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1.
目的 构建一种以肿瘤新生血管为靶向的顺磁性长循环纳米脂质体,并探讨其靶向肿瘤的能力。 方法 设计并采用FMOC(fluorenylmethyloxycarbonyl,FMOC)固相合成法合成RGD10肽(GARYCRGDCFDG)-赖氨酸-甘氨酸-甘氨酸(lysine-glycine-glycine,KGG臂)-棕榈酸(Pal)复合物;采用薄膜超声分散法制备包封MRI(magnetic resonance lmaging,MRI)造影剂GD-DTPA(Gadopentetate Dimeglumine)的血管靶向顺磁性长循环纳米脂质体(neovessel targeted PEGylated Gadopentetate Dimeglumine liposomes,T-PEG-GD LP)和普通顺磁性长循环纳米脂质体(PEGylated Gadopentetate Dimeglumine liposomes,PEG-GD-LP),采用激光粒度分析仪和透射电子显微镜进行形貌表征测定,超滤离心法测定其包封率,MRI扫描测定其信号强度;为验证T-PEG-GD-LP与肿瘤组织的特异性亲和力,检测了HUVEC、A549细胞对其的摄取能力。结果 透射电子显微镜显示T-PEG-GD-LP、PEG-GD-LP均呈规则的圆形或略呈椭圆形,粒径检测结果显示其平均粒径小于100nm,MRI测定T-PEG-GD-LP信号强度介于GD-DTPA与PEG-GD-LP之间,HUVEC、A549两种细胞对T-PEG-GD-LP的摄取量均高于GD-DTPA和PEG-GD-LP(P<0.05)。结论 构建的肿瘤新生血管靶向顺磁性长循环纳米脂质体具有良好的肿瘤靶向能力,可成为一种新型有效的肿瘤靶向MRI造影剂。 相似文献
2.
Hiroyuki Mizuguchi Tsuyoshi Nakanishi Mahito Nakanishi Tetsuhiko Nakagawa Shinsaku Nakagawa Tadanori Mayumi 《Cancer letters》1996,100(1-2):63-69
Previously, we reported that experimental i.p. administration of fusogenic liposomes containing fragment A of diphtheria toxin (DTA) completely regressed ascites tumors without any severe side effects. In this study, we examined the therapeutic effects of intratumor injection of fusogenic liposomes using ddY mice implanted with Sarcoma-180 (S-180) cells intradermally. Intratumor injections of fusogenic liposomes containing DTA significantly inhibited the tumor growth as assessed by the relative mean tumor volume, and by the survival time of the mice. No therapeutic effects were observed when simple liposomes containing DTA or empty fusogenic liposomes were administered. Using [3H]inulin encapsulated in fusogenic liposomes as a marker, we demonstrated that fusogenic liposomes delivered their contents into the solid tumor cells about 15 times more efficiently than simple liposomes. These results suggest that intratumor administration of fusogenic liposomes containing DTA is a highly effective approach to the local treatment of solid tumors. 相似文献
3.
Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels 总被引:6,自引:0,他引:6
Krasnici S Werner A Eichhorn ME Schmitt-Sody M Pahernik SA Sauer B Schulze B Teifel M Michaelis U Naujoks K Dellian M 《International journal of cancer. Journal international du cancer》2003,105(4):561-567
Recently, cationic liposomes have been shown to preferentially target the angiogenic endothelium of tumors. It was the aim of our study to investigate the influence of liposomal surface charge on the uptake and kinetics of liposomes into solid tumors and tumor vasculature. Experiments were performed in the amelanotic hamster melanoma A-Mel-3 growing in the dorsal skinfold chamber preparation of male Syrian golden hamsters. Fluorescently labeled liposomes with different surface charge were prepared. Accumulation of i.v. injected liposomes was assessed by quantitative intravital fluorescence microscopy of tumor and surrounding host tissue. The histological distribution of liposomes was analyzed by double-fluorescence microscopy 20 min after application of fluorescently labeled lectin as a vascular marker. After i.v. application of anionic and neutral liposomes, we observed an almost homogeneous distribution of liposome-induced fluorescence throughout the chamber preparation without specific targeting to tumor tissue. In contrast, cationic liposomes exhibited a significantly enhanced accumulation in tumor tissue and tumor vasculature up to 3-fold compared to surrounding tissue (p<0.05). The histological distribution of neutral and anionic liposomes revealed extravasation 20 min after i.v. injection, while cationic liposomes displayed a highly selective accumulation on the vascular endothelium. In conclusion, cationic liposomes exhibited a preferential uptake in angiogenic tumor vessels and therefore may provide an efficient tool for the selective delivery of diagnostic or therapeutic agents to angiogenic blood vessels of solid tumors. On the other hand, anionic and neutral liposomes may be used as carriers of drugs to the extravascular compartment of tumors due to their extravasation. 相似文献
4.
