壳聚糖负载硒代胱氨酸纳米粒子的制备及其体外抗肿瘤活性的研究

壳聚糖负载硒代胱氨酸纳米粒子的制备及其体外抗肿瘤活性的研究暨南大学本科生毕业论文第一章绪论1.1硒化学的研究进展硒是机体生命活动不可缺少的一种微量元素，被称为“生命奇效元素”ADDINEN.CITE<EndNote><Cite><Author>陈宝泉</Author><Year>2011</Year><RecNum>20</RecNum><DisplayText>[1]</DisplayText><record><rec-number>20</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">20</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>陈宝泉</author><author>史艳萍</author><author>李彩文</author><author>刘玉明</author></authors></contributors><titles><title>基于硒元素的抗癌药物研究进展</title><secondary-title>化学通报</secondary-title></titles><periodical><full-title>化学通报</full-title></periodical><number>08</number><keywords><keyword>硒</keyword><keyword>无机硒</keyword><keyword>有机硒</keyword><keyword>抗癌活性</keyword><keyword>作用机制</keyword></keywords><dates><year>2011</year></dates><isbn>0441-3776</isbn><urls></urls></record></Cite></EndNote>[\o"陈宝泉,2011#20"1]。1817年，硒由瑞典学者Berzelius发现，并命名为Selenium。但由于毒性，硒曾被认为是一种对高级生物有害的元素。1957年美国营养学家Schwarz和Foltz首次用硒治疗动物肝坏死取得成功后，硒逐渐明确为动物体内必需的微量元素ADDINEN.CITE<EndNote><Cite><Author>Brown</Author><Year>2001</Year><RecNum>9</RecNum><DisplayText>[2]</DisplayText><record><rec-number>9</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">9</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Brown,K.M.</author><author>Arthur,J.R.</author></authors></contributors><titles><title>Selenium,selenoproteinsandhumanhealth:areview</title><secondary-title>Publichealthnutrition</secondary-title></titles><periodical><full-title>Publichealthnutrition</full-title></periodical><pages>593-9</pages><volume>4</volume><number>2B</number><dates><year>2001</year><pub-dates><date>2001-Apr</date></pub-dates></dates><isbn>1368-9800</isbn><accession-num>MEDLINE:11683552</accession-num><urls><related-urls><url><GotoISI>://MEDLINE:11683552</url></related-urls></urls></record></Cite></EndNote>[\o"Brown,2001#9"2]。1973年，Rotruck等人发现硒是谷胱甘肽过氧化物酶GSH-Px的活性成分后ADDINEN.CITE<EndNote><Cite><Author>Rotruck</Author><Year>1973</Year><RecNum>10</RecNum><DisplayText>[3]</DisplayText><record><rec-number>10</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">10</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Rotruck,J.T.</author><author>Pope,A.L.</author><author>Ganther,H.E.</author><author>Swanson,A.B.</author><author>Hafeman,D.G.</author><author>Hoekstra,W.G.</author></authors></contributors><titles><title>Selenium:biochemicalroleasacomponentofglutathioneperoxidase</title><secondary-title>Science(NewYork,N.Y.)</secondary-title></titles><periodical><full-title>Science(NewYork,N.Y.)</full-title></periodical><pages>588-90</pages><volume>179</volume><number>4073</number><dates><year>1973</year><pub-dates><date>1973-Feb-9</date></pub-dates></dates><isbn>0036-8075</isbn><accession-num>MEDLINE:4686466</accession-num><urls><related-urls><url><GotoISI>://MEDLINE:4686466</url></related-urls></urls><electronic-resource-num>10.1126/science.179.4073.588</electronic-resource-num></record></Cite></EndNote>[\o"Rotruck,1973#10"3]，已经陆续有25种含硒蛋白被发现。