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1、共价修饰在多糖主链上，不仅可以对该载体材料定位示踪，其疏水基团还有利于包载疏水性药物分子。根据FWSC和FGSC溶液的荧光强度计算得两种荧光材料的荧光标记效率分别为139和1 23。利用离子交联法制各了WSC纳米粒(WSC NPs)，zeta电位和平均粒径分别为11 5 mV和185 5 nm：利用超声自组装法分别制各了GSC纳米粒(GSCNPs)、FWSC纳米粒(FWSC NPs)和FGSC纳米粒(FGSC NPs)，zeta电位依次为23 9mV，25 8mV和19 5mV，平均粒径依次为89 3 nm、92 9 run和100 8ixm。透射电镜观察WSC NPs和GSCNPs均为完整的
2、球形，其中自组装法制得的GSC NPs大小均一，分散均匀i相比较而言，离子交联法制得的WSC NPs大小差异较大，粒径分布较宽粒子间有团聚现象。红细胞溶血实验表明，WSCNPs和GSC NPs的溶血率均小于5，符合生物医用材料对溶血率的要求。蛋白吸附实验结果表明WSCNPs和GSCNPs对牛血清蛋白(BSA)均有较低水平的非特异性蛋白吸附，结合溶血实验共同证明了两种纳米粒均具有较好的血液相容性。MTl法检测了新型载体材料GSCNPs和FGSCNPs的细胞毒性，结果表明两种纳米粒对胎鼠成纤维细胞(MEF)、小鼠乳腺癌细胞(4T】)和人乳腺癌NPs，可以推断FGSCNPs的细胞吞噬不仅依赖于粒子表
3、面与细胞膜之间的静电作用，同样受益于靶向基团的修饰，使得三种模型细胞均对其有较高的细胞摄取率。以4TI为细胞模型，考察了DOXFWSCNPs，DOXFGSCNPs和l临床用药一盐酸阿霉素(ADR)对细胞的生长抑制效果，结果显示三种测试样品对细胞的生长抑制均随药物浓度的增大而提高，当药物浓度为2 pgml时，三种材料对细胞的生长抑制作用由强到弱依次是：DOXFt3SC NPsADRDOXFWSCNPs，说明DOX-FGSC NPs在低药物浓度时比ADR具有更好的肿瘤细胞生长抑制作用，该结论与荧光显微镜观察到的结果相一致。体外细胞实验结果初步判断由GSC制各的纳米载体利于细胞吞噬，具有肿瘤细胞靶向
4、性。建立小鼠乳腺癌动物模型，分别检测ADR，DOX-FWSC NPs与DOXFGSCNPs对荷瘤小鼠的体内抗肿瘤作用通过测量小鼠的肿瘤体积、体重、各组织中的药物分布，结果发现DOXFGSC NPs具有较好的抻痛效果且对机体均无明显毒副作用，不仅得益于其亲水外壳和较小的粒径使之被动靶向蓄积于肿瘤组织，还得益于其靶向基团的修饰，使其能利用受体一配体介导的毛动靶向作用，蓄积于肿瘤组织的同时减小药物在其他器官中的蓄积。双抗体一步夹心法测定了荷瘤小鼠各组织器官中的GLUTl表达水平对照相应组织中的药物含量，进步汪实DOXFGSC NPs对肿瘤组织的主动靶向性依赖于它对GLUTI的主动靶向性。本论文以水溶
5、性壳聚糖为基础材料，研究了一种新型受体一配体(GLUTI一葡萄糖)介导的肿瘤细胞靶向技术，通过体外、体内实验评价了该载体材料的生物安全性和靶向性。实验结果显示该靶向修饰的载体材料有望成为集药物缓控释、靶向定位蓄积于肿瘤组织于一体的功能性纳米载体系统。关键词：壳聚糖、靶向、葡萄糖转运蛋白、纳米粒、癌症治疗Chitosan based nanocarrier systems for tumor targeti ngAbst ractAt present，Cancel*has become one ofthefactorsthat endangerhuman health The keyto cal
6、lcer therapy is targeting treatment ReceptorLigand mediated tumor activetargeting technology in combination with nanotechnniogy，and the iisc of naturalbiodegradable materials as anti-ccer carriers，will be all effective approach forcanertherapyThe overexpression ofGlucose transporter protein 1(GLUTl)
7、in malignant cellsfacilitated the Receptor-Ligand(GLUTl-Glucose)mediated tumor targetingGlucose-conjugated water soluble chitosan(GSC)nanoparticle was developed fortargeted breast cRnccr the”pyGSC pdysaceharde was synthesized using suceimcacidlinker between glucosamine and water soluble ehitosan(WSC
8、)，confirmed byfourier transform infrared spectroscopy(FT-IR)，nuclear magnetic resonancespectroscopy(NMR)，thermal gravimetrie analysis(TG)and elemental analysis Thecritical aggregation concentration(CAC)of GSC was O 021 mgml，determined byfluorescence spccUoscopy using pyrenea fluore$cerIcc probe FITC