Naoto Oku Kanako Doi Yukihiro Namba Shoji Okada 《International journal of cancer. Journal international du cancer》1994,58(3):415-419
Long-circulating liposomes modified with a uronic-acid derivative, palmityl-D-glucuronide (PGIcUA), have been developed previously for the passive targeting of liposomes to tumor tissues. In this study, we examined the therapeutic effect of adriamycin (ADM) encapsulated in PGIcUA liposomes composed of dipalmitoylphosphatidylcholine (DPPC), cholesterol (Chol) and PGIcUA (molar ratio, 40/40/10) since this amount of PGIcUA was enough to endow liposomes with long-circulating activity. Long-circulating activity was also observed with palmityl-D-galacturonide (PGalUA) modified liposomes, suggesting that uronic acid plays an important role in preventing liposomes from being trapped in the reticuloendothelial system (RES). ADM was loaded in liposomes by a remote-loading method. Free or liposomal ADM was injected i.v. into BALB/c mice bearing s.c.-implanted Meth-A sarcoma. The liposomal formulation was efficient for reducing tumors, prolonging survival time and curing the animals, especially in the case of large tumors where free ADM was not. Furthermore, PGIcUA liposomes were more effective than conventional liposomes containing dipalmitoylphosphatidylglycerol (DPPG) instead of PGIcUA for prolonging survival time in mire. It might therefore be appropriate to use PGIcUA liposomes as the carriers of anticancer drugs. 相似文献
5.
6.
Recombinant adeno-associated virus (AAV) has attracted considerable interest as a potential vector for human gene therapy, but its transduction efficiency is quite low. The present study demonstrated AAV vector-associated liposomes to be more effective for in vitro gene transfer to human glioma cells than are liposomes containing plasmid DNA. Using vector-associated liposomes increased the transduction efficiency more than 10-fold compared to liposomes containing plasmid DNA and more than 6-fold compared to AAV alone. From these results, AAV vector-associated liposomes appear to be a good candidate for in vivo gene delivery to human gliomas. 相似文献
7.
Extensive Distribution of Liposomes in Rodent Brains and Brain Tumors Following Convection-Enhanced Delivery 总被引:4,自引:0,他引:4
Mamot C Nguyen JB Pourdehnad M Hadaczek P Saito R Bringas JR Drummond DC Hong K Kirpotin DB McKnight T Berger MS Park JW Bankiewicz KS 《Journal of neuro-oncology》2004,68(1):1-9
Liposomes labeled with various markers were subjected to local-regional administration with either direct injection or convection-enhanced delivery (CED) into rodent brains and brain tumor models. Direct injection of liposomes containing attached or encapsulated fluorochromes and/or encapsulated gold particles indicated that tissue localization of liposomes could be sensitively and specifically detected in the central nervous system (CNS). When CED was applied, liposomes achieved extensive and efficient distribution within normal mouse brains. Co-infusion of mannitol further increased tissue penetration of liposomes. Liposomes were also loaded with gadodiamide to monitor their CNS distribution in rats by magnetic resonance imaging (MRI). CED-infused liposomes were readily seen on MRI scans as large regions of intense signal at 2 h, and more diffuse regions at 24 h. Finally, labeled liposomes were infused via CED into tumor tissue in glioma xenograft models in rodent hosts. In intracranial U-87 glioma xenografts, CED-infused liposomes had distributed throughout tumor tissue, including extension into surrounding normal tissue. Greater penetration was observed using 40 versus 90 nm liposomes, as well as with mannitol co-infusion. To our knowledge, this is the first report of CED infusion of liposomes into the CNS. We conclude that CED of liposomes in the CNS is a feasible approach, and offers a promising strategy for targeting therapeutic agents to brain tumors. 相似文献
8.