1975年Awasthi等人首次明确指出，硒是人体必需的微量元素ADDINEN.CITE<EndNote><Cite><Author>Mills</Author><Year>1957</Year><RecNum>11</RecNum><DisplayText>[4]</DisplayText><record><rec-number>11</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">11</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Mills,G.C.</author></authors></contributors><titles><title>Hemoglobincatabolism.I.Glutathioneperoxidase,anerythrocyteenzymewhichprotectshemoglobinfromoxidativebreakdown</title><secondary-title>TheJournalofbiologicalchemistry</secondary-title></titles><periodical><full-title>TheJournalofbiologicalchemistry</full-title></periodical><pages>189-97</pages><volume>229</volume><number>1</number><dates><year>1957</year><pub-dates><date>1957-Nov</date></pub-dates></dates><isbn>0021-9258</isbn><accession-num>MEDLINE:13491573</accession-num><urls><related-urls><url><GotoISI>://MEDLINE:13491573</url></related-urls></urls></record></Cite></EndNote>[\o"Mills,1957#11"4]。此后，硒与硒化合物的生理作用受到普遍关注。1988年，我国已经把硒列为膳食营养素之一。近年来研究发现，硒与人类40种疾病有关，如大骨节病、克山病、白内障、癌症等。硒可以保护心脏、肝脏等免受损伤，对癌症、心血管疾病、艾滋病等起到治疗和控制作用ADDINEN.CITEADDINEN.CITE.DATA[\o"Agay,2005#23"5-7]。微量元素硒具有防癌，抗癌，抗氧化，拮抗重金属，抗逆境等多种生物学活性ADDINEN.CITE<EndNote><Cite><Author>朱金霞</Author><Year>2009</Year><RecNum>21</RecNum><DisplayText>[8]</DisplayText><record><rec-number>21</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">21</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>朱金霞</author><author>周文生</author><author>郭生虎</author></authors></contributors><titles><title>植物中微量元素硒的研究进展</title><secondary-title>安徽农业科学</secondary-title></titles><periodical><full-title>安徽农业科学</full-title></periodical><number>13</number><keywords><keyword>有机硒</keyword><keyword>硒蛋白</keyword><keyword>硒多糖</keyword><keyword>硒核酸</keyword><keyword>分离纯化</keyword></keywords><dates><year>2009</year></dates><isbn>0517-6611</isbn><urls></urls></record></Cite></EndNote>[\o"朱金霞,2009#21"8]。硒具有抗氧化作用，它是谷胱甘肽过氧化酶（GSH-Px）的活性中心，常以硒代半胱氨酸形式存在，GSH-Px能减轻或阻断自由基所致的脂质过氧化连锁反应，保护蛋白质、清除自由基和DNA及生物膜的完整性，修复损伤分子部位；同时能提高机体免疫能力，抵抗疾病ADDINEN.CITE<EndNote><Cite><Author>McKenzie</Author><Year>1998</Year><RecNum>16</RecNum><DisplayText>[9]</DisplayText><record><rec-number>16</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">16</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>McKenzie,RoderickC.</author><author>S.Rafferty,Teresa</author><author>Beckett,GeoffreyJ.</author></authors></contributors><titles><title>Selenium:anessentialelementforimmunefunction</title><secondary-title>ImmunologyToday</secondary-title></titles><periodical><full-title>ImmunologyToday</full-title></periodical><pages>342-345</pages><volume>19</volume><number>8</number><keywords><keyword>Selenium</keyword><keyword>immunodeficiency</keyword><keyword>selenoproteins</keyword><keyword>glutathioneperoxidase</keyword><keyword>diet</keyword></keywords><dates><year>1998</year></dates><isbn>0167-5699</isbn><urls><related-urls><url>/science/article/pii/S0167569998012948</url></related-urls></urls><electronic-resource-num>10.1016/s0167-5699(98)01294-8</electronic-resource-num></record></Cite></EndNote>[\o"McKenzie,1998#16"9]。