跳到主要內容

臺灣博碩士論文加值系統

(18.97.9.172) 您好!臺灣時間:2025/02/18 03:40
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:甘國邑
研究生(外文):Kuo-yi Kan
論文名稱:新型肝癌治療劑之研究-C/GP智慧型凝膠合併Doxorubicin和錸-188膠體之探討
論文名稱(外文):A novel pharmaceutical in hepatic tumor research – the study of used C/GP intelligent gel combined Doxorubicin and 188Re-colloid
指導教授:謝栢滄謝栢滄引用關係
指導教授(外文):Bor-Tsung Hsieh
學位類別:碩士
校院名稱:中臺科技大學
系所名稱:醫學影像暨放射科學系暨研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:98
中文關鍵詞:熱敏感型凝膠智慧型藥物釋放系統Doxorubincin188Re-tin collid
外文關鍵詞:doxorubicinC/GP hydrogeldrug delivery systemhepatic tumor
相關次數:
  • 被引用被引用:0
  • 點閱點閱:346
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
目的:利用直接腫瘤注射(I.T.)方式,將188Re-Dox-C/GP凝膠藥物固定於肝腫瘤,進行治療肝癌動物模型療效評估,與探討相關C/GP凝膠特性研究及放射凝膠藥物於體內滯留評估之研究。
材料與方法:一、C/GP凝膠時間研究:針對C/GP凝膠與Dox-C/GP凝膠藥物(25 µg & 0.4 mg/mL),在Tg凝膠溫度(37℃),經由UV分光度計量測,探討形成凝膠之時間點;二、體外藥物釋放研究:利用透析膜管(Spectra/pro®),封裝Dox sol.、Dox-C/GP及188Re-Dox-C/GP凝膠藥物,置於裝有PBS溶液燒杯中,於不同時間點採集樣品,經由螢光光度計分析Dox藥物含量;三、細胞毒性研究:將完成製備之C/GP凝膠與N1-S1肝癌細胞進行培養,評估C/GP凝膠對抑制N1-S1生長能力。四、平面閃爍&生物分佈研究:動物麻醉後,以I.T.給藥方式,將188Re-Dox-C/GP凝膠藥注射於病灶處,分別在給藥後0、24和48小時進行平面閃爍造影及定量分析其錸-188膠體於體內之滯留率;相同時間點,犧牲老鼠取其主要器官,透過γ-counter分析放射藥物活度;五、治療療效評估研究:荷肝腫瘤之大鼠,接受不同配方藥物注射後,監測體重變化在治療後第0、2及4週。同時間點,將同批老鼠,利用超音波掃描量測腫瘤之大小。療效存活評估,則是老鼠接受治療後60天,記錄實驗老鼠存活天數,經由生物統計分析是否具有顯著意義。完成存活時間測試後,針對188Re-Dox-C/GP凝膠藥物治療之肝癌老鼠,藉由CT掃描作比對是否與超音波診斷結果相符。隨即,將老鼠犧牲,取出主要來源器官,送往病理部門分析,評估藥物凝膠於肝腫瘤之治療效果。
結果:凝膠時間研究顯示C/GP凝膠與Dox-C/GP凝膠藥物(25 µg & 0.4 mg/mL),在Tg溫度下,所測得凝膠時間相近約4.5分鐘。但是,對於形成之凝膠特性則有所差異。在體外藥物釋放研究,以188Re-Dox-C/GP熱凝膠延緩Dox藥物釋放效果最佳,在藥物釋放後48小時,僅觀察到51±0.88 %Dox藥物被釋出。平面閃爍及生物分佈研究,表示I.T.注射188Re-Dox-C/GP凝膠溶液,能有效將錸-188膠體固定於病灶處,維持48無明顯擴散,其藥物滯留率為39%±0.132。體內生物分佈研究結果,證實以I.T.注射188Re-Dox-C/GP藥物,其錸-188放射藥物累積於腫瘤最高且對正常肝臟影響較小,唯有少量藥物活度累積於肺臟於注射後24小時。細胞毒性與治療肝腫瘤之療效研究,發現C/GP凝膠本身具抑制腫瘤能力。在CT造影與病理切片查驗,我們發現在C/GP凝膠合併放療及化療藥物的組織切片,其治療腫瘤之功效比188Re-C/GP凝膠藥物好,並伴隨有鈣化現象產生。
討論&結論:C/GP系統合併188Re-Tin colloid與Doxorubicin,經由I.T.注射給藥途徑,局部治療腫瘤,除了具備延緩藥物釋放能力及合併不同治療模式,提高治療肝腫瘤之功效外;凝膠本身亦具備抑制腫療生長能力,更大幅加強其治療效果且適用於未來臨床研究,針對無法切除腫瘤之肝癌病患,作為另一項選擇。
Objective: Intratumoral (I.T.) injected 188Re-Dox-C/GP gel into hepatic tumor, to execute treatment efficacy evaluation of liver cancer animal model and explore related characteristic of C/GP (chitosan/β-glycerophosphate) gel and biodistribution study. Materials and methods: gelation time study: C/GP gel and Dox-C/GP gel (25 µg & 0.4 mg/mL) were measured at 37℃ by UV-spectrophotometer from flowable liquid to semi-solid gel. (2) In vitro of drug released study: used the dialysis tube to encapsulate of doxorubicin (Dox) sol., Dox-C/GP, and 188Re (colloid)-Dox-C/GP gel, then them were immersed in phosphate