CN1772303A - 恶性肿瘤磁热疗用纳米磁粉－抗体靶向药物 - Google Patents

恶性肿瘤磁热疗用纳米磁粉－抗体靶向药物 Download PDF

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CN1772303A
CN1772303A CNA2005100950005A CN200510095000A CN1772303A CN 1772303 A CN1772303 A CN 1772303A CN A2005100950005 A CNA2005100950005 A CN A2005100950005A CN 200510095000 A CN200510095000 A CN 200510095000A CN 1772303 A CN1772303 A CN 1772303A
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nano
antibody
magnetic powder
tumor
targeted drug
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CNA2005100950005A
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朱宏
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Priority to CNA2005100950005A priority Critical patent/CN1772303A/zh
Publication of CN1772303A publication Critical patent/CN1772303A/zh
Priority to US12/091,329 priority patent/US20110177153A1/en
Priority to PCT/CN2006/002790 priority patent/WO2007048326A1/zh
Priority to JP2008536910A priority patent/JP2009512720A/ja
Priority to EP06805000.4A priority patent/EP1952825A4/en
Priority to CN2006101319946A priority patent/CN1951495B/zh
Pending legal-status Critical Current

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Abstract

本发明涉及一种恶性肿瘤磁热疗用纳米磁粉－抗体靶向药物。其特征在于：将纳米磁粉与抗体通过溶液混合偶联制成磁热疗用纳米靶向药物，纳米磁粉与抗体的重量配比为1∶0.0001～0.20，靶向药物的颗粒粒径为5～1000nm，靶向药物的纳米磁粉表面偶联有抗体1个或多个抗体并且偶联抗体具有生物活性；靶向药物的剂型为注射剂，在注射剂中药物分散为纳米颗粒，靶向药物通过注射主动靶向浓聚定位在与抗体具有较高特异性和亲和性的恶性肿瘤病灶，浓聚定位在恶性肿瘤病灶的靶向药物在磁热疗治疗仪交变磁场的作用下产生磁滞生热效应，磁滞生热能力为10－7000W/gFe，加热肿瘤至42－95℃，杀灭恶性肿瘤；靶向药物具有生物降解功能，用于恶性肿瘤磁热疗治疗和预防没有毒副作用。

Description

恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物
技术领域
本发明涉及一种恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物。
背景技术
2000年全球新发恶性肿瘤病历约1000万，死亡620万，现患病例2200万。预计2020年恶性肿瘤新发病例将达到1500万，死亡1000万，现患病例3000万。恶性肿瘤正在成为新世纪人类第一杀手，对全球社会经济将会造成巨大损失，开展恶性肿瘤新型药物和治疗新方法的研究具有十分重大的意义。