近年来，硒与硒化合物的抗肿瘤活性受到普遍关注，人们一直致力于设计和改造含硒化合物，以寻找抗肿瘤活性强，抗肿瘤谱广，毒副作用低，适用于临床的含硒抗肿瘤药物ADDINEN.CITE<EndNote><Cite><Author>陈宝泉</Author><Year>2011</Year><RecNum>20</RecNum><DisplayText>[1]</DisplayText><record><rec-number>20</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">20</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>陈宝泉</author><author>史艳萍</author><author>李彩文</author><author>刘玉明</author></authors></contributors><titles><title>基于硒元素的抗癌药物研究进展</title><secondary-title>化学通报</secondary-title></titles><periodical><full-title>化学通报</full-title></periodical><number>08</number><keywords><keyword>硒</keyword><keyword>无机硒</keyword><keyword>有机硒</keyword><keyword>抗癌活性</keyword><keyword>作用机制</keyword></keywords><dates><year>2011</year></dates><isbn>0441-3776</isbn><urls></urls></record></Cite></EndNote>[\o"陈宝泉,2011#20"1]。根据硒在自然界的存在形态，硒化合物可分为无机硒和有机硒化合物ADDINEN.CITE<EndNote><Cite><Author>Chasteen</Author><Year>2003</Year><RecNum>12</RecNum><DisplayText>[10]</DisplayText><record><rec-number>12</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">12</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Chasteen,T.G.</author><author>Bentley,R.</author></authors></contributors><titles><title>Biomethylationofseleniumandtellurium:Microorganismsandplants</title><secondary-title>ChemicalReviews</secondary-title></titles><periodical><full-title>ChemicalReviews</full-title></periodical><pages>1-25</pages><volume>103</volume><number>1</number><dates><year>2003</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0009-2665</isbn><accession-num>WOS:000180319600001</accession-num><urls><related-urls><url><GotoISI>://WOS:000180319600001</url></related-urls></urls><electronic-resource-num>10.1021/cr010210+</electronic-resource-num></record></Cite></EndNote>[\o"Chasteen,2003#12"10]。无机硒主要包括硒，硒酸盐(亚硒酸钠,亚硒酸锌等)，氧化硒，硫化硒，氯化硒以及硒化物（硒化氢，硒化钠，硒化钾等）等。有机硒主要包括硒多糖，含硒蛋白质，烷基硒，甲基硒酸以及人工合成的具有生物活性的有机硒化合物。硒在生物体内主要以有机硒化合物的形式存在，一类是含硒氨基酸，另一类是含硒蛋白质。无机硒具有较好的抗癌活性，但无机硒化合物脂溶性差，不易进入细胞，且具有蓄积毒性和致突变作用，限制了它在临床上的应用。而相比之下，有机硒化合物吸收率高，生物活性强，毒性低和环境污染小，不仅能够更好地发挥硒的作用，而且在激发免疫反应上也比无机硒显著，抗癌作用更强ADDINEN.CITE<EndNote><Cite><Author>宋春风</Author><Year>2009</Year><RecNum>47</RecNum><DisplayText>[11]</DisplayText><record><rec-number>47</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">47</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>宋春风</author><author>贾晓丽</author><author>唐晓光</author><author>娜日苏</author></authors></contributors><titles><title>硒的抗癌形式及抗癌效果研究进展</title><secondary-title>赤峰学院学报(自然科学版)</secondary-title></titles><periodical><full-title>赤峰学院学报(自然科学版)</full-title></periodical><number>09</number><keywords><keyword>硒</keyword><keyword>无机硒</keyword><keyword>有机硒</keyword><keyword>纳米硒</keyword><keyword>抗癌,</keyword><keyword>药物</keyword></keywords><dates><year>2009</year></dates><isbn>1673-260X</isbn><urls></urls></record></Cite></EndNote>[\o"宋春风,2009#47"11]。