buffer solution (PBS, 0.01M, pH =7.4) at different time, sample of PBS were withdrawn by fluorescence spectrometer analysis. (3) Cytotoxic study: the C/GP gel was prepared and co-incubation with N1-S1 cells for evaluation the survival cells in different time (4) Planar scintigraphy & biodistribtuion study: animals were anesthetized to perform and calculation of 188Re-Tin colloid retention rate on whole rat using planar scintigraphy at 1, 24, and 48 h drug delivery. At the same time point, the tumor-bearing rats were sacrificed to obtain source organs with radioactive of the obtained tissues were quantitatively analyzed by auto-γ-counter. (5)Therapeutic efficacy studies: the tumor-bearing rats were treated through 0.1 mL of normal saline, C/GP gel, 188Re-C/GP (37 MBq) and 188Re-Dox-C/GP (0.5 mg Dox and 37 MBq of 188Re-Tin colloid) gel-drug by I.T. injection for comparative treatment efficacy of hepatic tumor on body weight, tumor size, survival time and histological examinations. Results: the gelation time of different ration of Dox-C/GP gel and C/GP gel at 37℃ was 4.5 min. In vitro released of Dox study from 188Re-Dox-C/GP gel has the best of control drug delivery ability, only 51%±0.88 of accumulate drug were observed at 48 h. Observation 188Re of radioactivity on planar scintigrams at selected time points showed no obvious diffusion in injection site even 48h after injections with retention rate was 39%±0.132. In biodistibution study demonstrated that 188Re of radioactivity accumulated in tumor are highest than other organ, but still a part of 188Re-colloid distributed in lung were observed at 24h. I.T. injection of normal saline and different formulations gel-drug in treatment efficacy evaluations and in vitro of cytotoxic test, it found C/GP gel had inhibited tumor growth effect. Although, it can’t comparative both of 188Re-C/GP gel and 188Re-Dox-C/GP gel in tumor growth curve and survival time test by calculation tumor size and biostatistics analysis. However, for CT image and histology H&E stain analysis on 188Re-Dox-C/GP gel-group showed more calcification and apoptosis than 188Re-C/GP gel-group. Discussion/Conclusions: The C/GP system combined 188Re-Tin colloid and Doxorubicin by I.T. injections to treatment hepatic. Not only has prolonged drug delivery time but also radio-and chemotherapy model merge, for raised the treatment effects; the C/GP itself also has ability of inhibited tumor growth with more drastic increase in treatment efficacy. Perhaps this study will offer development of the potentiality for drug and a novel treatment model.
