人鼠嵌合抗肿瘤细胞核单抗—空间稳定脂质体研究
|
摘要
鉴于人鼠嵌合抗肿瘤细胞核单抗chTNT能特异性靶向肿瘤坏死区瘤细胞的核抗原—DNA-组蛋白复合物，作者希望尝试将chTNT作为靶向头基连接到空间稳定脂质体表面，制备成既具有较长血循环时间又能靶向肿瘤细胞核抗原的免疫脂质体，以期达到疗效不低于抗肿瘤细胞表面抗原抗体修饰的免疫脂质体，而又能靶向多种实体瘤细胞的目的。
本文首先从普通和稳定性脂质体膜材料制备出发，制备了蛋黄卵磷脂(EPC)、氢化卵磷脂(HEPC)、甲氧基聚乙二醇-磷脂酰乙醇胺或氢化磷脂酰乙醇胺(MPEG-EPE或MPEG-HEPE)以及抗体与脂质体的桥连剂—吡啶二硫丙酰基-聚乙二醇-磷脂酰乙醇胺或氢化磷脂酰乙醇胺(PDP-PEG-EPE或PDP-PEG-HEPE)及其中间体单氨基聚乙二醇(PEG-NH_2)。TLC、IR、HNMR证实所制备的膜材料均符合实验要求。
空间稳定免疫脂质体(chTNT-SLs或IgG-SLs)的制备是采用高压乳匀法先制备出含PDP-PEG-EPE的空间稳定脂质体(PDP-SLs)，再通过二硫苏糖醇(DTT)将其还原为表面带巯基的SLs(HS-SLs)，最后与衍生化后的抗体连接即得，其粒径分布均匀，平均粒径约为140nm，稍大于修饰前粒径。包载阿霉素(DOX)则在制得PDP-SLs后进行，继后再连接抗体。采用硫酸胺梯度法包载DOX时，膜组成为EPC／Chol／MPEG-EPE或再加PDP-PEG-EPE的脂质体，包载条件以50℃、30min为优；膜组成为HEPC／Chol／MPEG-HEPE或再加PDP-PEG-HEPE的脂质体，包载条件65℃、30min为优，且药脂比为1：5时，包封率可达95％以上。
空间稳定免疫脂质体的免疫活性是决定其能否主动靶向的关键。~(125)I标记法的检测结果表明：抗体连接效率为53.72％，脂质体表面抗体密度为75.23μgAb／μmol磷脂，处于较优的抗体密度范围内；chTNT和chTNT-SLs与Raji细胞的特异性结合率均约为5％，与其核抗原结合率约15％；chTNT、chTNT-SLs均能与~(125)I-chTNT竞争结合Raji细胞核抗原，提示二者均有相同的免疫结合位点。ELISA法测定结果表明：IgG-SLs免疫活性约为小鼠IgG的43.7％，chTNT-SLs的免疫活性约为chTNT的50％，提示采用硫醚键方式将抗体连接于脂质体表面PEG末端的方法能在一定程度上保留抗体的免疫活性；chTNT-SLs与Raji细胞、KB细胞核抗原均能特异性结合，提示其具有广谱抗肿瘤细胞核抗原的作用。
空间稳定免疫脂质体的粒径及所包载DOX的膜泄漏稳定性决定着其在体内的生物学行为，在血循环中滞留时间长短是决定其能否靶向实体瘤组织的关键。放置过程中粒径变化结果提示，空间稳定免疫脂质体的稳定性介于普通脂质体和空间稳定脂质体之间；DOX-SL-IgG在37℃的PBS和1％人血浆中振荡放置10h药物泄漏或释放率分别为20.7％和9.5％，提示DOX空间稳定免疫脂质体膜阻
止DOX泄漏性能较好;’“，I标记chTNT一CLS和chT’NT一SLS在大鼠体内药动学检
测结果表明，后者在血液中清除慢，滞留时间比前者长。HPLC一荧光检测法测定
Dox一sLS、Dox一sL一IgG和Dox在大鼠体内药动学的结果表明，药动学行为均
符合两室模型，但DOX脂质体的tl几均比DOX长得多，提示DOX空间稳定免
疫脂质体具有血液长循环特性。
空间稳定免疫脂质体在实体瘤组织积聚程度是其能否发挥疗效的基础，影像
学定位是了解其在靶位动态积聚程度和速度的一种较为直观的方法。将磁共振用
顺磁性显像剂的主药成分札喷酸复合物(Gd一DTPA)包载于脂质体中，制备成
Gd一SL一chTNT。通过对给药后不同时相点的荷SKOV3瘤裸鼠进行磁共振增强扫
描，结果表明，Gd一SL一ch丁NT在瘤体部位强化特征不同于游离Gd一DTPA，表现
为12h和24h的后续强化效应。提示:空间稳定免疫脂质体能在实体瘤积聚，且
积聚是个渐进过程。
DOX一SL一chTNT在荷SKOV3瘤裸鼠体内的初步抑瘤试验结果表明:
DOX一SL一ch飞NT的瘤体相对体积和瘤重与空白对照组相比，均有显著性差异
(P<0.ol和p<0.05);其体积和重量抑瘤率分别为41 .20%和42.34%，与接有非
特异性小鼠杭体IgG的DOX一SL一IgG相比有统计学差异(P<0 .1);与Dox给药
后对体重影响相比，DOx一SL一chTNT和Dox一sL一IgG组体重均稳中有升。提示:
在相同药物剂量条件下，杭肿瘤细胞核单抗修饰的空间稳定免疫脂质体的杭肿瘤
效果明显好于普通非特异性抗体修饰的空间稳定免疫脂质体，但两者均能明显降
低DOX引起的毒副作用。
Due to its specific targeting to the nuclear antigent-DNA-histone, within necrotic tumor cells, chimeric TNT was attached to the surface of sterically stablized liposomes (SLs) as a targeting group in order that the immunoliposomes with both long circulation time and active targeting to nuclear antigen were obtained. It was expected that the therapeutic effect of chTNT-SLs would be increased, compared to the immunoliposomes modified with monoclonal antibody with recognition to tumor cell's surface antigen, and would target to variety kinds of solid tumors.
In this study, the lipid materials, such as egg phosphatidylcholine (EPC) or hydrogenated egg phosphatidylcholine (HEPC), methoxy polyethylene glycol-phosphatidylethanolamine (MPEG-EPE or MPEG-HEPE), for preparing either conventional liposomes (CLs) or SLs were synthesized first. The coupling agents, pyridyldithioproprionate-PEG-EPE/HEPE (PDP-PEG-EPE or PDP-PEG-HEPE), for the attachment of antibody to liposomes were also synthesized. The purity and physicochemical properties of all these materials were assayed and proved using TLC, IR and NMR methods to meet the demand for preparing liposomes.