H. Mizuguchi M. Nakanishi T. Nakanishi T. Nakagawa S. Nakagawa T. Mayumi 《British journal of cancer》1996,73(4):472-476
Previously we reported that fusogenic liposomes, prepared by fusing simple liposomes with Sendai virus particles, could introduce their contents directly and efficiently into the cytoplasm. In this study, we examined the anti-tumour activity of fusogenic liposomes containing fragment A of diphtheria toxin (DTA). Fusogenic liposomes containing DTA showed high cytotoxicity against sarcoma-180 (S-180) cells in vitro. When these liposomes were administered into the abdominal cavity of ddY mice carrying S-180, tumour cells completely disappeared in four of six tumour-bearing mice without decrease in body weight. Neither simple liposomes containing DTA nor empty fusogenic liposomes had any effect on tumour suppression. We conclude that fusogenic liposomes containing DTA are new and potentially effective tools for the treatment of ascites tumours without any severe side-effects. 相似文献
9.
Intracellular targeting therapy of cisplatin-encapsulated transferrin-polyethylene glycol liposome on peritoneal dissemination of gastric cancer 总被引:8,自引:0,他引:8
Iinuma H Maruyama K Okinaga K Sasaki K Sekine T Ishida O Ogiwara N Johkura K Yonemura Y 《International journal of cancer. Journal international du cancer》2002,99(1):130-137
Peritoneal dissemination in gastric cancer is a common fatal clinical condition with few effective therapies available. We studied the therapeutic effect of a tumor-targeting drug delivery system that uses cisplatin-encapsulated and Tf-conjugated PEG liposomes (Tf-PEG liposomes) in nude mice with peritoneal dissemination of human gastric cancer cells. Small unilamellar Tf-PEG, PEG or DSPC/CH liposomes (bare liposomes) encapsulating cisplatin were prepared by reverse-phase evaporation followed by extrusion. Electron microscopic studies revealed that Tf-PEG liposomes were internalized into tumor cells by receptor-mediated endocytosis. To examine the biodistribution of each liposome and cisplatin level, nude mice were inoculated i.p. with 10(7) MKN45P human gastric tumor cells. On the fourth day after tumor inoculation, (3)H-CHE-labeled and cisplatin-encapsulated Tf-PEG, PEG or bare liposome were inoculated i.p. The Tf-PEG liposome-administered group maintained high liposome and cisplatin levels in ascites and showed a prolonged residence time in the peripheral circulation. Uptake of Tf-PEG liposomes into the liver and spleen was significantly lower than that of bare liposomes. Uptake of Tf-PEG liposomes in disseminated tumor cells of ascites and the greater omentum was significantly higher than that of PEG or bare liposomes and a significant increase in cisplatin levels was observed in these tumor cells. Mice receiving Tf-PEG liposomes 1 and 4 days after the day of tumor inoculation showed significantly higher survival rates compared with those receiving PEG liposomes without Tf, bare liposomes or free cisplatin solution. These results suggest that cisplatin-encapsulated Tf-PEG liposomes may be useful as a new intracellular targeting carrier for treatment of gastric cancer with peritoneal dissemination. 相似文献
10.