其中含硒氨基酸硒代半胱氨酸（selenocysteine）是生物合成和掺入到蛋白质分子中的第21种氨基酸ADDINEN.CITE<EndNote><Cite><Author>黄峙</Author><Year>2001</Year><RecNum>22</RecNum><DisplayText>[12]</DisplayText><record><rec-number>22</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">22</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>黄峙</author><author>郑文杰</author><author>郭宝江</author></authors></contributors><titles><title>含硒生物大分子化合物研究进展</title><secondary-title>海南大学学报(自然科学版)</secondary-title></titles><periodical><full-title>海南大学学报(自然科学版)</full-title></periodical><number>02</number><keywords><keyword>生物大分子</keyword><keyword>硒蛋白</keyword><keyword>硒酶</keyword><keyword>含硒多糖</keyword><keyword>含硒核酸</keyword></keywords><dates><year>2001</year></dates><isbn>1004-1729</isbn><urls></urls></record></Cite></EndNote>[\o"黄峙,2001#22"12]。从此有机硒化合物的研究引起了广泛关注，Shahd等人在2005年报道了有机硒化合物Methylseleninicacid(MSA)和它莫西芬一起可以治疗子宫内膜癌和乳腺癌ADDINEN.CITE<EndNote><Cite><Author>Satoh</Author><Year>1992</Year><RecNum>13</RecNum><DisplayText>[13]</DisplayText><record><rec-number>13</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">13</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Satoh,M.</author><author>Naganuma,A.</author><author>Imura,N.</author></authors></contributors><titles><title>Effectofcoadministrationofseleniteonthetoxicityandantitumoractivityofcis-diamminedichloroplatinum(II)givenrepeatedlytomice</title><secondary-title>Cancerchemotherapyandpharmacology</secondary-title></titles><periodical><full-title>Cancerchemotherapyandpharmacology</full-title></periodical><pages>439-43</pages><volume>30</volume><number>6</number><dates><year>1992</year><pub-dates><date>1992</date></pub-dates></dates><isbn>0344-5704</isbn><accession-num>MEDLINE:1394800</accession-num><urls><related-urls><url><GotoISI>://MEDLINE:1394800</url></related-urls></urls><electronic-resource-num>10.1007/bf00685594</electronic-resource-num></record></Cite></EndNote>[\o"Satoh,1992#13"13]。1.2硒代胱氨酸的研究现状1.2.1硒代胱氨酸的性质硒代氨基酸在有机硒化合物中，有特殊的重要性。在哺乳动物组中，硒代氨基酸是硒的主要存在形式，包括硒代胱氨酸(SeCys)和硒代蛋氨酸(SeMet)。硒代胱氨酸是胱氨酸分子中S被Se所取代后的含硒氨基酸ADDINEN.CITE<EndNote><Cite><Author>杨培慧</Author><Year>2003</Year><RecNum>49</RecNum><DisplayText>[14]</DisplayText><record><rec-number>49</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">49</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>杨培慧</author><author>郑志雯</author><author>冯德雄</author><author>蔡继业</author><author>陈建平</author></authors></contributors><titles><title>硒代胱氨酸和硒代蛋氨酸电化学检测的比较</title><secondary-title>分析化学</secondary-title></titles><periodical><full-title>分析化学</full-title></periodical><number>02</number><keywords><keyword>硒代胱氨酸</keyword><keyword>硒代蛋氨酸</keyword><keyword>循环伏安法</keyword><keyword>银电极</keyword></keywords><dates><year>2003</year></dates><isbn>0253-3820</isbn><urls></urls></record></Cite></EndNote>[\o"杨培慧,2003#49"14]。结构式如图1.1。图1.1硒代胱氨酸的结构式1.2.2硒代胱氨酸的抗癌作用SeC，是一种天然存在的含硒氨基酸，在化学预防与治疗方面具有巨大的潜力。