicking solid tumor microtissues shows higher permeability of CPPecp-modified liposomal drug than that of unmodified liposomal drug. Moreover, in vivo epithelial tumor-bearing mouse model with treatment of CPPecp-modified liposomal drug demonstrates no dramatic weight decrease as original drug does, suggesting low side effects during medication. Our new formulation inhibits in vivo tumor progression to a much significant extent than unmodified liposomal drug. Our engineering strategy provides an alternative solution for unmet medical need to reduce the dosage of liposomal drugs and alleviate chemotherapeutic side effects in cancer therapy, which in turn contributes to further development of translational medicine.
    URI: http://nthur.lib.nthu.edu.tw/dspace/handle/987654321/86861
    Source: http://thesis.nthu.edu.tw/cgi-bin/gs/hugsweb.cgi?o=dnthucdr&i=sGH02102080605.id
    Appears in Collections:[分子與細胞生物研究所] 博碩士論文

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