传统的恶性肿瘤治疗方法主要是手术、放疗和化疗。通常只有10％-20％的恶性肿瘤病人有机会手术，并且手术易给病人带来较大的痛苦，术后容易复发和转移；而放疗和化疗靶向不明确，在杀灭肿瘤细胞的同时也破坏正常细胞，毒副作用较大。近些年，由于具有高效、低毒、副作用小等特点的抗体靶向药物的出现，抗体偶联放射核素、毒素、化疗药物以及抗体偶联前体药物等靶向药物已成为广泛研究应用的抗肿瘤的新型药物和恶性肿瘤治疗的新手段，抗体靶向药物的应用为恶性肿瘤的治疗和预防提供了新的机遇和效果。但上述靶向药物中抗体偶联的放射核素、毒素、化学药物以及前体药物等效应分子仍具有共同的缺陷，它们都具有较强的毒副作用，虽然靶向药物的毒性较未偶联抗体的核素、毒素或化疗药物明显降低，然而其应用对人体来说仍具有一定的非特异毒性，包括血液毒性和对正常组织的毒性，这使其在临床应用上仍有一定的局限性，恶性肿瘤治疗用抗体靶向药物的发展需要无毒副作用的新型效应分子。
恶性肿瘤磁热疗是一种利用如下4种物理和生物等效应，即(1)磁热种子(即磁性颗粒或材料，如纳米磁粉)可以感应体外交变磁场产生磁滞生热效应；(2)恶性肿瘤的血流量只有正常组织的10-15％，加热肿瘤后肿瘤周围正常组织血流加速、散热快、温升小，而肿瘤内散热困难、温度可高于周围正常组织5-10℃；(3)正常细胞48℃以上死亡，恶性肿瘤细胞大于42℃死亡，肿瘤细胞耐热性差；(4)较低频率的交变磁场在人体组织中穿透性好、不衰减、不损伤正常组织、可以安全有效地到达深部和大体积的肿瘤内部；使导入肿瘤病灶的磁热种子在磁热疗治疗仪的交变磁场作用下产生磁滞生热效应、加热恶性肿瘤至42-48℃，而正常组织基本不升温，实现精确定位和无毒副作用的选择性杀灭恶性肿瘤的热疗新方法。近几年，大量的动物试验和临床试验研究成果证明，应用磁热疗治疗恶性肿瘤不仅可以有效杀灭肿瘤，使肿瘤完全消退，并且没有毒副作用。磁热疗是一种具有广阔应用前景的肿瘤治疗新方法，它的出现为恶性肿瘤的安全治愈提供了希望。磁热疗中的磁热种子实际上是一种无毒副作用物理效应分子。但迄今为止，磁热疗中磁热种子仍需通过埋植、局部注射、介导等方式导入肿瘤病灶，尚未见将纳米磁粉与抗体偶联制成磁热疗用将磁热种子(即纳米磁粉)主动靶向导入肿瘤病灶的靶向药物的文献报道。
发明内容
本发明的目的是针对上述不足之处提供一种恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物。由于磁热疗用纳米磁粉-抗体靶向药物是以纳米磁粉为效应分子(即磁热疗用磁热种子)和以抗体为导向分子，由抗体与纳米磁粉偶联构成的，具有抗体对与其具有较高特异性和亲和性的恶性肿瘤的靶向功能、纳米磁粉效应分子的磁热疗无毒副作用功能和纳米颗粒药物的穿透性，能够将纳米磁粉主动靶向导入恶性肿瘤病灶的磁热疗用纳米靶向药物。它具有偶联抗体药物的主动靶向、载磁药物的磁性靶向和纳米载体药物的被动靶向等复合靶向功能和利用磁热疗治疗恶性肿瘤的技术功能，它的应用可以通过动静脉或腹腔注射或导入等给药途径，使靶向药物主动靶向浓聚定位在与抗体具有较高特异性和亲和性的恶性肿瘤病灶，实现恶性肿瘤的无毒副作用的磁热疗治疗。并且应用不同抗体制成的纳米磁粉-抗体靶向药物可以为各种恶性肿瘤的治疗和预防提供一种靶向磁热疗、高效杀灭、安全无毒副作用的新手段。
本发明是采取以下技术方案实现的：一种恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于(1)以具有磁滞生热能力的纳米磁粉为效应分子、以抗体为导向分子，将纳米磁粉与抗体通过溶液混合偶联制成具有主动靶向、磁性靶向和被动靶向功能的磁热疗用纳米靶向药物，纳米磁粉与抗体的重量配比为1∶0.0001～0.20，靶向药物的颗粒粒径为5～1000nm，靶向药物的纳米磁粉表面偶联有抗体1个或多个抗体并且偶联抗体具有生物活性；(2)靶向药物的应用需要制成复合溶媒或纯水的靶向药物注射剂，靶向药物制成注射剂使药物分散为纳米颗粒，具有良好的穿透性以及与相关的恶性肿瘤细胞具有良好的特异性和亲和性，在体内外具有良好的导向作用，但和正常细胞无交叉反应；(3)靶向药物通过注射主动靶向高倍浓聚定位在与抗体具有较高特异性和亲和性的恶性肿瘤病灶；(4)靶向药物在磁热疗治疗仪交变磁场的作用下使肿瘤病灶的纳米磁粉产生磁滞生热效应加热肿瘤至42-95℃，进行高效杀灭、安全无毒副作用的靶向磁热疗治疗和预防，杀灭恶性肿瘤；(5)靶向药物具有生物降解性，药物应用剂量通常小于100mg，用于恶性肿瘤磁热疗治疗和预防没有毒副作用。为了便于储存，靶向药物可以通过干燥制成可用于临用前配制注射剂的固体粉体。