Chen等ADDINEN.CITE<EndNote><Cite><Author>Chen</Author><Year>2009</Year><RecNum>26</RecNum><DisplayText>[15]</DisplayText><record><rec-number>26</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">26</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Chen,Tianfeng</author><author>Wong,Yum-Shing</author></authors></contributors><titles><title>Selenocystineinducesreactiveoxygenspecies–mediatedapoptosisinhumancancercells</title><secondary-title>Biomedicine&amp;Pharmacotherapy</secondary-title></titles><periodical><full-title>Biomedicine&amp;Pharmacotherapy</full-title></periodical><pages>105-113</pages><volume>63</volume><number>2</number><keywords><keyword>Selenium</keyword><keyword>Selenocystine</keyword><keyword>Anticanceractivity</keyword><keyword>Apoptosis</keyword><keyword>Reactiveoxygenspecies</keyword></keywords><dates><year>2009</year></dates><isbn>0753-3322</isbn><urls><related-urls><url>/science/article/pii/S0753332208000826</url></related-urls></urls><electronic-resource-num>10.1016/j.biopha.2008.03.009</electronic-resource-num></record></Cite></EndNote>[\o"Chen,2009#26"15]通过实验比较几种含硒化合物对八种人类癌症细胞的抗癌活性，实验证明，SeC与亚硒酸盐对A375，MCF-7，HepG2，SW620等癌细胞的细胞毒性比硒代蛋氨酸，硒甲基硒氨酸，硒酸盐等强。且SeC对人类正常纤维原细胞Hs68的细胞毒性很小，IC50>400μΜ，毒性远小于亚硒酸盐。因此，SeC具有更广谱高效的抗肿瘤活性，且对正常细胞的毒性较小。因此，SeC是一种新型高效的抗肿瘤药物。虽然SeC作为抗肿瘤药物具有较强的抗肿瘤活性，但是从Chen等ADDINEN.CITE<EndNote><Cite><Author>Chen</Author><Year>2008</Year><RecNum>33</RecNum><DisplayText>[16]</DisplayText><record><rec-number>33</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">33</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Chen,Tianfeng</author><author>Wong,Yum-Shing</author></authors></contributors><titles><title>SelenocystineInducesS-PhaseArrestandApoptosisinHumanBreastAdenocarcinomaMCF-7CellsbyModulatingERKandAktPhosphorylation</title><secondary-title>JournalofAgriculturalandFoodChemistry</secondary-title></titles><periodical><full-title>JournalofAgriculturalandFoodChemistry</full-title></periodical><pages>10574-10581</pages><volume>56</volume><number>22</number><dates><year>2008</year><pub-dates><date>2008/11/26</date></pub-dates></dates><publisher>AmericanChemicalSociety</publisher><isbn>0021-8561</isbn><urls><related-urls><url>/10.1021/jf802125t</url></related-urls></urls><electronic-resource-num>10.1021/jf802125t</electronic-resource-num><access-date>2012/05/27</access-date></record></Cite></EndNote>[\o"Chen,2008#33"16]实验结果表明，SeC的水溶性与稳定性较差，进入MCF-7细胞发挥作用的时间比较长，36h之后才观察到明显的细胞凋亡的现象，且72h后的IC50=16.2±5.2μΜ，说明SeC不易进入肿瘤细胞，对细胞的渗透性不强。因此，希望借助纳米药物载体来提高细胞吸收，减少它进入肿瘤细胞的时间。1.3纳米药物载体在肿瘤治疗中的应用1.3.1纳米技术的研究进展早在1959年，著名物理诺贝尔奖获得者Feynman就预言了纳米科技的出现及前景。1990年7月，在美国巴尔的摩召开了第一界国际纳米科技会议，标志着纳米科技的正式诞生。纳米，是尺寸度量单位，1纳米=10-9米，相当于4个原子并列的直径。所谓纳米技术则是指0.1-100nm内的物质或结构的构造技术，即纳米级材料的设计，制造，测量和控制技术ADDINEN.CITE<EndNote><Cite><Author>韩新爱</Author><Year>2009</Year><RecNum>23</RecNum><DisplayText>[17]</DisplayText><record><rec-number>23</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">23</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>韩新爱</author><author>曾慧兰</author></authors></contributors><titles><title>纳米技术在肿瘤诊治中的应用与发展</title><secondary-title>广东医学</secondary-title></titles><periodical><full-title>广东医学</full-title></periodical><number>01</number><dates><year>2009</year></dates><isbn>1001-9448</isbn><urls></urls></record></Cite></EndNote>[\o"韩新爱,2009#23"17]。