The unilamellar liposomes with controllable sizes were prepared using the above mentioned materials via high pressure homogenization method. chTNT-SLs or IgG-SLs were prepared following the procedures below: First, SLs containing PDP-PEG-EPE were prepared. Then, the dithiol-bond of PDP was reduced to -SH by dithiothreitol (DTT) and HS-SLs were thus obtained. Finally, the derivative chTNT or IgG (maleimidophenylbutyrate-chTNT or IgG, MPB-chTNT or MPB-IgG)
was linked to the surface of SLs.
The target recognition was the key factor to the in vivo initiative targeting effect of sterically stabilized immunoliposomes (SILs). In this study, 125I radiolabeling tests were carried out. The results showed that the coupling ratio of antibody to liposomes was 53.72%, and the antibody density was 75.23ug/umol lipid. The binding ratio of chTNT and chTNT-SLs to Raji cells were about 5%, and to nuclear antigen, 15%. Both chTNT and chTNT-SLs could competitively bind with nuclear antigen against 125I-chTNT, which suggested that they all have same binding site. ELISA studies confirmed that the immunoreactivities of IgG-SLs and chTNT-SLs was about 43.7% and 50%, respectively, of murine IgG and chTNT, which indicated that the linkage method of antibodies to the terminal of PEG of liposome surface via thioether bond could retain their recognition. chTNT-SLs could bind specificly to nuclear antigen of both Raji cells and KB cells, which indicated that chTNT-SLs can target to different tumor cells.
Doxorubicin (DOX) loaded liposomes were prepared by ammonium sulfate gradient method. The preparation conditions were optimized using Star design method. When the lipid composition included EPC, Choi and MPEG-EPE (with or without PDP-PEG-EPE), the liposomes could be obtained at 50C for 30 mins. But if the EPC was replaced by HEPC, the preparing condition would be 65C for 30 mins. The entrapment efficiency might reach 95% when the drug/phospholipid ratio was 1:5. After Dox was entrapped in liposomes, the antibody was conjugated to the liposomes, if necessary.
The physical stability of liposomes influences the in vivo biological behavior. The size changing of liposomes during restoration at 4 C was investigated, and SILs stay between CLs and SLs on size stability. When DOX-SL-IgG were suspended in either PBS or 1% human plasma at 37C for 10 hrs, the leakage ratio of DOX was both relatively low (20.7%, 9.5%), which indicated that liposomes membrane could contain stably entrapped drugs.
The circulation time of SILs determines the targeting effect to the solid tumors. The pharmacokinetic studies of 125I-chTNT-CLs and 125I-chTNT-SLs showed that the latter had longer circulation time. The pharmacokinetic performance of DOX-SLs, DOX-SL-IgG and DOX were also studied using HPLC-fluorescent assay, and the results showed that the pharmacokinetic module of DOX entrapped liposomes met the two-chamber module.
本文首先从普通和稳定性脂质体膜材料制备出发，制备了蛋黄卵磷脂(EPC)、氢化卵磷脂(HEPC)、甲氧基聚乙二醇-磷脂酰乙醇胺或氢化磷脂酰乙醇胺(MPEG-EPE或MPEG-HEPE)以及抗体与脂质体的桥连剂—吡啶二硫丙酰基-聚乙二醇-磷脂酰乙醇胺或氢化磷脂酰乙醇胺(PDP-PEG-EPE或PDP-PEG-HEPE)及其中间体单氨基聚乙二醇(PEG-NH_2)。TLC、IR、HNMR证实所制备的膜材料均符合实验要求。
空间稳定免疫脂质体(chTNT-SLs或IgG-SLs)的制备是采用高压乳匀法先制备出含PDP-PEG-EPE的空间稳定脂质体(PDP-SLs)，再通过二硫苏糖醇(DTT)将其还原为表面带巯基的SLs(HS-SLs)，最后与衍生化后的抗体连接即得，其粒径分布均匀，平均粒径约为140nm，稍大于修饰前粒径。包载阿霉素(DOX)则在制得PDP-SLs后进行，继后再连接抗体。采用硫酸胺梯度法包载DOX时，膜组成为EPC／Chol／MPEG-EPE或再加PDP-PEG-EPE的脂质体，包载条件以50℃、30min为优；膜组成为HEPC／Chol／MPEG-HEPE或再加PDP-PEG-HEPE的脂质体，包载条件65℃、30min为优，且药脂比为1：5时，包封率可达95％以上。
空间稳定免疫脂质体的免疫活性是决定其能否主动靶向的关键。~(125)I标记法的检测结果表明：抗体连接效率为53.72％，脂质体表面抗体密度为75.23μgAb／μmol磷脂，处于较优的抗体密度范围内；chTNT和chTNT-SLs与Raji细胞的特异性结合率均约为5％，与其核抗原结合率约15％；chTNT、chTNT-SLs均能与~(125)I-chTNT竞争结合Raji细胞核抗原，提示二者均有相同的免疫结合位点。ELISA法测定结果表明：IgG-SLs免疫活性约为小鼠IgG的43.7％，chTNT-SLs的免疫活性约为chTNT的50％，提示采用硫醚键方式将抗体连接于脂质体表面PEG末端的方法能在一定程度上保留抗体的免疫活性；chTNT-SLs与Raji细胞、KB细胞核抗原均能特异性结合，提示其具有广谱抗肿瘤细胞核抗原的作用。
空间稳定免疫脂质体的粒径及所包载DOX的膜泄漏稳定性决定着其在体内的生物学行为，在血循环中滞留时间长短是决定其能否靶向实体瘤组织的关键。放置过程中粒径变化结果提示，空间稳定免疫脂质体的稳定性介于普通脂质体和空间稳定脂质体之间；DOX-SL-IgG在37℃的PBS和1％人血浆中振荡放置10h药物泄漏或释放率分别为20.7％和9.5％，提示DOX空间稳定免疫脂质体膜阻
止DOX泄漏性能较好;’“，I标记chTNT一CLS和chT’NT一SLS在大鼠体内药动学检
测结果表明，后者在血液中清除慢，滞留时间比前者长。HPLC一荧光检测法测定
Dox一sLS、Dox一sL一IgG和Dox在大鼠体内药动学的结果表明，药动学行为均
符合两室模型，但DOX脂质体的tl几均比DOX长得多，提示DOX空间稳定免
疫脂质体具有血液长循环特性。
空间稳定免疫脂质体在实体瘤组织积聚程度是其能否发挥疗效的基础，影像
学定位是了解其在靶位动态积聚程度和速度的一种较为直观的方法。将磁共振用
顺磁性显像剂的主药成分札喷酸复合物(Gd一DTPA)包载于脂质体中，制备成
Gd一SL一chTNT。通过对给药后不同时相点的荷SKOV3瘤裸鼠进行磁共振增强扫
描，结果表明，Gd一SL一ch丁NT在瘤体部位强化特征不同于游离Gd一DTPA，表现
为12h和24h的后续强化效应。提示:空间稳定免疫脂质体能在实体瘤积聚，且
积聚是个渐进过程。
DOX一SL一chTNT在荷SKOV3瘤裸鼠体内的初步抑瘤试验结果表明:
DOX一SL一ch飞NT的瘤体相对体积和瘤重与空白对照组相比，均有显著性差异
(P<0.ol和p<0.05);其体积和重量抑瘤率分别为41 .20%和42.34%，与接有非
特异性小鼠杭体IgG的DOX一SL一IgG相比有统计学差异(P<0 .1);与Dox给药
后对体重影响相比，DOx一SL一chTNT和Dox一sL一IgG组体重均稳中有升。提示:
在相同药物剂量条件下，杭肿瘤细胞核单抗修饰的空间稳定免疫脂质体的杭肿瘤
效果明显好于普通非特异性抗体修饰的空间稳定免疫脂质体，但两者均能明显降
低DOX引起的毒副作用。
Due to its specific targeting to the nuclear antigent-DNA-histone, within necrotic tumor cells, chimeric TNT was attached to the surface of sterically stablized liposomes (SLs) as a targeting group in order that the immunoliposomes with both long circulation time and active targeting to nuclear antigen were obtained. It was expected that the therapeutic effect of chTNT-SLs would be increased, compared to the immunoliposomes modified with monoclonal antibody with recognition to tumor cell's surface antigen, and would target to variety kinds of solid tumors.