所述的纳米磁粉为颗粒粒径1～5nm、5～10nm、10～20nm、20～40nm、30～50nm、50～100nm、1～100nm以及100～1000nm，纳米磁粉表面经过表面活性剂、表面改性剂改性、修饰或有机、无机物质包裹、包被或未经改性修饰和包裹包被的铁磁性、亚铁磁性和超顺磁性纳米磁粉。纳米磁粉表面经过1次或多次表面活性剂、表面改性剂改性、修饰或有机、无机物质包裹、包被的目的是使纳米磁粉具有不同功能化的表面，如阴离子化表面、阳离子化表面、非离子化表面、氨基化表面、巯基化表面、羟基化表面、羧基化表面、无机物表面、聚合物表面、生物表面以及其它能与抗体偶联的功能化表面。其中的表面活性剂和表面改性包括十二烷基硫酸钠、油酸钠、正癸酸、聚乙二醇、葡聚糖、核苷酸、多肽，纳米磁粉与表面活性剂或表面改性剂的原料重量比例为1∶0.0001～0.20。而有机物质包括脂质体、聚乳酸、聚己内酯、蛋白质；无机物质包括二氧化硅纳米颗粒、氧化铝纳米颗粒、金纳米颗粒；纳米磁粉与有机或无机物质的原料重量比例为1∶0.01～5.0。
所述的抗体为针对肿瘤特异性抗原及肿瘤相关抗原，独特型决定簇，某些细胞因子的受体、激素及一些瘤基因的产物为相关靶分子的各种抗体，包括各种多克隆抗体、单克隆抗体、抗体Fab片段、基因工程抗体，其中分子量较小、特异性和亲和力较高的抗体Fab片段或基因工程抗体等抗体在免疫原性、穿透性以及各种水解酶的抵抗力方面都优于常规的单抗，比常规的单抗更易穿透到达肿瘤部位。抗体可以选用抗CEA(carcinoembryonic antigen)、AFP(alpha-fetoprotein)、CA19-9(carbohydrate antigen 19-9)、CA125(cancer antigen 125)、PSA(prostate soecific antigen)、hCG(hunan chorionic gonadotropin)、CA15-3、PAP、CA50、hCG、SCC、β2M(β2-microglobulin)、NSE(neuro-specific enolase)、HER2和TPA(tissue polypeptide antigen)抗体以及抗人肝癌单克隆抗体HAb18(humanized antibody 18)，也可以选用其它抗体。
所述的通过溶液混合偶联为在水溶液、纯水或有机单质及其溶液中混合偶联。
所述的靶向药物在注射剂中为纳米颗粒是为了使靶向药物具有良好的穿透性，并且具有与相关肿瘤细胞良好的特异性和亲和性。
所述的靶向药物通过注射主动靶向高倍浓聚定位为靶向药物主动靶向浓聚定位在恶性肿瘤病灶的浓度是正常组织血液中药物浓度的1-1000倍。
所述的靶向药物在磁热疗治疗仪的交变磁场作用下的磁滞生热能力为10-7000W/gFe。
所述的靶向药物注射剂包括靶向药物偶联后制成的注射剂和临用前用靶向药物干燥固体粉体配制的注射剂。靶向药物制成干燥固体粉体有利于药物长期储存和性能保持稳定。
所述的复合溶媒或纯水的靶向药物注射剂为靶向药物分散在生理盐水、磷酸盐缓冲液(PBS)、聚乙二醇、核苷酸等溶有无机、有机、生物、非生物物质的复合溶媒中或纯水中的制剂，其中靶向药物与复合溶媒或纯水的重量比例为1∶0.5～100，注射剂溶媒中纯水与无机或有机或生物或非生物物质的重量比例为1∶0～0.20。
本专利提出了把纳米磁粉作为一种抗体靶向药物的无毒副作用物理效应分子的新概念。同时提出了一种将纳米磁粉与抗体偶联制成恶性肿瘤磁热疗用靶向药物、用于通过静动脉或腹腔注射使靶向药物主动靶向浓聚定位在肿瘤病灶，并且在体外磁热疗治疗仪交变磁场的作用下，浓聚病灶的的纳米磁粉产生磁滞生热效应使肿瘤加热至42-48℃，而正常组织基本不升温，选择性杀灭恶性肿瘤，实现恶性肿瘤高效杀灭、安全无毒副作用的靶向磁热疗治疗和预防的新策略。