目錄
中文摘要 I
英文摘要 II
圖目錄 VII
表目錄 VI
前言 1
1.1. 研究背景 1
1.2. 研究目的 3
2. 文獻回顧 4
2.1. 甲殼素凝膠作為控制藥物釋放系統 4
2.1.1. 光敏感式甲殼素水凝膠 6
2.1.2. 熱敏感式甲殼素凝膠 10
2.1.3. 疏水性修飾乙二醇甲殼素水凝膠 17
2.2. 具備療效之放射性核種 24
2.3. 臨床肝癌治療方式 25
2.4. 應用C/GP藥物釋放系統原位形成凝膠治療肝癌腫瘤 26
2.5. 前期完成研究188Re-C/GP凝膠治療肝癌可行性評估[43] 29
2.5.1. 不同凝膠時間配方之錸-188熱凝膠於加馬閃爍造影研究 29
2.5.2. 不同凝膠時間配方之錸-188熱凝膠於體內生物分佈研究 31
2.5.3. 188Re-C/GP水凝膠直接腫瘤注射治療肝癌動物模型之體內劑量評估研究[48-49] 37
3. 材料與方法 39
3.1. 材料 39
3.2. Dox-C/GP水凝膠製備與凝膠時間特性研究 41
3.2.1. Dox-C/GP水凝膠之製備 41
3.2.2. C/GP凝膠時間特性研究[45] 41
3.3. C/GP熱凝膠合併化療藥物Dox和放療藥物錸-188膠體製備流程 42
3.4. C/GP凝膠合併Dox和錸-188膠體進行體外藥物釋放動力學研究 43
3.5. 肝癌動物模型建立[50] 44
3.6. C/GP水凝膠抑制對N1-S1生長之評估 45
3.7. 動物平面閃爍照影研究 46
3.7.1. 188Re-Dox-C/GP凝膠藥物於體內滯留性評估 46
3.7.2. 188Re-Dox-C/GP凝膠體內滯留性ROI定量分析 47
3.8. 188Re-Dox-C/GP凝膠體內生物分佈研究 48
3.9. 188Re-Dox-C/GP凝膠治療腫瘤療效評估 49
3.9.1. 體重監測 49
3.9.2. 抑制腫瘤生長療效評估 49
3.9.3. 治療肝癌老鼠存活曲線分析 50
3.9.4. H&E染色病理切片檢驗[53] 50
3.10. 統計分析 51
4. 結果 52
4.1. 體外測試C/GP凝膠時間特性研究 52
4.2. C/GP凝膠合併Dox和錸-188膠體進行體外藥物釋放動力學研究 53
4.3. C/GP凝膠抑制對N1-S1生長評估 54
4.4. 188Re-Dox-C/GP藥物體內滯留性研究 55
4.5. 188Re-Dox-C/GP藥物在體內生物分佈研究 56
4.6. C/GP凝膠合併放療與化療藥物治療肝腫瘤療效評估 58
4.6.1. 療效評估之體重監測 58
4.6.2. C/GP凝膠合併Dox與錸-188膠體治療腫瘤之生長曲線評估 59
4.6.3. 療效之存活評估 61
4.6.4. H&E染色病理切片檢驗 63
5. 討論 65
5.1. 體外測試Dox-C/GP凝膠時間特性之探討 65
5.2. 188Re-Dox-C/GP水凝膠於體外藥物釋放動力學研究之探討 67
5.3. 188Re-Dox-C/GP藥物於生物體內滯留性評估探討 70
5.4. 治療腫瘤之療效評估探討 72
5.4.1. 188Re-Dox-C/GP藥物治療肝癌療效探討 72
5.4.2. H&E染色之病理研究探討 76
5.5. 188Re-Dox-C/GP凝膠系統於體內安全性評估 78
6. 結論 81
7. 參考文獻 82
1.Livraghi, T., et al., Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology, 2008. 47(1): p. 82-89.
2.Szyszko, T., et al., Therapy options for treatment of hepatic malignancy. European Journal of Nuclear Medicine and Molecular Imaging, 2008. 35(10): p. 1824-1826.
3.Bhattarai, N., et al., Chitosan-based hydrogels for controlled, localized drug delivery. Advanced Drug Delivery Reviews, 2010. 62(1): p. 83-99.