In this study, the lipid materials, such as egg phosphatidylcholine (EPC) or hydrogenated egg phosphatidylcholine (HEPC), methoxy polyethylene glycol-phosphatidylethanolamine (MPEG-EPE or MPEG-HEPE), for preparing either conventional liposomes (CLs) or SLs were synthesized first. The coupling agents, pyridyldithioproprionate-PEG-EPE/HEPE (PDP-PEG-EPE or PDP-PEG-HEPE), for the attachment of antibody to liposomes were also synthesized. The purity and physicochemical properties of all these materials were assayed and proved using TLC, IR and NMR methods to meet the demand for preparing liposomes.
The unilamellar liposomes with controllable sizes were prepared using the above mentioned materials via high pressure homogenization method. chTNT-SLs or IgG-SLs were prepared following the procedures below: First, SLs containing PDP-PEG-EPE were prepared. Then, the dithiol-bond of PDP was reduced to -SH by dithiothreitol (DTT) and HS-SLs were thus obtained. Finally, the derivative chTNT or IgG (maleimidophenylbutyrate-chTNT or IgG, MPB-chTNT or MPB-IgG)
was linked to the surface of SLs.
The target recognition was the key factor to the in vivo initiative targeting effect of sterically stabilized immunoliposomes (SILs). In this study, 125I radiolabeling tests were carried out. The results showed that the coupling ratio of antibody to liposomes was 53.72%, and the antibody density was 75.23ug/umol lipid. The binding ratio of chTNT and chTNT-SLs to Raji cells were about 5%, and to nuclear antigen, 15%. Both chTNT and chTNT-SLs could competitively bind with nuclear antigen against 125I-chTNT, which suggested that they all have same binding site. ELISA studies confirmed that the immunoreactivities of IgG-SLs and chTNT-SLs was about 43.7% and 50%, respectively, of murine IgG and chTNT, which indicated that the linkage method of antibodies to the terminal of PEG of liposome surface via thioether bond could retain their recognition. chTNT-SLs could bind specificly to nuclear antigen of both Raji cells and KB cells, which indicated that chTNT-SLs can target to different tumor cells.
Doxorubicin (DOX) loaded liposomes were prepared by ammonium sulfate gradient method. The preparation conditions were optimized using Star design method. When the lipid composition included EPC, Choi and MPEG-EPE (with or without PDP-PEG-EPE), the liposomes could be obtained at 50C for 30 mins. But if the EPC was replaced by HEPC, the preparing condition would be 65C for 30 mins. The entrapment efficiency might reach 95% when the drug/phospholipid ratio was 1:5. After Dox was entrapped in liposomes, the antibody was conjugated to the liposomes, if necessary.
The physical stability of liposomes influences the in vivo biological behavior. The size changing of liposomes during restoration at 4 C was investigated, and SILs stay between CLs and SLs on size stability. When DOX-SL-IgG were suspended in either PBS or 1% human plasma at 37C for 10 hrs, the leakage ratio of DOX was both relatively low (20.7%, 9.5%), which indicated that liposomes membrane could contain stably entrapped drugs.
The circulation time of SILs determines the targeting effect to the solid tumors. The pharmacokinetic studies of 125I-chTNT-CLs and 125I-chTNT-SLs showed that the latter had longer circulation time. The pharmacokinetic performance of DOX-SLs, DOX-SL-IgG and DOX were also studied using HPLC-fluorescent assay, and the results showed that the pharmacokinetic module of DOX entrapped liposomes met the two-chamber module.
引文
1. Sharifi J, Khawli LA et al. Characterization of a phage display-derived human monoclonal antibody (NHS76) counterpart to chimeric TNT-1 directed against necrotic regions of solid tumors. Hybrid Hybridomics. 2001, 20(5-6): 305-312.
2. Khawli LA, Biela B et al. Comparison of Recombinant Derivatives of Chimeric TNT-3 Antibody for the Radioimaging of Solid Tumors. Hybrid Hybridomics, 2003, 22(1): 1-9.
3. Khawli LA, Mizokami MM et al. Pharmacokinetic characteristics and biodistribution of radioiodinated chimeric TNT-1, -2, and -3 monoclonal antibodies after chemical modification with biotin. Cancer Biother Radiopharm, 2002, 17(4): 359-370.
4. Khawli LA, Biela BH et al. Stable, genetically engineered F(ab')_2 fragments of chimeric TNT-3 expressed in mammalian cells. Hybrid Hybridomics, 2002, 21(1): 11-18.
5. Hornick JL, Sharifi J et al. A new chemically modified chimeric TNT-3 monoclonal antibody directed against DNA for the radioimmunotherapy of solid tumors. Cancer Biother Radiopharm,1998, 13(4): 255-268.
6. Hornick JL, Sharifi J et al. Single amino acid substitution in the Fc region of chimeric TNT-3 antibody accelerates clearance and improves immunoscintigraphy of solid tumors. J Nucl Med, 2000, 41(2): 355-62.
7. Mizokami MM, Hu P et al. Chimeric TNT-3 antibody/murine interferon-gamma fusion protein for the immunotherapy of solid malignancies. Hybrid Hybridomics, 2003, 22(4): 197-207.
8. Sharifi J. Khawli LA et al. Generation of human interferon gamma and tumor Necrosis factor alpha chimeric TNT-3 fusion proteins. Hybrid Hybridomics, 2002, 21(6): 421-432.
9. Biela BH, Khawli LA et al. Chimeric TNT-3/human beta-glucuronidase fusion proteins for antibody-directed enzyme prodrug therapy (ADEPT). Cancer Biother Radiopharm, 2003, 18(3): 339-353.