本发明的靶向药物是由抗体与不同粒径的纳米磁粉偶联构成的纳米颗粒药物，由于药物实现了纳米化，其在体内具有良好的穿透性、生物相容性、在血液中具有长循环稳定性，使它不仅具有抗体导向的主动靶向功能，而且具有载磁药物的磁性靶向功能和利用肿瘤的EPR效应(enhanced permeability and retention effect)的纳米药物颗粒的被动靶向功能，是一种具有主动靶向功能和多种其它靶向功能的复合靶向药物。
本发明的靶向药物中的抗体Fab片段、基因工程抗体，由于其分子量较小，比常规的单抗更易穿透到达肿瘤部位。采用分子量较小、特异性和亲和力较高的抗体构成的磁热疗用纳米磁粉-抗体靶向药物具有更好穿透功能和靶向功能。
本发明的靶向药物以纳米磁粉为磁热疗用磁热种子、抗体为导向分子，其中的纳米磁粉可以通过动静脉或腹腔注射或导入等给药途径，在抗体的导向等靶向功能作用下，实现药物主动靶向浓聚定位在与抗体具有较高特异性和亲和性的肿瘤病灶，在磁热疗治疗仪交变磁场的作用下，患者病灶的纳米磁粉产生显著的磁滞生热效应，使肿瘤病灶迅速升温至42-95℃，对肿瘤进行42-48℃的磁热疗治疗，也可以进行高于48℃的磁热疗治疗。
本发明的磁热疗用靶向药物的应用通常可以通过1次1小时以及1小时以上的磁热疗有效杀灭与抗体具有较高特异性和亲和性的恶性肿瘤，甚至使肿瘤完全消退；也可以通过多次1小时以及1小时以上的磁热疗有效杀灭与抗体具有较高特异性和亲和性的恶性肿瘤，甚至使肿瘤完全消退。
本发明的靶向药物中纳米磁粉可以生物降解，通常治疗用药物剂量小于100mg，它的应用具有生物降解性和无毒副作用的特点。
本发明的靶向药物不仅可以用于与抗体具有较高特异性和亲和性的恶性肿瘤的靶向磁热疗治疗，而且可以用于与抗体具有较高特异性和亲和性的恶性肿瘤靶向磁热疗预防，即可以用于已经检测到的和未检测到的恶性肿瘤的主动靶向磁热疗治疗，仅有极小的恶性肿瘤且影象设备无法检测到的早期恶性肿瘤的主动靶向磁热疗治疗，仅有几个细胞时的早期恶性肿瘤的主动靶向磁热疗治疗，转移恶性肿瘤细胞和癌栓的主动靶向磁热疗杀灭治疗，以及正常人定期和不定期地进行恶性肿瘤细胞主动靶向磁热疗杀灭的预防性治疗。
以下结合实施例对本发明作进一步的说明。
实施例1
将粒径分布范围为1～5nm、约10nm和10～40nm、30～50nm、50～100nm、100～150nm与950nm并分别经油酸钠、正癸酸、聚乙二醇等进行表面改性修饰或分别经葡聚糖、脂质体、纳米SiO2等进行包裹包被或未经表面修饰改性和包裹包被的超顺磁性和亚铁磁性纳米磁粉与抗人肝癌单克隆抗体HAb18片段HAb18F(ab′)2分别以重量配比为1∶0.2、1∶0.1和1∶0.1、1∶0.05、1∶0.001、1∶0.0001在水溶液中混合偶联制得纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物。采用Zetasizer3000激光粒度分析仪测定表明，由粒径分布范围为1～5nm、约10nm和10～40nm、30～50nm、50～100nm、100～150nm与950nm的纳米磁粉制得的靶向药物粒径分布范围分别为15～20nm、约20nm和20～70nm、40～80nm、60～130nm、110～180nm与960～1000nm，其中纳米磁粉与油酸钠、正癸酸、聚乙二醇的原料重量投料比例分别为1∶0.0001、1∶0.05、1∶0.20，纳米磁粉与葡聚糖、脂质体、纳米SiO2的原料重量投料比例分别为1∶0.01、1∶0.1、1∶5.0，纳米磁粉的表面改性修饰和包裹包被对药物的颗粒粒径有不同程度的影响。
实施例2
经JEM-2010 UHR高分辨率透射电镜分析表明，上述实施例1中由颗粒粒径约10nm的超顺磁性纳米磁粉与抗人肝癌单克隆抗体HAb18片段HAb18F(ab′)2偶联构成的靶向药物的颗粒粒径约为20nm，药物中纳米磁粉与抗体形成了良好的偶联，药物的纳米磁粉表面偶联着1个抗人肝癌单克隆抗体HAb18片段HAb18F(ab′)2。
实施例3