纳米材料具有小尺寸效应、量子尺寸效应，表面效应和宏观量子隧道效应四大效应。当物体达到纳米级后，纳米粒子在热学、光学、磁学力学及电化学方面表现出独特的优势ADDINEN.CITE<EndNote><Cite><Author>桑士晶</Author><Year>2012</Year><RecNum>29</RecNum><DisplayText>[18]</DisplayText><record><rec-number>29</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">29</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>桑士晶</author><author>杨瑞</author></authors></contributors><titles><title>纳米技术前景展望</title><secondary-title>中国新技术新产品</secondary-title></titles><periodical><full-title>中国新技术新产品</full-title></periodical><number>06</number><keywords><keyword>纳米材料</keyword><keyword>奇异物性</keyword><keyword>纳米颗粒</keyword></keywords><dates><year>2012</year></dates><isbn>1673-9957</isbn><urls></urls></record></Cite></EndNote>[\o"桑士晶,2012#29"18]。进入21世纪，纳米技术迅速发展，作为一个多学科交叉领域，涉及面广应用十分广泛。纳米技术与材料已经在航天，汽车，消费日用品，生物医学领域获得应用，并取得一些列举世瞩目的成果ADDINEN.CITE<EndNote><Cite><Author>樊东黎</Author><Year>2011</Year><RecNum>25</RecNum><DisplayText>[19]</DisplayText><record><rec-number>25</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">25</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>樊东黎</author></authors></contributors><titles><title>纳米技术和纳米材料的发展和应用</title><secondary-title>金属热处理</secondary-title></titles><periodical><full-title>金属热处理</full-title></periodical><number>02</number><dates><year>2011</year></dates><isbn>0254-6051</isbn><urls></urls></record></Cite></EndNote>[\o"樊东黎,2011#25"19]。随着纳米技术向医学界不断渗透，纳米技术在生物医药方面的应用，特别在肿瘤的诊断和治疗方面，受到了广泛的关注ADDINEN.CITE<EndNote><Cite><Author>韩新爱</Author><Year>2009</Year><RecNum>23</RecNum><DisplayText>[17]</DisplayText><record><rec-number>23</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">23</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>韩新爱</author><author>曾慧兰</author></authors></contributors><titles><title>纳米技术在肿瘤诊治中的应用与发展</title><secondary-title>广东医学</secondary-title></titles><periodical><full-title>广东医学</full-title></periodical><number>01</number><dates><year>2009</year></dates><isbn>1001-9448</isbn><urls></urls></record></Cite></EndNote>[\o"韩新爱,2009#23"17]。纳米技术在肿瘤治疗中的应用主要表现在一下几个方面：控释载药微粒，靶向载药微粒，磁导航靶向载药微粒，基因载体ADDINEN.CITE<EndNote><Cite><Author>唐胜利</Author><Year>2003</Year><RecNum>12</RecNum><DisplayText>[20]</DisplayText><record><rec-number>12</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">12</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>唐胜利</author></authors></contributors><titles><title>纳米技术与肿瘤治疗</title><secondary-title>国外医学.肿瘤学分册</secondary-title></titles><periodical><full-title>国外医学.肿瘤学分册</full-title></periodical><number>04</number><keywords><keyword>纳米</keyword><keyword>肿瘤</keyword><keyword>药物载体</keyword><keyword>基因载体</keyword><keyword>治疗</keyword></keywords><dates><year>2003</year></dates><isbn>1000-8225</isbn><urls></urls></record></Cite></EndNote>[\o"唐胜利,2003#12"20]。其中，纳米药物载体在医学领域中控释缓释的应用极为广泛，提高药物的利用率疗效和减少药物的副作用已成为医药研究领域的一项重要课题。1.3.2纳米药物载体的研究进展理想的纳米粒载体应是无毒和可生物的。