- 學位論文
硼中子捕獲治療劑-含硼RGD胜肽之合成
Synthesis of boronated RGD peptide for boron neutron capture therapy
摘要
硼中子捕獲治療的優勢在於它是一種二要素結合(binary)系統，即選擇一合適之含硼藥物為腫瘤組織所吸收，再給予中子的照射，由於10B和熱中子的結合產生高線性能量轉移(LET)輻射，若此含硼藥物集中在腫瘤組織，則可利用高LET之輻射能量殺死腫瘤細胞。相對地，若正常組織細胞吸收比例抑低則傷害可降至最低；而αvβ3 integrin是一種與腫瘤血管新生及腫瘤轉移相關的細胞黏著受器(cell adhesion receptor)，其具有Arg-Gly-Asp(RGD)序列之胜肽具有高度的專一結合特性，如能在其RGD胜肽上鍵結了含硼化合物，必能發展出具有潛力的硼中子捕獲治療劑。 在本研究合成的過程中，以4-iodobenzoic acid為起始物，進行保護反應、硼化反應及去保護反應，即得到化合物4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (TDBA)，以化合物進而行酸基的活化反應，形成NHS-activated ester。上述合成產物皆經由氫核磁共振光譜及碳核磁共振光譜予以鑑定確認。進而將NHS-activated ester分別與mono-RGD 胜肽及dimer-RGD 胜肽進行耦合反應，以高效能液相層析儀(HPLC)分離純化，依滯留時間在14.5分鐘及16.2分鐘分別觀察出硼化mono-RGD胜肽及硼化dimer-RGD胜肽之耦合化合物，以MALDI-TOF-Mass鑑定其分子量分別為885.23 Da及1615.286 Da。
並列摘要
Boron neutron capture therapy (BNCT) is a binary therapy that is to select a suitable boronated drug absorbed by tumor tissue and then to give thermal neutron irradiation. By nuclear reaction of 10B with thermal neutron, high linear energy transfer (LET) radiations including α2+ and 7Li+ can be produced. If the boronated drug is able to concentrate on tumor tissue, the resulted high-LET radiations will kill tumor with sparing of the normal tissue. αvβ3 integrin is an important cell adhesion receptor involved in tumor-induced angiogenesis and tumor metastasis. The high binding specificity to αvβ3 integrins of the peptides containing Arg-Gly-Asp(RGD) residue suggests that the RGD peptides conjugated boronated compound may be developed as a potential BNCT agent. In this study, using 4-iodobenzoic acid as starting material to proceed via protection, boronation and deprotection, the boronated compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (TDBA) was obtained. By activation of carboxyl group, the TDBA was converted to NHS-activated ester. The aforementioned products were confirmed by 1H and 13C-NMR. While proceeding coupling reaction in the NHS-activated ester with mono-RGD peptide, or dimer-RGD peptide, high performance liquid chromatography (HPLC) was employed to separate and purify the coupling products, the boronated mono-RGD peptide and boronated dimer-RGD peptide with retention times at 14.5 min or 16.2 min, respectively. The molecular weights identified by MALDI-TOF-Mass for the boronated mono-RGD and the boronated dimmer-RGD are 885.23 Da and 1615.286 Da, respectively.
參考文獻
延伸閱讀
- 劉育村（2007）。硼化RGD胜肽之合成與硼中子捕獲治療之生物評估〔碩士論文，國立清華大學〕。華藝線上圖書館。https://doi.org/10.6843/NTHU.2007.00533
- 黃亨通、李瑞成、丁幹（1992）。「硼中子捕捉療法」之尋癌藥物化學。化學，50(4)，421-433。https://doi.org/10.6623/chem.1992047
- 楊昇（2014）。加速器型硼中子捕獲治療超熱中子束之濾屏匯聚設計及假體劑量分析〔碩士論文，國立清華大學〕。華藝線上圖書館。https://www.airitilibrary.com/Article/Detail?DocID=U0016-2912201413524661
- Chun, H. Y. (2016). 以硼酸為中子捕獲治療藥物於腫瘤治療之作用機制探討 [master's thesis, National Tsing Hua University]. Airiti Library. https://www.airitilibrary.com/Article/Detail?DocID=U0016-2309201616094245
- Yen, W. A. (2020). Dehydrogenation and Polymerization of Ammonia-borane Using Boron Cations [master's thesis, National Taiwan University]. Airiti Library. https://doi.org/10.6342/NTU202003450