(1)将原料重量比例为1∶0.005的纳米磁粉与油酸钠在水中混合后，再将原料重量比例为1∶0.005的纳米磁粉与十二烷基硫酸钠在水中混合制成纳米磁粉经过2次修饰改性的功能化表面。(2)将原料重量比例为1∶0.01的纳米磁粉与聚乙二醇在水中混合后，再将原料重量比例为1∶1.5的纳米磁粉与二氧化硅纳米颗粒在水中混合制成纳米磁粉经过1次改性和1次包裹的功能化表面。(3)将原料重量比例为1∶0.01的纳米磁粉与聚乙二醇在水中混合后，再将溶于乙醇的脂质体溶液与水中的聚乙二醇改性纳米磁粉混合制成经过1次改性和1次包被的功能化表面，其中纳米磁粉与脂质体的原料重量比例为1∶0.5。
实施例4
将上述实施例1中的靶向药物经浓度1％的PBS水溶液洗涤后再离心，除去上清，分别用纯水、浓度1％的PBS水溶液、核苷酸水溶液(其中注射剂溶媒中纯水与核苷酸的重量比例为1∶0.20)制成靶向药物与纯水、浓度1％的PBS水溶液、核苷酸水溶液的重量比例为1∶0.5、1∶10和1∶100的靶向药物注射剂。
实施例5
将上述实施例1中的靶向药物经浓度1％的生理盐水洗涤后再离心，除去上清，经冷冻干燥制成靶向药物固体粉体。
实施例6
(1)ELISA(enzyme-linked immunosorbent assay)实验测得颗粒粒径为20～70nm的纳米磁粉-抗CEA抗体片段Fab靶向药物的免疫活性为63％。(2)体外稳定性实验表明，颗粒粒径为20～70nm的纳米磁粉-抗CEA抗体靶向药物注射液经37℃孵育24小时，无论在生理盐水中还是人血清白蛋白中，纳米磁粉脱落都小于5％，纳米磁粉-抗CEA抗体靶向药物在体外稳定。
实施例7
(1)ELISA实验测得颗粒粒径为40～80nm的纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物的免疫活性为57％。(2)体外稳定性实验表明，颗粒粒径为40～80nm的纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物注射液经37℃孵育24小时，无论在生理盐水中还是人血清白蛋白中，纳米磁粉脱落都小于5％，纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物在体外稳定。
实施例8
(1)将颗粒粒径为50～100nm的铁磁性纳米磁粉(其磁滞生热功率为10W/gFe)-抗CEA抗体靶向药物与结肠癌细胞LS174T混合，在超声功率为1～25W时经Zetasizer2000激光粒度分析仪检测，纳米磁粉-抗CEA抗体靶向药物与癌细胞以及纳米磁粉颗粒与抗体结合不脱落。(2)将颗粒粒径为40～80nm的纳米磁粉-抗CEA抗体靶向药物与结肠癌细胞LS174T、血细胞、正常肝细胞混合在一起，经磁分离后，仅结肠癌细胞LS174T在磁场下滞留，血细胞和正常肝细胞与结肠癌细胞LS174T完全分离。实验结果表明，纳米磁粉与抗CEA抗体具有较强的偶联结合力和稳定性，纳米磁粉-抗CEA抗体靶向药物与结肠癌细胞LS174T具有良好的靶向性和较强的亲和力，纳米磁粉-抗CEA抗体靶向药物与血液和肝脏等具有良好的生物相容性。
实施例9
(1)将颗粒粒径为50～100nm的铁磁性纳米磁粉(其磁滞生热功率为10W/gFe)-抗人肝癌单克隆抗体HAb18靶向药物与人肝癌细胞HHCC混合，在超声功率为1～25W时经Zetasizer2000激光粒度分析仪检测，纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物与癌细胞以及纳米磁粉颗粒与抗体结合不脱落。(2)将颗粒粒径为20～70nm的纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物与人肝癌细胞HHCC、血细胞、正常肝细胞混合在一起，经磁分离后，仅有人肝癌细胞HHCC在磁场下滞留，血细胞和正常肝细胞与人肝癌细胞HHCC完全分离。实验结果表明，纳米磁粉与抗人肝癌单克隆抗体HAb18具有较强的偶联结合力和稳定性，纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物与人肝癌细胞HHCC具有良好的靶向性和较强的亲和力，纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物与血液和肝脏等具有良好的生物相容性。
实施例10