一种理想的纳米药物载体应具备以下特征ADDINEN.CITE<EndNote><Cite><Author>钱倩</Author><Year>2006</Year><RecNum>18</RecNum><DisplayText>[21]</DisplayText><record><rec-number>18</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">18</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>钱倩</author><author>王伯瑶</author></authors></contributors><titles><title>纳米药物载体在医药领域中的研究进展</title><secondary-title>济宁医学院学报</secondary-title></titles><periodical><full-title>济宁医学院学报</full-title></periodical><number>02</number><dates><year>2006</year></dates><isbn>1000-9760</isbn><urls></urls></record></Cite></EndNote>[\o"钱倩,2006#18"21]：①具有较高的载药量②具有较高的包封率③制备和纯化方法简便，容易放大到工业化生产④载体材料可生物降解，毒性较低或没有毒性⑤具有适当的粒径与粒型⑥具有较长的体内循环时间纳米药物载体的种类有以下几种（如图1.2所示）：①纳米聚合物药物载体，包括：聚合物纳米粒（纳米囊和纳米球）纳米树突状聚合物和聚合物胶束②纳米脂质体药物载体，③纳米病毒药物载体，④碳纳米管ADDINEN.CITE<EndNote><Cite><Author>张士新</Author><Year>2010</Year><RecNum>15</RecNum><DisplayText>[22]</DisplayText><record><rec-number>15</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">15</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>张士新</author><author>李芳秋</author></authors></contributors><titles><title>纳米药物载体在肿瘤治疗中的应用</title><secondary-title>中华肿瘤防治杂志</secondary-title></titles><periodical><full-title>中华肿瘤防治杂志</full-title></periodical><number>13</number><keywords><keyword>纳米药物载体</keyword><keyword>肿瘤</keyword><keyword>靶向</keyword><keyword>综述文献</keyword></keywords><dates><year>2010</year></dates><isbn>1673-5269</isbn><urls></urls></record></Cite></EndNote>[\o"张士新,2010#15"22]。虽然，纳米药物载体作为载药系统有诸多优点，但仍存在一些问题，如生物相容性以及细胞毒性等。因此，寻找生物相容性好，低毒性的纳米药物载体成为了近年来研究的目标。图1.2纳米药物载体的类型目前，用于纳米药物载体研究的生物可降解聚合物主要有合成聚合物和天然高分子聚合物。合成聚合物主要有聚乳酸（PLA）、聚乙醇酸（PGA）、聚乳酸共聚乙醇酸（PLGA）、聚已内酯（PCL）、聚氰基丙烯酸烷基酯、聚羟基丁酸、聚原酸酯、聚酐等。天然高分子聚合物主要包括天然多糖，多肽以及其他亲水性生物可降解聚合物ADDINEN.CITE<EndNote><Cite><Author>胡兴</Author><Year>2003</Year><RecNum>19</RecNum><DisplayText>[23]</DisplayText><record><rec-number>19</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">19</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>胡兴</author><author>邹国林</author></authors></contributors><titles><title>生物可降解聚合物纳米粒给药载体</title><secondary-title>氨基酸和生物资源</secondary-title></titles><periodical><full-title>氨基酸和生物资源</full-title></periodical><number>02</number><keywords><keyword>生物可降解聚合物</keyword><keyword>纳米粒</keyword><keyword>给药载体</keyword></keywords><dates><year>2003</year></dates><isbn>1006-8376</isbn><urls></urls></record></Cite></EndNote>[\o"胡兴,2003#19"23]。但是，通过化学方法合成得到的大部分药物载体在生物相容性，可降解性以及细胞毒性等方面还存在不尽如意的地方ADDINEN.CITE<EndNote><Cite><Author>Duncan</Author><Year>2005</Year><RecNum>14</RecNum><DisplayText>[24]</DisplayText><record><rec-number>14</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">14</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Duncan,R.</author><author>Izzo,L.