4.Berrada, A., et al., A novel non-toxic camptothecin formulation for cancer chemotherapy. Biomaterials, 2005. 26: p. 2115–2120.
5.Azhdarinia, A., et al., Regional Radiochemotherapy Using In Situ Hydrogel. Pharmaceutical Research, 2005. 22(5): p. 776-783.
6.Ruel-Gariépy, E., et al., Characterization of thermosensitive chitosan gels for the sustained delivery of drugs. International Journal of Pharmaceutics, 2000. 203(1-2): p. 89-98.
7.Molinaro, G., et al., Biocompatibility of thermosensitive chitosan-based hydrogels: an in vivo experimental approach to injectable biomaterials. Biomaterials, 2002. 23: p. 2717–2722.
8.Chenite, A., et al., A. Novel injectable neutral solutions of chitosan form biodegradible gels in situ for bioactive therapeutic delivery, Biomaterials, 2000. 21: p. 2155-2161.
9.Ono, K., et al., Photocrosslinkable chitosan as a biological adhesive, J. Biomed. Mater. Res., 2000. 49(part A): p. 289–295.
10.Ishihara, M., et al., Chitosan hydrogel as a drug delivery carrier to control angiogenesis, J.Artif. Organs., 2006. 9: p. 8–16.
11.Obara, K., et al., Controlled release of paclitaxel from photocrosslinked chitosan hydrogels and its subsequent effect on subcutaneous tumor growth in mice, J. Control. Release, 2005. 110: p. 79–89.
12.Buschmann, M., et al., Gel formation of polyelectrolyte aqueous solutions by thermally induced changes in ionization state, Canada Patent WO, 2007. 0513112007.
13.Ruel-Gariepy, E., et al., A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel, Eur. J. Pharm. Biopharm, 2004. 57: p. 53–63.
14.Chenite, A., et al., Rheological characterisation of thermogelling chitosan/glycerol-phosphate solutions, Carbohydr. Polym, 2001. 46: p. 39–47.
15.Cho, J., et al., Physical gelation of chitosan in the presence of b-glycerophosphate: the effect of temperature, Biomacromolecules, 2005. 6: p. 3267–3275.
16.Hang Thu Ta, et al., Injectable chitosan hydrogels for localized cancer therapy, Journal of Controlled Release, 2008. 126: p. 205-216.
17.Ruel-Gariepy, E., et al., Thermosensitive chitosan-based hydrogel containing liposomes for the delivery of hydrophilic molecules, J. Control. Release, 2002. 82: p. 373–383.
18.Han, H.D., et al., A chitosan hydrogel-based cancer drug delivery system exhibits synergistic antitumor effects by combiningwith a vaccinia viral vaccine, Int. J. Pharm, 2008. 350: p. 27–34.
19.Kwon, S., et al., Physicochemical characteristics of self-assembled nanoparticles based on glycol chitosan bearing 5β-cholanic acid, Langmuir, 2003. 19: p. 10188–10193.
20.Min, K.H., et al., Hydrophobically modified glycol chitosan nanoparticles-encapsulated camptothecin enhance the drug stability and tumor targeting in cancer therapy, Journal of Controlled Release, 2008. 127: p. 208-218
21.Van-Hattum, A.H., et al., The activity profile of the hexacyclic camptothecin derivative DX-8951f in experimental human colon cancer and ovarian cancer, Biochem. Pharmacol, 2002. 64: p. 1267–1277.
22.Lerchen, H.G., et al., Design and optimization of 10-O-linked camptothecin glycoconjugates as anticancer agents, J. Med. Chem, 2001. 44: p. 4186–4195.
23.Knoght, V., et al., Anticancer effect of 9-nitrocamptothecin liposome aerosol on human cancer xenografts in nude mice, Cancer Chemother. Pharmacol, 1999. 44: p. 177–186.
24.Herben, V.M., et al., Clinical pharmacokinetics of topotecan, Clin. Pharmacokinet, 1996. 31: p. 85–102.
25.Gottlieb, J.A., et al., Treatment of malignant melanoma with camptothecin (NSC-100880), Cancer Chemother. Rep, 1972. 56: p. 103–105.