将荷结肠癌细胞LS174T裸鼠尾静脉注射颗粒粒径为20～50nm的纳米磁粉(其磁滞生热功率为7000W/gFe)-抗CEA抗体靶向药物30mg后30分钟后处死，取肿瘤和心、脑、脾、肾、肠、肝等重要器官进行扫描电镜研究。电镜和能谱分析结果表明，注射靶向药物的裸鼠肿瘤毛细血管血液中和肿瘤组织中Fe元素(Fe元素是纳米磁粉的主要元素，约占纳米磁粉重量的70％。)占组织中Fe、Ca、Si、Al、Mg、K、Na、P、O、C等10种主要元素的重量比例分别从对照组(未注射靶向药物的)裸鼠肿瘤毛细血管血液中和肿瘤组织中的0.08％和0％提高到23.11％和0.83％，并且也高于注射靶向药物的裸鼠非肿瘤血管血液中的0.14％、正常肝脏组织中的0.14％和其它器官中的0.14％以下。靶向药物在裸鼠肿瘤毛细血管血液中和肿瘤组织中比对照组(未注射靶向药物的)裸鼠肿瘤毛细血管血液中和肿瘤组织中以及注射靶向药物的裸鼠非肿瘤血管血液中和正常肝组织中分别增高289倍和-(由于对照组肿瘤中测不到Fe，无法计算)以165倍和165倍，即靶向药物在肿瘤中的含药量至少高于其它部位165倍，纳米磁粉-抗CEA抗体靶向药物在体内具有显著的靶向性能，能使靶向药物靶向浓聚定位在肿瘤病灶，而在其他部位不聚集。
实施例11
将荷人肝癌细胞HHCC裸鼠尾静脉注射颗粒粒径为20～50nm的纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物30mg后30分钟后处死，取肿瘤和心、脑、脾、肾、肠、肝等重要器官进行扫描电镜研究。电镜和能谱分析结果表明，注射靶向药物的裸鼠肿瘤毛细血管血液中和肿瘤组织中Fe元素(Fe元素是纳米磁粉的主要元素，约占纳米磁粉重量的70％。)占组织中Fe、Ca、Si、Al、Mg、K、Na、P、O、C等10种主要元素的重量比例分别从对照组(未注射靶向药物的)裸鼠肿瘤毛细血管血液中和肿瘤组织中的0.08％和0％提高到24.38％和0.76％，并且也高于注射靶向药物的裸鼠非肿瘤血管血液中的0.14％、正常肝脏组织中的0.14％和其它器官中的0.14％以下。靶向药物在裸鼠肿瘤毛细血管血液中和肿瘤组织中比对照组(未注射靶向药物的)裸鼠肿瘤毛细血管血液中和肿瘤组织中以及注射靶向药物的裸鼠非肿瘤血管血液中和正常肝组织中分别增高304倍和-(由于对照组肿瘤中测不到Fe，无法计算)以174倍和174倍，即靶向药物在肿瘤中的含药量至少高于其它部位174倍，纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物在体内具有显著的靶向性能，能使靶向药物靶向浓聚定位在肿瘤病灶，而在其他部位不聚集。
实施例12
取荷人胃癌细胞N87裸鼠16只，测定并计算肿瘤体积后，按肿瘤体积随机分成两组，第一组为对照组，每只裸鼠肿瘤部位注射纯水0.3ml，第二组每只裸鼠腹腔注射含有30mg纳米磁粉(其磁滞生热功率为1000W/gFe)-抗HER2抗体靶向药物的注射剂0.3ml，将第二组裸鼠置入磁热疗治疗仪交变磁场下42-43℃治疗1小时2次，治疗10天后处死上述裸鼠、分离肿瘤，称取肿瘤重量。结果表明，第一组瘤重2.36±0.53g，第二组瘤重0.97±0.29g，治疗组的抑瘤率为59％，P值小于0.01。
实施例13
取荷人肝癌细胞HHCC裸鼠16只，测定并计算肿瘤体积后，按肿瘤体积随机分成两组，第一组为对照组，每只裸鼠肿瘤部位注射纯水0.3ml，第二组每只裸鼠腹腔注射含有30mg纳米磁粉(其磁滞生热功率为2000W/gFe)-抗人肝癌单克隆抗体HAb18靶向药物的注射剂0.3ml，将第二组裸鼠置入磁热疗治疗仪交变磁场下42-43℃治疗65分钟2次，治疗10天后处死上述裸鼠、分离肿瘤，称取肿瘤重量。结果表明，第一组瘤重2.97±0.65g，第二组瘤重1.02±0.31g，治疗组的抑瘤率为66％，P值小于0.01。
实施例14
取荷人肺癌A549裸鼠16只，测定并计算肿瘤体积后，按肿瘤体积随机分成两组，第一组为对照组，每只裸鼠肿瘤部位注射纯水0.3ml，第二组每只裸鼠腹腔注射含有30mg纳米磁粉(其磁滞生热功率为2000W/gFe)-抗CEA抗体靶向药物的注射剂0.3ml，将第二组裸鼠置入磁热疗治疗仪交变磁场下42-43℃治疗65分钟2次，治疗10天后处死上述裸鼠、分离肿瘤，称取肿瘤重量。结果表明，第一组瘤重1.97±0.53g，第二组瘤重0.79±0.37g，治疗组的抑瘤率为60％，P值小于0.01。