10. Hornick JL, Khawli LA et al. Pretreatment with a monoclonal antibody/ interleukin-2 fusion protein directed against DNA enhances the delivery of therapeutic molecules to solid tumors. Clin Cancer Res, 1999, 5(1): 51-60.
11. Li J, Hu P et al. LEC/chTNT-3 fusion protein for the immunotherapy of experimental solid tumors. J Immunother, 2003, 26(4): 320-331.
12．王肇炎，陈正玉，赖清宏编，阿霉素的临床应用(第二版)，人民卫生出版社，1994。
13．解咏清，阿霉素。医药工业，1987，18(4)：188-189。
14．张覃沐，抗肿瘤药物与心脏毒性。新药与临床，1985，4(2)：30-32。
15．吕焕章，阿霉素的心脏毒性及防护药物的研究进展。国外医药-合成药、生化药、制剂分册，1994，15(2)：67-69。
16．李素英，阿霉素的心脏毒副作用及其防治。心血管病学进展，1995，16(1)：38-39。
17. Torchilin VP et al. Poly(ethylene glycol)-coated anti-cardiac myosin immunoliposomes: factors influencing targeted accumulation in the infracted myocardium. Biochim Biophys Acta, 1996,1279: 75-83.
18. DEL de Menezes et al. In vitro and in vivo targeting of immunoliposomal doxorubicin to human B-cell lymphoma. Cancer Res, 1998, 58: 3320-3330.
19. Lundberg BB et al. Specific binding of sterically stabilized anti-B-cell immunoliposomes and cytotoxicity of entrapped doxorubicin. Int J Pharm, 2000, 205: 101-108.
20. Moase EH et al. Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer. Biochim Biophys Acta, 2001,1510: 43-55.
21. Park JW et al. Tumor targeting using anti-her2 immunoliposomes. J Control Release, 2001,74:95-113.
22. Nielsen UB et al. Internalizing antibodies and targeted cancer therapy: direct silection from phage display libraries. Pharm Sci Tech Today, 2000, 3(8): 282-291.
23. Torchilin VP, Klibanov AL et al. Targeted accumulation of polyethylene glycol-coated immunoliposomes in infracted rabbit myocardium. FASEB J, 1992, 6: 2716.
24. Torchilin VP and Papisov MI. J Liposome Res, 1994, 4: 725.
25. Blume G, Cevc G et al. Specific targeting with poly(ethylene glycol)-modified liposomes: coupling of homing devices to the ends of the polymeric chains combines effective target binding with long circulation times. Biochim Biophys Acta, 1993, 1149: 180-184.
26. Maruyama K, Takizaua T et al. Targetability of novel immunoliposome modified with amphipathic poly(ethylene glycol) conjugated at their distal terminals to monoclonal antibodies. Biochim Biophys Acta, 1995,1234:74-83.
27. Haran G, Cohen R, et al. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta, 1993, 1151: 201-215.
28. Allen TM, Hansen C et al. Liposomes contaning synthetic lipid derivative of PEG show prolong circulation half-lives in vivo. Biochim Biophys Acta, 1991, 1066(1): 29-36.
29. Pahadjopoulos D, Allen TM et al. Sterically stabilized liposomes: improvements in pharmokinetics and antitumor therapertic efficacy. Proc Natl Acad Sci USA, 1991, 88(24): 11460-11464.
30. Gabizon A, Catane R et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in PEG coated liposomes. Cancer Res, 1994, 54(4): 987.
31. Allen TM, Brandeis E, et al. A new strategy for attachment of antibodies to sterically stabilized liposomes resulting in efficient targeting to cancer cells. Biochim BiophysActa, 1995, 1237: 99-108.
32. Zalipsky S, Gilon C et al. Attachment of drugs to polyethylene glycols. Eur Polym J, 1983, 19(12): 1177-1183.
33. Zalipsky S, Chang JL et al. Preparation and applications of polyethylene glycol-polystyrene graft resin supports for solid-phase peptide synthesis. React Polym, 1994, 22: 243-258.
34. Zalipsky S and Barany G. Preparation of polyethylene glycol derivatives with two different functional groups at the termini. Polym Preprints Am Chem Soc Div Polym Chem, 1986, 27: 1-2.
35. Furukawa S, Katayama N et al. Preparation of polyethylene glycol-bound nad and its application in a model enzyme reactor. FEBS Lett. 1980, 12(2): 239-242.
36. Carlsson J, Drevin H et al. Protein thiolation and reversible protein-protein conjugation. N-Succinimidyl 3-(2-pyridyldithio)propionate, a new hetero bifunctional reagent. Biochem J, 1978, 173: 723-737.
37. Schneider T, Sachse A et al. Generation of contrast-carrying liposomes of defined size with a new continuous high pressure extrusion method. Int J Pharm, 1995, 117: 1-12.
38. Mrsny R J, Volwerk JJ et al. A simplified procedure for lipid phosphorus analysis shows that digestion rates vary with phospholipid structure. Chem Phys Lipids, 1986, 39:185-191
39. Mercadal M, Domingo JC, et al. N-Palmitoylphosphatidylethanolamine
stabilizes liposomes in the presence of human serum: effect of lipidic composition and system characterization. Biochim Biophys Acta, 1995, 1235: 281-288.
40. Epstein AL and Clevenger CV. Identification of nuclear antigens in human cells by immunofluorescence, immunoelectron microscopy, and immunobiochemical methods using monoclonal antibodies. Progress in Nonhistone Protein Research, 1985, 1:117-134.
41. Sarma VR, Silverton EW et al. The three-dimensional structure at 6(?), resolution of a human rG1 immunoglobulin molecule. J Biol Chem, 1971, 246: 3752-3759.
42. Fonseca MJ, vanWinden ECA et al. Doxorubicin induces aggregation of small negatively charged liposomes. Eur J Pharma Biopharm, 1997, 43:9-17.
43. Mercadal M, Domingo JC et al. A novel strategy affords high-yield coupling of antibody to extremities of liposomal surface-grafted PEG chains. Biochim Biophys Acta, 1999, 1418: 232-238.
44．张宇峰、谢蜀生等。具有活性羧基末端的长循环脂质体的制备和分布。药学学报，2000，35(11)：854-859。
45. Hansen CB, Kao GY et al. Attachment of antibodies to sterically stabilized liposomes: evaluation, comparison and optimization of coupling procedures. Biochim Biophys Acta, 1995, 1239: 133-144.
46．吴伟，崔光华。星点设计-效应面优化法及其在药学中的应用。国外医学(药学分册)，2000，27(5)：292-298。
47. Litzinger DC, Buiting AMJ et al. Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly(ethylene glycol)-containing liposomes. Biochim Biophys Acta, 1994, 1990: 99-107.
48. Nagayasu A, Uchiyama K et al. Is control of distribution of liposomes between trmors and bone marrow possible? Biochim Biophys Acta, 1996, 1278: 29-34.
49. Bally MB, Naya R et al. Studies on the myelosuppressive activity of doxorubicin entrapped in liposomes. Cancer Chemother Pharmacol, 1990, 27: 13-19.