26.Moertel, C.G., et al., Phase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinal cancer, Cancer Chemother. Rep., 1972. 56: p. 95–101.
27.Muggia, F.M., et al., Phase I clinical trial of weekly and daily treatment with camptothecin: correlation with pre-clinical studies, Cancer Chemother. Rep., 1972. 56: p. 515–521.
28.Weingart, J.D., et al., Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the intracranial 9 L aliosarcoma model, Int. J. Cancer, 1995. 62: p. 605–609.
29.Storm, P.B., et al., Polymer delivery of camptothecin against 9L gliosarcoma: release, distribution, and efficacy, J. Neurooncol, 2002. 56: p. 209–217.
30.Jain, R.A., et al., The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices, Biomaterials, 2000. 21: p. 2475–2490.
31.Fassberg, J., et al., A kinetic and mechanistic study of the hydrolysis of camptothecin and some analogues, J. Pharm, 1992. 81: p. 676–684.
32.Hertberg, R.P., et al., Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity, J.Med. Chem, 1989. 32:p. 715–720.
33.Burke, T.G., et al., The structural basis of camptothecin interactions with human serum albumin: impact on drug stability, J. Med. Chem, 1994. 37: p. 40–46.
34.Hwang, H.Y., et al., Tumor targetability and antitumor effect of docetaxel-loaded hydrophobically modified glycol chitosan nanoparticles, J. Control. Release., 2008. 128: p. 23-31
35.Qi, L., et al., In vitro and in vivo suppression of hepatocellular carcinoma growth by chitosan nanoparticles. European Journal of Cancer, 2007. 43(1): p. 184-193.
36.Hamoudeh, M., et al., Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer, Advanced Drug Delivery Reviews, 2008. 60: p. 1329–1346
37.Garrean, S. et al., Yttrium-90 internal radiation therapy for hepatic malignancy. Surgical Oncology, 2005. 14(4): p. 179-193.
38.Sundram, F., Radionuclide therapy of hepatocellular carcinoma. 2006.
39.Changa, Y.J., et al., Therapeutic efficacy and microSPECT/CT imaging of 188Re-DXR-liposome in a C26 murine colon carcinoma solid tumor model. Nuclear Medicine and Biology, 2010. 37: p. 95–104
40.Azab, A. K., et al., Prevention of tumor recurrence and distant metastasis formation in a breast cancer mouse model by biodegradable implant of 131I-norcholesterol. J. Control. Release, 2007. 123: p. 116–122.
41.Zhi-kui, C., et al., US-guided interstitial chemotherapy using paclitaxel temperature-responsive gel for breast cancer treatment in rat. Journal of Cancer Research and Clinical Oncology, 2010. 136(4): p. 537-545.
42.Chen, Z. k., et al., Interstitial chemotherapy using thermosensitive gel-coated ricin in nude mice bearing a human hepatoma. Hepatology Research, 2010. 40: p. 188–195
43.Huang, L. K. et al., Local delivery of rhenium-188 colloid into hepatic tumor sites in rats using thermo-sensitive chitosan hydrogel: effects of gelling time of chitosan as delivery system. J Radioanal Nucl Chem, 2011. 290: p. 39–44
44.Kwak, M., et al., Suppression of in vivo tumor growth by using a biodegradable thermosensitive hydrogel polymer containing chemotherapeutic agent. Investigational New Drugs, 2010. 28(3): p. 284-290.
45.Dang, Q.F., et al., Controlled gelation temperature, pore diameter and degradation of a highly porous chitosan-based hydrogel. Carbohydrate Polymers, 2011. 83: p.171-178
46.Soundararajan, A., et al., [186Re]Liposomal doxorubicin (Doxil): in vitro stability, pharmacokinetics, imaging and biodistribution in a head and neck squamous cell carcinoma xenograft model. Nuclear Medicine and Biology, 2009. 36(5): p. 515-524.
47.Kang, G.D., et al., Controlled release of doxorubicin from thermosensitive poly(organophosphazene) hydrogels. International Journal of Pharmaceutics, 2006. 319(1-2): p. 29-36.