实施例15
取荷结肠癌细胞LS174T裸鼠16只，测定并计算肿瘤体积后，按肿瘤体积随机分成两组，第一组为对照组，每只裸鼠肿瘤部位注射纯水0.3ml，第二组每只裸鼠尾静脉注射含有50mg纳米磁粉(其磁滞生热功率为300W/gFe)-抗CEA抗体靶向药物的注射剂0.3ml，将第二组裸鼠置入磁热疗治疗仪交变磁场下42-43℃治疗1小时，治疗10天后处死上述裸鼠、分离肿瘤，称取肿瘤重量。结果表明，第一组瘤重2.97±0.65g，第二组瘤重0.12±0.31g，治疗组的抑瘤率为96％，P值小于0.01，并且其中2只裸鼠肿瘤完全消退，3只裸鼠肿瘤残余组织病理图片分析发现肿瘤细胞全部凝固性坏死，2只裸鼠肿瘤残余组织病理图片分析发现仅有少量未坏死肿瘤细胞。同时，在治疗后十天对第二组裸鼠进行体重和不良反应观测，未见明显异常，裸鼠处死后，取心、脑、脾、肾、肠、肝等重要器官做病理检查，未见明显异常。动物实验结果显示，采用纳米磁粉-抗CEA抗体靶向药物进行磁热疗可以实现靶向、高效、安全、无毒副作用杀灭肿瘤，甚至使肿瘤完全消退，纳米磁粉-抗CEA抗体靶向药在结肠癌、肺癌等多种癌症靶向治疗中有重要的应用价值。
实施例16
取荷人肝癌细胞HHCC裸鼠16只，测定并计算肿瘤体积后，按肿瘤体积随机分成两组，第一组为对照组，每只裸鼠肿瘤部位注射纯水0.3ml，第二组每只裸鼠尾静脉注射含有50mg纳米磁粉(其磁滞生热功率为300W/gFe)-抗人肝癌单克隆抗体HAb18片段HAb18F(ab′)2靶向药物的注射剂0.3ml，将第二组裸鼠置入磁热疗治疗仪交变磁场下42-43℃治疗1小时，治疗10天后处死上述裸鼠、分离肿瘤，称取肿瘤重量。结果表明，第一组瘤重2.97±0.65g，第二组瘤重0.12±0.31g，治疗组的抑瘤率为96％，P值小于0.01，并且其中2只裸鼠肿瘤完全消退，2只裸鼠肿瘤残余组织病理图片分析发现肿瘤细胞全部凝固性坏死，3只裸鼠肿瘤残余组织病理图片分析发现仅有少量未坏死肿瘤细胞。同时，在治疗后十天对第二组裸鼠进行体重和不良反应观测，未见明显异常，裸鼠处死后，取心、脑、脾、肾、肠、肝等重要器官做病理检查，未见明显异常。动物实验结果显示，采用纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药物进行磁热疗可以实现靶向、高效、安全、无毒副作用杀灭肿瘤，甚至使肿瘤完全消退，纳米磁粉-抗人肝癌单克隆抗体HAb18靶向药在肝癌靶向治疗中有重要的应用价值。
值得指出的是，选用其它抗体制成的纳米磁粉-抗体靶向药用于与抗体具有较高特异性和亲和性的恶性肿瘤的靶向磁热疗治疗和预防也可以取得同上的治疗和预防效果。
实施例17
取小白鼠和豚鼠各10只，在小白鼠和豚鼠腹腔分别注射0.5ml含0.3g和1.5ml含1.0g的纳米磁粉-抗CEA抗体靶向药物，观察7天和30天后未见不良反应和体重下降，处死后，取心、脑、脾、肾、肠、肝等重要器官切片做病理检查，未见明显异常。观察30天后处死后，取心、脑、脾、肾、肠、肝等重要器官做磁热疗治疗试验，未见发热出现。通常肿瘤磁热疗治疗仅需要20～100mg纳米磁粉-抗CEA抗体靶向药物，从上述初步毒副实验结果可知，本发明的纳米磁粉-抗CEA抗体靶向药物具有生物降解性和无毒副作用。
实施例18
取小白鼠和豚鼠各10只，在小白鼠和豚鼠腹腔分别注射0.5ml含0.3g和1.5ml含1.0g的纳米磁粉-抗HER2抗体靶向药物，观察7天和30天后未见不良反应和体重下降，处死后，取心、脑、脾、肾、肠、肝等重要器官切片做病理检查，未见明显异常。观察30天后处死后，取心、脑、脾、肾、肠、肝等重要器官做磁热疗治疗试验，未见发热出现。通常肿瘤磁热疗治疗仅需要20～100mg纳米磁粉-抗HER2抗体靶向药物，从上述初步毒副实验结果可知，本发明的纳米磁粉-抗HER2抗体靶向药物具有生物降解性和无毒副作用。

Claims (9)