50. Sivakumar PA, Panduranga Rao K. Polymerized (ethylene glycol) dimetha crylate-cholesteryl methacrylate liposomes: preparation and stability studies. Reactive & Functional Polymers, 2001, 49:179-187.
51．王黎，候宝光等。氢化与非氢化卵磷脂对阿霉素脂质体体內外稳定性的影响。药学学报，2001，36(6)：444-447。
52．徐小薇，付强等。HPLC法测定兔血浆及淋巴组织申的阿霉素。中国药学杂志，1996，31(2)：96-99。
53. Harasym TO, Bally MB et al. Clearance properties of liposomes involving conjugated proteins for targeting. Adv Drug Del Rev, 1998, 32:99-118.
54. Maruyama K, Takahashi N et al. Immunoliposomes bearing polyethyleneglycol-coupled Fab' fragment show prolonged circulation time and high extravasation into targeted solid tumors in vivo. FEBS Lett, 1997, 413: 177-180.
55. Du H, Chandaroy P et al. Grafted poly-(ethylene glycol) on lipid surfaces inhibits protein adsorption and cell adhesion. Biochim Biophys Acta, 1997, 1326: 236-248.
56. Harasym TL, Tardi P et al. Poly(ethylene glycol)-modified phospholipids prevent aggregation during covalent conjugation of proteins to liposomes, Bioconj Chem, 1995, 6: 187-194.
57. Klibanov AL, Maruyama K et al. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett, 1990, 268: 235-237.
58. Blume G, Cevc G. Liposomes for the sustained drug release in vivo. Biochim Biophys Acta, 1990, 1029: 91-97.
59. Park JW, Kirpotin DB et al. Tumor targeting using anti-her2 immunoliposomes. J Contr Release, 2001, 74: 95-113.
60. Emanuel N, Kedar E et al. Targeted delivery of doxorubicin via sterically stabilized immunoliposomes: Pharmacokinetics and biodistribution in trmor-bearing mice. Pharrn Res, 1996, 13: 861-868.
61．孙丽，游强等。RP-HPLC外标法测定钆喷酸葡胺原料及其注射液的含量。中国药事，2003，17(3)：175-176。
62．王翔林，陈红等。用荧光法测定磁显葡胺的含量。沈阳药科大学学报，1999，16(2)：114-117。
63. Rubesova E, Berger F et al. Gd-labeled liposomes for monitoring liposome-encapsulated chemotherapy: quantification of regional uptake in tumor and effect on drug delivery. Acad Radiol, 2002, 9(suppl 2): S525-S527.
64．张弘炜，范健。脂质体阿霉素与阿霉素对小鼠毒性作用的比较研究。铁道医学，2000，28(6)：362-364。
65. Mayer LD, Tai LCL et al. Influence of vesicle size, lipid composition and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res, 1989, 49: 5922-5930.
66. Nagayasu A, Uchiyama K et al. The size of liposomes: a factor which affects
their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs. Adv Drug Del Rev 1999, 40(1-2): 75-87
67. Matsuzaki K, Nakayama M et al. Role of disulfide linkages in tachyplesin-lipid interactions. Biochemistry 1993, 32(43): 11704-11710
68. Matsuzaki K, Yoneyama S et al. Membrane permeabilization mechanisms of a cyclic antimicrobial peptide, tachyplesin I, and its linear analog. Biochemistry 1997, 36(32): 9799-9806
69. Masuzaki K, Sugishita K et al. Relationship of membrane curvature to the formation of pores by magainin 2. Biochemistry 1998, 37(34): 11856-11863
70. Hong K, Vacquier VD. Fusion of liposomes induced by a cationic protein from the acrosome granule of abalone spermatozoa. Biochemistry 1986, 25(3): 543-549
71. Kitamura A, Kiyota T et al. Morphological behavior of acidic and neutral liposomes induced by basic amphiphilic alpha-helical peptides with systematically varied hydrophobic-hydrophilic balance. Biophys J 1999, 76(3): 1457-1468
72. Matsuzaki K, Murase O et al. Optical characterization of liposomes by right angle light scattering and turbidity measurement. Biochim Biophys Acta, 2000, 1467:219-226
73. Kerker M, in: S Ross (Ed.). Chemistry and Physics of Interfaces-Ⅱ, American Chemical Society, Washington, DC[M], 1971, pp171-186
74. Bangham AD, de Gier J et al. Osmotic properties and water permeability of phospholipid liquid crystals. Chem Phys Lipids, 1967, 1: 225-246
75. Yoshikawa W, Akutsu H, Kyogoku Y. Light-scattering properties of osmotically active liposomes. Biochim Biophys Acta, 1983, 735:397-406
76. Chong CS and Colbow K. Light scattering and turbidity measurements on lipid vesicles. Biochim Biophys Acta, 1976, 436:260-282
77. Nir S, Bentz J et al. Aggregation and fusion of phospholipid vesicles. Prog SurfSci 1983, 13:1-124
78. Batzri S and Korn ED. Single bilayer liposomes prepared without sonication. Biochim Biophys Acta, 1973, 298:1015-1019
79. Kremer JMH, Esker MWJ v.d. et al. Vesicles of variable diameter prepared by a modified injection method. Biochemistry, 1977, 16(17): 3932-3935
80. Phillips NC, Dahman J. Immunogenicity of immunolipsomes: reactivity against
species-specific IgG and liposomal phospholipids. Immunol Lett, 1995, 45: 149-152.
81. Mountain, Adair JR. Engineering antibodies for therapy, Biotechnol Genet Eng Rev, 1992: 10: 1-142.
82. Shahinian S, Silvius JR. A novel strategy affords high yield coupling of antibody Fab' fragments to liposomes. Biochim Biophys Acta, 1995, 1239: 157-167.
83. Singh AM, Owais Met al. Use of specific polyclonal antibodies for specific drug targeting to malaria infected erythrocytes in vivo. Indian J Biochem Biophys, 1993, 30: 411-413.
84. Endoh H, Suzuki Y et al. Antibody coating of liposomes with 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide and the effect on target specificity. J Immunol Methods, 1981, 44: 79-85.
85. Torchilin VP, Khaw BA et al. Preservation of antimyosin antibody activity after covalent coupling to liposomes. Biochem Biophys Res Commun, 1979, 89: 1114-1119.
86. Heath TD, Fraley RT et al. Antibody targeting of liposomes: Cell specificity obtained by conjugation of F(ab')2 to vesicle surface. Science, 1980, 210: 539-541.
87. Leserman LD, Barber J et al. Targeting to cells of fluorescent liposomes covalently coupled with monoclonal antibody or protein A. Nature, 1980, 288: 602-604.
88. Martin FJ, Hubbell WL et al. Immunospecific targeting of liposomes to cells: A novel and efficient method for covalent attachment of Fab' fragments via disulfide bonds. Biochemistry, 1981, 20:4229-4238.