</author></authors></contributors><titles><title>Dendrimerbiocompatibilityandtoxicity</title><secondary-title>AdvancedDrugDeliveryReviews</secondary-title></titles><periodical><full-title>AdvancedDrugDeliveryReviews</full-title></periodical><pages>2215-2237</pages><volume>57</volume><number>15</number><dates><year>2005</year><pub-dates><date>Dec14</date></pub-dates></dates><isbn>0169-409X</isbn><accession-num>WOS:000234302000009</accession-num><urls><related-urls><url><GotoISI>://WOS:000234302000009</url></related-urls></urls><electronic-resource-num>10.1016/j.addr.2005.09.019</electronic-resource-num></record></Cite></EndNote>[\o"Duncan,2005#14"24]。近年来，生物大分子材料由于其可再生性，无毒性以及良好的生物相容性，生物可降解性和黏膜粘附性等优点成为药物载体研究的热点，于是利用生物大分子材料来制备纳米药物载体的研究应运而生。用于纳米药物载体的生物大分子主要包含蛋白质和多糖两大类。蛋白质一般包括如明胶，白蛋白，丝蛋白等物质，多糖类一般包括如壳聚糖，海藻酸钠，环糊精，果胶等物质。由于生物大分子可以从自然界的动植物中获得，生物相容性良好，并且可被生物体内的酶降解，毒副作用较小，且分子上带有的羟基，氨基，羧基等大量可反应的官能团，可作为化学修饰的位点，因此它们作为药物载体材料具有广阔的应用前景ADDINEN.CITE<EndNote><Cite><Author>陈孟婕</Author><Year>2011</Year><RecNum>13</RecNum><DisplayText>[25]</DisplayText><record><rec-number>13</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">13</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>陈孟婕</author><author>姚晋荣</author><author>邵正中</author><author>陈新</author></authors></contributors><titles><title>基于生物大分子的纳米药物载体</title><secondary-title>化学进展</secondary-title></titles><periodical><full-title>化学进展</full-title></periodical><number>01</number><keywords><keyword>天然高分子</keyword><keyword>纳米载体</keyword><keyword>药物控制释放</keyword></keywords><dates><year>2011</year></dates><isbn>1005-281X</isbn><urls></urls></record></Cite></EndNote>[\o"陈孟婕,2011#13"25]。1.4壳聚糖纳米粒子在纳米药物载体领域的制备和应用1.4.1壳聚糖的结构与性质壳聚糖也称为甲壳胺或几丁聚糖壳聚糖，是一种天然的生物高分子线性多氨基多糖，为甲壳素的脱乙酰化产物。在自然界中，壳聚糖广泛存在于低等植物菌类，藻类的细胞，节肢动物虾，蟹，蝇蛆和昆虫的外壳，贝类，软体动物（如鱿鱼，乌贼）的外壳和软骨，高等植物的细胞壁等，每年生物合成的资源量高大100亿t，是地球上仅次于植物纤维的第二大生物资源ADDINEN.CITE<EndNote><Cite><Author>于永鹏</Author><Year>2011</Year><RecNum>30</RecNum><DisplayText>[26]</DisplayText><record><rec-number>30</rec-number><foreign-keys><keyapp="EN"db-id="25255apw6t05d9ewedtvsr2kpse5spwfat92">30</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>于永鹏</author><author>徐孝旭</author></authors></contributors><titles><title>壳聚糖作为药物缓释载体的应用及进展</title><secondary-title>材料导报</secondary-title></titles><periodical><full-title>材料导报</full-title></periodical><number>S1</number><keywords><keyword>壳聚糖</keyword><keyword>降解性能</keyword><keyword>亲和性</keyword><keyword>药物缓释载体</keyword></keywords><dates><year>2011</year></dates><isbn>1005-023X</isbn><urls></urls></record></Cite></EndNote>[\o"于永鹏,2011#30"26]。壳聚糖的化学名称为(1-4)2-氨基-2脱氧-D-葡聚糖，甲壳素的化学名称为(1-4)2-乙酰胺基-2脱氧-D-葡聚糖ADDINEN.CITEADDINEN.CITE.DATA[\o"Julkapli,2011#1"27]。结构式如图1.3所示。图1.3壳聚糖与甲壳素的结构甲壳素(B)壳聚糖壳聚糖的每个C6单元均含有一个氨基，两个自由羟基。由于氨基的存在，它是自然界中唯一带正电荷的碱性多糖。它不溶于水和有机溶剂，但是能溶于PH<6.5的乙酸（1-3%）溶液中ADDINEN.CITE<EndNote><Cite><Author>Sinha</Author><Year>2004</Year><RecNum>6</RecNum><DisplayText>[28]</DisplayText><record><rec-number>6</rec-number><foreign-keys><keyapp="EN"db-id="tszrdpewx9swrbe9rvlpp22wzzae99zvsfss">6</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sinha,V.R.</author><author>Singla,A.K.</author><author>Wadhawan,S.</author><author>Kaushik,R.</author><author>Kumria,R.</author><author>Bansal,K.</author><author>Dhawan,S.</author></authors></contributors><titles><title>Chitosanmicrospheresas