Lee CM Tanaka T Murai T Kondo M Kimura J Su W Kitagawa T Ito T Matsuda H Miyasaka M 《Cancer research》2002,62(15):4282-4288
An increased level of chondroitin sulfate (CS) expression on the cell surface is often associated with malignant transformation and the progression of tumor cells. In this study, CSs expressed on highly metastatic tumor cells were used as a target for the selective delivery of anticancer drugs by polyethylene glycol (PEG)-coated liposomes that contained a new cationic lipid 3,5-dipentadecycloxybenzamidine hydrochloride (TRX-20). We found that PEG-coated TRX-20 liposomes (TRX-20 liposomes) bound preferentially to certain CSs, such as CS B, CS D, and CS E, whereas PEG-coated liposomes lacking TRX-20 showed no significant binding to any of the glycosaminoglycans tested. In vitro, TRX-20 liposomes, but not plain PEG liposomes, avidly bound to and were readily internalized by highly metastatic tumor cells such as LM8G5 and ACHN cells, which express large amounts of CS on the cell surface. When TRX-20 liposomes were loaded with cisplatin, they effectively killed the CS-expressing tumor cells in vitro, whereas cisplatin-PEG liposomes lacking TRX-20 were totally ineffective. When injected systemically, TRX-20 liposomes preferentially accumulated in the liver and in solid s.c. LM8G5 tumors. Therapeutic experiments in mice bearing a s.c. LM8G5 tumor revealed that cisplatin-loaded TRX-20 liposomes were significantly more effective in reducing the local tumor growth than cisplatin-loaded plain PEG liposomes or free cisplatin. Furthermore, the cisplatin-loaded TRX-20 liposomes markedly suppressed metastatic spreading of LM8G5 tumor cells to the liver, significantly increasing the survival time of the tumor-bearing mice. These results demonstrate that the CS-targeted delivery of anticancer drugs by novel cationic liposomes represents a potentially useful strategy to prevent the local growth and metastasis, particularly to the liver, of tumor cells that have enhanced expression of CS. 相似文献
11.
Matsumoto Y Iwamoto Y Matsushita T Ueoka R 《International journal of cancer. Journal international du cancer》2005,115(3):377-382
Hybrid liposomes can be prepared by simply ultrasonicating a mixture of vesicular and micellar molecules in a buffer solution. The physical properties of these liposomes, such as size, membrane fluidity, phase transition temperature and hydrophobicity can be controlled by changing the composition. Hybrid liposomes composed of dimyristoylphosphatidylcholine and polyoxyethylene (10) dodecyl ether were found to inhibit the growth of human promyelocytic leukemia (HL-60) cells without using any drugs. Induction of apoptosis by hybrid liposomes in HL-60 cells was verified on the basis of fluorescence microscopy and flow cytometry analysis, after fusion and accumulation of hybrid liposomes, which was revealed on the basis of microphysiometer. We elucidated the pathways of apoptosis induced by the hybrid liposomes. That is, hybrid liposomes fused and accumulated in tumor cell membranes, and the apoptosis signal first passed through mitochondria, caspase-9 and caspase-3, second through Fas, caspase-8, caspase-3 and then reached the nucleus. Hybrid liposomes themselves can induce apoptosis in human tumor cells along with high inhibitory effects on the growth of tumor cells. 相似文献
12.
H Konno H Suzuki T Tadakuma K Kumai T Yasuda T Kubota S Ohta K Nagaike S Hosokawa K Ishibiki 《Cancer research》1987,47(16):4471-4477
The monoclonal antibody, 19-F-12 (IgG2b), against human alpha-fetoprotein was conjugated to liposomes containing Adriamycin, and the therapeutic effects of the conjugate were experimentally studied using the alpha-fetoprotein-producing human hepatoma strain, Li-7, maintained in BALB/c nu/nu male mice. Three i.v. injections of liposomes containing Adriamycin (7.5 mg/kg) into tumor-bearing mice significantly inhibited the tumor growth, and the therapeutic effect of the antibody-conjugated liposomes was greater than that of unconjugated liposomes, as judged from the tumor weights and histological findings. Furthermore, the experiments were repeated with Adriamycin (4-5 mg/kg) in free form, since administration of Adriamycin (7.5 mg/kg) in free form was highly toxic for the mice. The results still indicated that the therapeutic effect of Adriamycin in 19-F-12 conjugated liposomes was superior to that of free Adriamycin or Adriamycin in unconjugated liposomes. In contrast to the treatment for Li-7 in nude mice, the therapeutic effect of Adriamycin in 19-F-12 conjugated liposomes was not much different from that of Adriamycin in normal mouse IgG (IgG2b fraction) conjugated liposomes against alpha-fetoprotein-negative human breast cancer strain MX1. Tissue distribution studies after i.v. injection of Adriamycin in various forms into mice revealed that preferential delivery of Adriamycin to tumors occurred to some extent with antibody-conjugated liposomes as compared to the unconjugated liposomes. In addition, reduction of the distribution of Adriamycin to the heart was achieved by administering the drug in the liposome-entrapped form, and this enabled the use of a higher dose (7.5 mg/kg) of Adriamycin without toxic side effect. 相似文献
13.