89. Matthay KK, Heath TD et al. Specific enhancement of drug deliver to AKR lymphoma by antibody-targeted small unilamellar vesicles. Cancer Res, 1984, 44:1880-1886.
90. Martin FJ, Papahadjopoulos D. Irreversible coupling of immunoglobulin fragments to preformed vesicles. J Biol Chem, 1982, 257: 286-288.
91. Derksen JTP, Scherphof GL. An improved method for the covalent coupling of protein to liposomes. Biochim Biophys Acta, 1985, 814: 151-155.
92. Loughrey HC, Ferraretto et al. Characterization of biotinylated liposomes for in vivo targeting applications. FEBS Lett, 1993,332:183-188.
93. Longman SA, Cullis PR et al. A two-step targeting approach for delivery of
doxorubicin-loaded liposomes to tumor cells in vivo. Cancer Chemother Pharmacol, 1995, 36: 91-101.
94. Ishida T, Iden DL et al. A combinatorial approach to producing sterically stabilized (Stealth) immunoliposomal drugs. FEBS Lett, 1999, 460: 129-133.
95. Torchilin VP, Levchenko TS et al. p-Nitrophenylcarbonyl-PEG-PE-liposomes fast and simple attachment of specific ligands including monoclonal antibodies to distal ends of PEG chains via p-nitrophenylcarbonyl groups. Biochim Biophys Acta, 2001, 1511: 397-411.
96. Aragnol D, Leserman LD. Immune clearance of liposomes inhibited by an anti-Fc receptor antibody in vivo. Proc Natl Acad Sci USA, 1986, 83: 2699-2703.
97. Sedmak DD, Davis DH et al. Expression of IgG Fc receptor antigens in placenta and on endothelial cells in humans. American J Pathol, 1991, 138(1): 175-181.
98. 3-(2-Pyridyldithio)propionic acid hydrazide as a cross-linker in the formation of liposome-antibody conjugates. Bioconj Chem, 1996, 7: 490-496.
99. Ishida O, Maruyama K et al. Size-dependent extravasation and interstitial localization of polyethyleneglycol liposomes in solid tumor-bearing mice. Int J Pharm, 1999, 190: 49-56.
100. Rosenecker, Zhang W et al. Icreased liposome extravasation in selected tissues: Effect of substance P. Proc Natl Acad Sci USA, 1996, 93: 7236-7241.
101. Suzuki M, Hori K et al. Functional characterization of the microcirculation in rumors. Cancer Metastasis Rev. 1984, 3: 115-126.
2. Khawli LA, Biela B et al. Comparison of Recombinant Derivatives of Chimeric TNT-3 Antibody for the Radioimaging of Solid Tumors. Hybrid Hybridomics, 2003, 22(1): 1-9.
3. Khawli LA, Mizokami MM et al. Pharmacokinetic characteristics and biodistribution of radioiodinated chimeric TNT-1, -2, and -3 monoclonal antibodies after chemical modification with biotin. Cancer Biother Radiopharm, 2002, 17(4): 359-370.
4. Khawli LA, Biela BH et al. Stable, genetically engineered F(ab')_2 fragments of chimeric TNT-3 expressed in mammalian cells. Hybrid Hybridomics, 2002, 21(1): 11-18.
5. Hornick JL, Sharifi J et al. A new chemically modified chimeric TNT-3 monoclonal antibody directed against DNA for the radioimmunotherapy of solid tumors. Cancer Biother Radiopharm,1998, 13(4): 255-268.
6. Hornick JL, Sharifi J et al. Single amino acid substitution in the Fc region of chimeric TNT-3 antibody accelerates clearance and improves immunoscintigraphy of solid tumors. J Nucl Med, 2000, 41(2): 355-62.
7. Mizokami MM, Hu P et al. Chimeric TNT-3 antibody/murine interferon-gamma fusion protein for the immunotherapy of solid malignancies. Hybrid Hybridomics, 2003, 22(4): 197-207.
8. Sharifi J. Khawli LA et al. Generation of human interferon gamma and tumor Necrosis factor alpha chimeric TNT-3 fusion proteins. Hybrid Hybridomics, 2002, 21(6): 421-432.
9. Biela BH, Khawli LA et al. Chimeric TNT-3/human beta-glucuronidase fusion proteins for antibody-directed enzyme prodrug therapy (ADEPT). Cancer Biother Radiopharm, 2003, 18(3): 339-353.
10. Hornick JL, Khawli LA et al. Pretreatment with a monoclonal antibody/ interleukin-2 fusion protein directed against DNA enhances the delivery of therapeutic molecules to solid tumors. Clin Cancer Res, 1999, 5(1): 51-60.
11. Li J, Hu P et al. LEC/chTNT-3 fusion protein for the immunotherapy of experimental solid tumors. J Immunother, 2003, 26(4): 320-331.
12．王肇炎，陈正玉，赖清宏编，阿霉素的临床应用(第二版)，人民卫生出版社，1994。
13．解咏清，阿霉素。医药工业，1987，18(4)：188-189。
14．张覃沐，抗肿瘤药物与心脏毒性。新药与临床，1985，4(2)：30-32。
15．吕焕章，阿霉素的心脏毒性及防护药物的研究进展。国外医药-合成药、生化药、制剂分册，1994，15(2)：67-69。
16．李素英，阿霉素的心脏毒副作用及其防治。心血管病学进展，1995，16(1)：38-39。
17. Torchilin VP et al. Poly(ethylene glycol)-coated anti-cardiac myosin immunoliposomes: factors influencing targeted accumulation in the infracted myocardium. Biochim Biophys Acta, 1996,1279: 75-83.
18. DEL de Menezes et al. In vitro and in vivo targeting of immunoliposomal doxorubicin to human B-cell lymphoma. Cancer Res, 1998, 58: 3320-3330.
19. Lundberg BB et al. Specific binding of sterically stabilized anti-B-cell immunoliposomes and cytotoxicity of entrapped doxorubicin. Int J Pharm, 2000, 205: 101-108.
20. Moase EH et al. Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer. Biochim Biophys Acta, 2001,1510: 43-55.
21. Park JW et al. Tumor targeting using anti-her2 immunoliposomes. J Control Release, 2001,74:95-113.
22. Nielsen UB et al. Internalizing antibodies and targeted cancer therapy: direct silection from phage display libraries. Pharm Sci Tech Today, 2000, 3(8): 282-291.
23. Torchilin VP, Klibanov AL et al. Targeted accumulation of polyethylene glycol-coated immunoliposomes in infracted rabbit myocardium. FASEB J, 1992, 6: 2716.
24. Torchilin VP and Papisov MI. J Liposome Res, 1994, 4: 725.
25. Blume G, Cevc G et al. Specific targeting with poly(ethylene glycol)-modified liposomes: coupling of homing devices to the ends of the polymeric chains combines effective target binding with long circulation times. Biochim Biophys Acta, 1993, 1149: 180-184.