48.Stabin, M.G. et al., Physical Models and Dose Factors for Use in Internal Dose Assessment. Health Physics, 2003. 85(3): p. 294-310.
49.Chang, C.-H., et al., Comparative Dosimetric Evaluation of Nanotargeted 188Re-(DXR)-Liposome for Internal Radiotherapy. Cancer Biotherapy & Radiopharmaceuticals, 2008. 23(6): p. 749-758.
50.Wang, S.J., et al., Knapp FF Jr, Nucl Med, 1998. 39(10): p. 1752–1757
51.Carlsson, G., et al., Estimation of liver tumor volume using different formulas—An experimental study in rats, Journal of Cancer Research and Clinical Oncology, 1983. 105(1): p. 20-23.
52.Fang, F., et al., Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand. Acta Pharmacol Sin, 2005. 26(11): p. 1373-1381.
53.Cao, W., et al., Heated lipiodol as an embolization agent for transhepatic arterial embolization in VX2 rabbit liver cancer model. European Journal of Radiology, 2010. 73(2): p. 412-419.
54.Zhang, H., et al., Rhenium-188-HEDP therapy for the palliation of pain due to osseous metastases in lung cancer patients. Cancer Biother. Radiopharm, 2003. 18: p. 719–726.
55.Wohlfrom, M., et al., Endovascular irradiation with the liquid beta-emitter Rhenium-188 to reduce restenosis after experimental wall injury. Cardiovasc. Res, 2001. 49: p. 169–176.
56.Dadachova, E., et al., Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection. Proc. Natl. Acad, 2003. 100: p. 10942–10947.
57.Dadachova, E., et al., Rhenium-188 as an alternative to Iodine-131 for treatment of breast tumors expressing the sodium/iodide symporter (NIS). Nucl. Med. Biol., 2002. 29: p. 13–18.
58.Scheffler, J., et al., Application of rhenium-188 HEDP in bone metastases therapy. Nucl. Med. Rev. Cent. East. Eur., 2003. 6: p. 55–57.
59.Chung, H. J., et al., Synthesis and characterization of Pluronic® grafted chitosan copolymer as a novel injectable biomaterial. Current Applied Physics, 2005. 5: p. 485–488.
60.Ganji, F., et al., Gelation time and degradation rate of chitosan-based injectable hydrogel. Journal of Sol–Gel Science and Technology, 2007. 42: p. 47–53.
61.Tan, M. L., et al., Review: doxorubicin delivery systems based on chitosan for cancer therapy. JPP., 2009. 61: p. 131-142.
62.Lee, H.S., et al., Clinical correlation between brain natriutetic peptide and anthracyclin-induced cardiac toxicity, Cancer Res. Treat, 2008. 40(3): p.121–126.
63.Licata, S., et al., Doxorubicin metabolism and toxicity in human myocardium: role of cytoplasmic deglycosidation and carbonyl reduction, Chem. Res. Toxicol, 2000. 13(5): p. 414–420.
64.Wong, C.-Y.O., et al., Regional Yttrium-90 Microsphere Treatment of Surgically Unresectable and Chemotherapy-Refractory Metastatic Liver Carcinoma. Cancer Biotherapy & Radiopharmaceuticals, 2006. 21(4): p. 305-313.
65.Tarik F. Massoud., et al. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes & Development, 2003. 17: p. 545–580.
66.Mi, F.-L., Chitosan-polyelectrolyte complexation for the preparation of gel beads and controlled release of anticancer drug. I. Effect of phosphorous polyelectrolyte complex and enzymatic hydrolysis of polymer, J. Appl. Polymer Sci, 1999. 74: p. 1868–1879.
67.Mi, F.-L., et al., Kinetic study of chitosantri polyphosphate complex reaction and acid-resistive properties of the chitosan-tripolyphosphate gel beads prepared by in-liquid curing method, J. Polymer Sci. B Polymer. Phys, 1999. 37: p. 1551–1564.
68.J. Cho, et al., Physical gelation of chitosan in the presence of b-glycerophosphate: the effect of temperature, Biomacromolecules , 2005. 6: p. 3267–3275.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top