9、 was covalenflylinked with GSC for fother fluorescence localizationThe fJuoescent labelingefficiency ofFWSC and FGSC was l 39and I 23respectivelyWSC NPs was prepared by ionic crosslinking method GSC，FWSC and FGSCcould form self-assembled nanoparticles under ultrasonicationThe nanoparticleswere chara
10、cterized by dynamic light scattering，the zeta potential ofWSC NPs，GSCNPsFWSCNPs and FGSCNPswasll 5m v，23 9mv25 8mV andl9 5mVwiththeir average size of 185 5 rim，89 3 nm，92 9 nm and 100 8 nm，respectivelyWSCNPs and GSC NPs observed by transmission electron microzcope exhibited sphericalmorphology WSC N
11、Ps and GSC NPs showed low hemolysis rate(ADRDOX-FWSC NPsthe result of which indicated that DOX-FGSC NPs had better tRmor cell growthinhibitory effect than ADR at low drug concentrations The in vitro experimentalresults demonStratod that GSC NPs was favomble for tumor cell phagocytosisinitially showe
12、dtargeting effecttotumor cellsThe in vivo andtumor effect of ADRDOX-FWSC NPs and DOXFGSC NPswerc studied in 4TI bearing mice after j v injection DOXFGSC NPs couldobviouslyinhibitthe growth oftulnor and deducethe side effects ofDOXto normaltissues The hydrophilie shell and small perlicle size of DOX-
13、FGSC NPs facilitatedthe passive targeting to tumor tissues Meanwhile，the surface modifications oftargetinggroup enabledthe nanocarriersto activetargetingtotumortissue。aswell asreduce the acettmulation in other organS The concentration of GLUTl in varioustissues oftumorbeatingmicewasmeasured by ELISA
14、 GLUTl was overexpressedintumor,which was consistent with the drug distribution，further confirmed thatDOXFGSC NPs could active targeting to GIUTlOur results showed that nanoparticles decorated with glucose have specificvIreorgenizntion and interaction with GLUTI over-expressed by rumor cells，whichre
15、nders GSC NPs a promising anticancer drug delivery cartier for targeted cafflcert11empyKey words：Chitosan1argering，glUCOSe transporter 1NanoparticIesCancer therapy警蠹；囊瓣；f二生：“j；壬：皇?j：黼嘲副麓赎甜蝉艇鬻jj一醚一鼍憋。，；i；k，；，一o二+-呻。一?oI5立纠镀五卜瓣莩二-oq一0燕_。tL。L _冀：j矗一趣瓠：墨“一 j一j_；*!：-：芝鳝?二：j“。，一-I：o一蜥q峙L，一-1“：-o：Ij一- “一，二=j二i_rj、；鲁：+iml，0，l岬幕卸恤u曙，曩叫jjf。jw21生物材料 2 2壳聚糖简述23壳聚糖基纳米药物载体的制备一23 I共价交联法 232离子交联法 23 3沉淀析出法 一23 4大分子复合法2 35自组装法 一24壳聚糖基纳米药物载体的应用2 4 1化疗药物载体 2 4 2基困药物载体 2 4 3蛋白质药物载体 2 4 4其他药物载体 3本论文的选题依据以及研究内容3 1选题依据 TX56778890002233 16 17