26. Maruyama K, Takizaua T et al. Targetability of novel immunoliposome modified with amphipathic poly(ethylene glycol) conjugated at their distal terminals to monoclonal antibodies. Biochim Biophys Acta, 1995,1234:74-83.
27. Haran G, Cohen R, et al. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta, 1993, 1151: 201-215.
28. Allen TM, Hansen C et al. Liposomes contaning synthetic lipid derivative of PEG show prolong circulation half-lives in vivo. Biochim Biophys Acta, 1991, 1066(1): 29-36.
29. Pahadjopoulos D, Allen TM et al. Sterically stabilized liposomes: improvements in pharmokinetics and antitumor therapertic efficacy. Proc Natl Acad Sci USA, 1991, 88(24): 11460-11464.
30. Gabizon A, Catane R et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in PEG coated liposomes. Cancer Res, 1994, 54(4): 987.
31. Allen TM, Brandeis E, et al. A new strategy for attachment of antibodies to sterically stabilized liposomes resulting in efficient targeting to cancer cells. Biochim BiophysActa, 1995, 1237: 99-108.
32. Zalipsky S, Gilon C et al. Attachment of drugs to polyethylene glycols. Eur Polym J, 1983, 19(12): 1177-1183.
33. Zalipsky S, Chang JL et al. Preparation and applications of polyethylene glycol-polystyrene graft resin supports for solid-phase peptide synthesis. React Polym, 1994, 22: 243-258.
34. Zalipsky S and Barany G. Preparation of polyethylene glycol derivatives with two different functional groups at the termini. Polym Preprints Am Chem Soc Div Polym Chem, 1986, 27: 1-2.
35. Furukawa S, Katayama N et al. Preparation of polyethylene glycol-bound nad and its application in a model enzyme reactor. FEBS Lett. 1980, 12(2): 239-242.
36. Carlsson J, Drevin H et al. Protein thiolation and reversible protein-protein conjugation. N-Succinimidyl 3-(2-pyridyldithio)propionate, a new hetero bifunctional reagent. Biochem J, 1978, 173: 723-737.
37. Schneider T, Sachse A et al. Generation of contrast-carrying liposomes of defined size with a new continuous high pressure extrusion method. Int J Pharm, 1995, 117: 1-12.
38. Mrsny R J, Volwerk JJ et al. A simplified procedure for lipid phosphorus analysis shows that digestion rates vary with phospholipid structure. Chem Phys Lipids, 1986, 39:185-191
39. Mercadal M, Domingo JC, et al. N-Palmitoylphosphatidylethanolamine
stabilizes liposomes in the presence of human serum: effect of lipidic composition and system characterization. Biochim Biophys Acta, 1995, 1235: 281-288.
40. Epstein AL and Clevenger CV. Identification of nuclear antigens in human cells by immunofluorescence, immunoelectron microscopy, and immunobiochemical methods using monoclonal antibodies. Progress in Nonhistone Protein Research, 1985, 1:117-134.
41. Sarma VR, Silverton EW et al. The three-dimensional structure at 6(?), resolution of a human rG1 immunoglobulin molecule. J Biol Chem, 1971, 246: 3752-3759.
42. Fonseca MJ, vanWinden ECA et al. Doxorubicin induces aggregation of small negatively charged liposomes. Eur J Pharma Biopharm, 1997, 43:9-17.
43. Mercadal M, Domingo JC et al. A novel strategy affords high-yield coupling of antibody to extremities of liposomal surface-grafted PEG chains. Biochim Biophys Acta, 1999, 1418: 232-238.
44．张宇峰、谢蜀生等。具有活性羧基末端的长循环脂质体的制备和分布。药学学报，2000，35(11)：854-859。
45. Hansen CB, Kao GY et al. Attachment of antibodies to sterically stabilized liposomes: evaluation, comparison and optimization of coupling procedures. Biochim Biophys Acta, 1995, 1239: 133-144.
46．吴伟，崔光华。星点设计-效应面优化法及其在药学中的应用。国外医学(药学分册)，2000，27(5)：292-298。
47. Litzinger DC, Buiting AMJ et al. Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly(ethylene glycol)-containing liposomes. Biochim Biophys Acta, 1994, 1990: 99-107.
48. Nagayasu A, Uchiyama K et al. Is control of distribution of liposomes between trmors and bone marrow possible? Biochim Biophys Acta, 1996, 1278: 29-34.
49. Bally MB, Naya R et al. Studies on the myelosuppressive activity of doxorubicin entrapped in liposomes. Cancer Chemother Pharmacol, 1990, 27: 13-19.
50. Sivakumar PA, Panduranga Rao K. Polymerized (ethylene glycol) dimetha crylate-cholesteryl methacrylate liposomes: preparation and stability studies. Reactive & Functional Polymers, 2001, 49:179-187.
51．王黎，候宝光等。氢化与非氢化卵磷脂对阿霉素脂质体体內外稳定性的影响。药学学报，2001，36(6)：444-447。
52．徐小薇，付强等。HPLC法测定兔血浆及淋巴组织申的阿霉素。中国药学杂志，1996，31(2)：96-99。
53. Harasym TO, Bally MB et al. Clearance properties of liposomes involving conjugated proteins for targeting. Adv Drug Del Rev, 1998, 32:99-118.
54. Maruyama K, Takahashi N et al. Immunoliposomes bearing polyethyleneglycol-coupled Fab' fragment show prolonged circulation time and high extravasation into targeted solid tumors in vivo. FEBS Lett, 1997, 413: 177-180.
55. Du H, Chandaroy P et al. Grafted poly-(ethylene glycol) on lipid surfaces inhibits protein adsorption and cell adhesion. Biochim Biophys Acta, 1997, 1326: 236-248.
56. Harasym TL, Tardi P et al. Poly(ethylene glycol)-modified phospholipids prevent aggregation during covalent conjugation of proteins to liposomes, Bioconj Chem, 1995, 6: 187-194.
57. Klibanov AL, Maruyama K et al. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett, 1990, 268: 235-237.
58. Blume G, Cevc G. Liposomes for the sustained drug release in vivo. Biochim Biophys Acta, 1990, 1029: 91-97.
59. Park JW, Kirpotin DB et al. Tumor targeting using anti-her2 immunoliposomes. J Contr Release, 2001, 74: 95-113.
60. Emanuel N, Kedar E et al. Targeted delivery of doxorubicin via sterically stabilized immunoliposomes: Pharmacokinetics and biodistribution in trmor-bearing mice. Pharrn Res, 1996, 13: 861-868.
61．孙丽，游强等。RP-HPLC外标法测定钆喷酸葡胺原料及其注射液的含量。中国药事，2003，17(3)：175-176。
62．王翔林，陈红等。用荧光法测定磁显葡胺的含量。沈阳药科大学学报，1999，16(2)：114-117。
63. Rubesova E, Berger F et al. Gd-labeled liposomes for monitoring liposome-encapsulated chemotherapy: quantification of regional uptake in tumor and effect on drug delivery. Acad Radiol, 2002, 9(suppl 2): S525-S527.