1、一种恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于：(1)以具有磁滞生热能力的纳米磁粉为效应分子、以抗体为导向分子，将纳米磁粉与抗体通过溶液混合偶联制成具有主动靶向、磁性靶向和被动靶向功能的磁热疗用纳米靶向药物，纳米磁粉与抗体的重量配比为1∶0.0001～0.20，靶向药物的颗粒粒径为5～1000nm，靶向药物的纳米磁粉表面偶联有抗体1个或多个抗体并且偶联抗体具有生物活性；(2)靶向药物的剂型为注射剂，在注射剂中药物分散为纳米颗粒，具有良好的穿透性以及与相关的恶性肿瘤细胞具有良好的特异性和亲和性；(3)靶向药物通过注射主动靶向浓聚定位在与抗体具有较高特异性和亲和性的恶性肿瘤病灶，靶向药物在恶性肿瘤病灶的浓度达到正常组织血液中药物浓度的1-1000倍；(4)浓聚定位在恶性肿瘤病灶的靶向药物在磁热疗治疗仪交变磁场的作用下产生磁滞生热效应，磁滞生热能力为10-7000W/gFe，加热肿瘤至42-95℃，杀灭恶性肿瘤；(5)靶向药物具有生物降解功能，药物应用剂量通常小于100mg，用于恶性肿瘤磁热疗治疗和预防没有毒副作用。
2、根据权利要求1所述的恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于所述的纳米磁粉为颗粒粒径1～5nm、5～10nm、10～20nm、20～40nm、30～50nm、50～100nm、1～100nm以及100～1000nm，纳米磁粉表面经过表面活性剂、表面改性剂改性、修饰或有机、无机物质包裹、包被或未经改性修饰和包裹包被的铁磁性、亚铁磁性和超顺磁性纳米磁粉。
3、根据权利要求1或2所述的恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于其中的表面活性剂和表面改性包括十二烷基硫酸钠、油酸钠、正癸酸、聚乙二醇、葡聚糖、核苷酸、多肽，纳米磁粉与表面活性剂或表面改性剂的原料重量比例为1∶0.0001～0.20。
4、根据权利要求1或2所述的恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于有机物质包括脂质体、聚乳酸、聚己内酯、蛋白质；无机物质包括二氧化硅纳米颗粒、氧化铝纳米颗粒、金纳米颗粒；纳米磁粉与有机或无机物质的原料重量比例为1∶0.01～5.0。
5、根据权利要求1所述的恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于所述的抗体为针对肿瘤特异性抗原及肿瘤相关抗原，独特型决定簇，某些细胞因子的受体、激素及一些瘤基因的产物为相关靶分子的各种抗体，包括各种多克隆抗体、单克隆抗体、抗体Fab片段、基因工程抗体，其中分子量较小、特异性和亲和力较高的抗体Fab片段或基因工程抗体等抗体在免疫原性、穿透性以及各种水解酶的抵抗力方面都优于常规的单抗，比常规的单抗更易穿透到达肿瘤部位。
6、根据权利要求1或5所述的恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于所述的抗体选用抗CEA、AFP、CA19-9、CA125、PSA、hCG、CA15-3、PAP、CA50、hCG、SCC、β2M、NSE、HER2和TPA抗体、抗人肝癌单克隆抗体HAb18以及其它抗体。
7、根据权利要求1所述的恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于所述的通过溶液混合偶联为在水溶液、纯水或有机单质及其溶液中混合偶联。
8、根据权利要求1所述的恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于所述的靶向药物注射剂包括靶向药物偶联后制成的注射剂和临用前用靶向药物干燥固体粉体配制的注射剂。
9、根据权利要求1或8所述的恶性肿瘤磁热疗用纳米磁粉-抗体靶向药物，其特征在于所述的复合溶媒或纯水的靶向药物注射剂为靶向药物分散在生理盐水、磷酸盐缓冲液(PBS)、聚乙二醇、核苷酸等溶有无机、有机、生物、非生物物质的复合溶媒中或纯水中的制剂，其中靶向药物与复合溶媒或纯水的重量比例为1∶0.5～100，注射剂射剂溶媒中纯水与无机或有机或生物或非生物物质的重量比例为1∶0～0.20。
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