64．张弘炜，范健。脂质体阿霉素与阿霉素对小鼠毒性作用的比较研究。铁道医学，2000，28(6)：362-364。
65. Mayer LD, Tai LCL et al. Influence of vesicle size, lipid composition and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res, 1989, 49: 5922-5930.
66. Nagayasu A, Uchiyama K et al. The size of liposomes: a factor which affects
their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs. Adv Drug Del Rev 1999, 40(1-2): 75-87
67. Matsuzaki K, Nakayama M et al. Role of disulfide linkages in tachyplesin-lipid interactions. Biochemistry 1993, 32(43): 11704-11710
68. Matsuzaki K, Yoneyama S et al. Membrane permeabilization mechanisms of a cyclic antimicrobial peptide, tachyplesin I, and its linear analog. Biochemistry 1997, 36(32): 9799-9806
69. Masuzaki K, Sugishita K et al. Relationship of membrane curvature to the formation of pores by magainin 2. Biochemistry 1998, 37(34): 11856-11863
70. Hong K, Vacquier VD. Fusion of liposomes induced by a cationic protein from the acrosome granule of abalone spermatozoa. Biochemistry 1986, 25(3): 543-549
71. Kitamura A, Kiyota T et al. Morphological behavior of acidic and neutral liposomes induced by basic amphiphilic alpha-helical peptides with systematically varied hydrophobic-hydrophilic balance. Biophys J 1999, 76(3): 1457-1468
72. Matsuzaki K, Murase O et al. Optical characterization of liposomes by right angle light scattering and turbidity measurement. Biochim Biophys Acta, 2000, 1467:219-226
73. Kerker M, in: S Ross (Ed.). Chemistry and Physics of Interfaces-Ⅱ, American Chemical Society, Washington, DC[M], 1971, pp171-186
74. Bangham AD, de Gier J et al. Osmotic properties and water permeability of phospholipid liquid crystals. Chem Phys Lipids, 1967, 1: 225-246
75. Yoshikawa W, Akutsu H, Kyogoku Y. Light-scattering properties of osmotically active liposomes. Biochim Biophys Acta, 1983, 735:397-406
76. Chong CS and Colbow K. Light scattering and turbidity measurements on lipid vesicles. Biochim Biophys Acta, 1976, 436:260-282
77. Nir S, Bentz J et al. Aggregation and fusion of phospholipid vesicles. Prog SurfSci 1983, 13:1-124
78. Batzri S and Korn ED. Single bilayer liposomes prepared without sonication. Biochim Biophys Acta, 1973, 298:1015-1019
79. Kremer JMH, Esker MWJ v.d. et al. Vesicles of variable diameter prepared by a modified injection method. Biochemistry, 1977, 16(17): 3932-3935
80. Phillips NC, Dahman J. Immunogenicity of immunolipsomes: reactivity against
species-specific IgG and liposomal phospholipids. Immunol Lett, 1995, 45: 149-152.
81. Mountain, Adair JR. Engineering antibodies for therapy, Biotechnol Genet Eng Rev, 1992: 10: 1-142.
82. Shahinian S, Silvius JR. A novel strategy affords high yield coupling of antibody Fab' fragments to liposomes. Biochim Biophys Acta, 1995, 1239: 157-167.
83. Singh AM, Owais Met al. Use of specific polyclonal antibodies for specific drug targeting to malaria infected erythrocytes in vivo. Indian J Biochem Biophys, 1993, 30: 411-413.
84. Endoh H, Suzuki Y et al. Antibody coating of liposomes with 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide and the effect on target specificity. J Immunol Methods, 1981, 44: 79-85.
85. Torchilin VP, Khaw BA et al. Preservation of antimyosin antibody activity after covalent coupling to liposomes. Biochem Biophys Res Commun, 1979, 89: 1114-1119.
86. Heath TD, Fraley RT et al. Antibody targeting of liposomes: Cell specificity obtained by conjugation of F(ab')2 to vesicle surface. Science, 1980, 210: 539-541.
87. Leserman LD, Barber J et al. Targeting to cells of fluorescent liposomes covalently coupled with monoclonal antibody or protein A. Nature, 1980, 288: 602-604.
88. Martin FJ, Hubbell WL et al. Immunospecific targeting of liposomes to cells: A novel and efficient method for covalent attachment of Fab' fragments via disulfide bonds. Biochemistry, 1981, 20:4229-4238.
89. Matthay KK, Heath TD et al. Specific enhancement of drug deliver to AKR lymphoma by antibody-targeted small unilamellar vesicles. Cancer Res, 1984, 44:1880-1886.
90. Martin FJ, Papahadjopoulos D. Irreversible coupling of immunoglobulin fragments to preformed vesicles. J Biol Chem, 1982, 257: 286-288.
91. Derksen JTP, Scherphof GL. An improved method for the covalent coupling of protein to liposomes. Biochim Biophys Acta, 1985, 814: 151-155.
92. Loughrey HC, Ferraretto et al. Characterization of biotinylated liposomes for in vivo targeting applications. FEBS Lett, 1993,332:183-188.
93. Longman SA, Cullis PR et al. A two-step targeting approach for delivery of
doxorubicin-loaded liposomes to tumor cells in vivo. Cancer Chemother Pharmacol, 1995, 36: 91-101.
94. Ishida T, Iden DL et al. A combinatorial approach to producing sterically stabilized (Stealth) immunoliposomal drugs. FEBS Lett, 1999, 460: 129-133.
95. Torchilin VP, Levchenko TS et al. p-Nitrophenylcarbonyl-PEG-PE-liposomes fast and simple attachment of specific ligands including monoclonal antibodies to distal ends of PEG chains via p-nitrophenylcarbonyl groups. Biochim Biophys Acta, 2001, 1511: 397-411.
96. Aragnol D, Leserman LD. Immune clearance of liposomes inhibited by an anti-Fc receptor antibody in vivo. Proc Natl Acad Sci USA, 1986, 83: 2699-2703.
97. Sedmak DD, Davis DH et al. Expression of IgG Fc receptor antigens in placenta and on endothelial cells in humans. American J Pathol, 1991, 138(1): 175-181.
98. 3-(2-Pyridyldithio)propionic acid hydrazide as a cross-linker in the formation of liposome-antibody conjugates. Bioconj Chem, 1996, 7: 490-496.
99. Ishida O, Maruyama K et al. Size-dependent extravasation and interstitial localization of polyethyleneglycol liposomes in solid tumor-bearing mice. Int J Pharm, 1999, 190: 49-56.
100. Rosenecker, Zhang W et al. Icreased liposome extravasation in selected tissues: Effect of substance P. Proc Natl Acad Sci USA, 1996, 93: 7236-7241.
101. Suzuki M, Hori K et al. Functional characterization of the microcirculation in rumors. Cancer Metastasis Rev. 1984, 3: 115-126.