The targeted delivery to cells by liposomes and leakage under delivery conditions of fluorodeoxyuridine (FdUR) and fluorodeoxyuridine monophosphate (FdUMP) have been evaluated using a two-compartment growth inhibition assay. Under cell culture conditions, FdUR leaks 100% from all liposomes regardless of charge or phase transition temperature. Under the same conditions, FdUMP leaks 100% from egg yolk phosphatidylglycerol liposomes, 47% from distearoylphosphatidylglycerol liposomes, 44% from egg yolk phosphatidylcholine liposomes, and 10% from distearoylphosphatidylcholine liposomes. All liposomes were prepared from a 67:33 mixture of phospholipid and cholesterol. The two-compartment assay demonstrates directly that neither of these drugs is delivered selectively to the target cells by the liposomes, suggesting that they are liposome independent drugs. 相似文献
14.
K S Bragman T D Heath D Papahadjopoulos 《Journal of the National Cancer Institute》1984,73(1):127-131
Encapsulation of methotrexate-gamma-aspartate in antibody-conjugated liposomes increased its toxicity for K562 cells, a human leukemia cell line that expresses Fc receptors and human glycophorin A. The liposomes were conjugated with either nonspecific mouse IgG, which interacts with an Fc receptor, or with monoclonal anti-human glycophorin, which interacts simultaneously with an Fc receptor and human glycophorin in the cell membrane. The drug in antibody-directed liposomes was up to 20 times more effective than the free drug, and it was 55 times more effective than the drug in liposomes bearing no surface ligand. The efficacy of drug delivery with liposomes directed only to an Fc receptor was reduced ninefold in the presence of soluble human IgG. Efficacy of drug delivery with liposomes directed both to the Fc receptor and to glycophorin A was not reduced by human IgG or soluble antiglycophorin A, but it was reduced twofold in the presence of both soluble ligands. These results were qualitatively consistent with previous studies on the binding of targeted liposomes to K562 cells. 相似文献
15.
Antineoplastic activity of sterically stabilized alkylphosphocholine liposomes in human breast carcinomas 总被引:2,自引:0,他引:2
D. Arndt R. Zeisig I. Eue B. Sternberg I. Fichtner 《Breast cancer research and treatment》1997,43(3):237-246
New sterically stabilized liposomes derived from the antitumoragent hexadecylphosphocholine with reduced uptake by the mononuclearphagocyte system and improved antitumor activities were developedand tested. The bilayer of such sterically stabilizedliposomes consists of hexadecylphosphocholine, cholesterol and polyethylene glycol-linkedphosphoethanolamine. The measurement of carbon clearance in miceshows that these stabilized liposomes, in contrast toconventional alkylphosphocholine liposomes, are not largely engulfed bythe mononuclear phagocyte system. Their therapeutic activity onexperimental human breast carcinomas MaTu, MT-1 and MT-3was tested in nude mice. Especially in theMaTu models the sterically stabilized hexadecylphosphocholine liposomes resultedin significantly reduced tumor growth in comparison toconventional hexadecylphosphocholine liposomes or free hexadecylphosphocholine. The enhancedtherapeutic efficacy of sterically stabilized hexadecylphosphocholine liposomes isprobably related to the extended circulation time ofthe formulation and its accumulation in tumors. 相似文献
16.
Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-positive and FR-negative cell lines, KB and A549, respectively, for their cytotoxic effects. Significant enhancement in carboplatin potency and intracellular drug accumulation was observed in KB cells when treated with FRT liposomes, compared to free drug and non-targeted liposomes. No enhancement was observed in the FR-negative A549 cells. The increase in carboplatin potency was hypothesized to be associated with an increase in the formation of DNA-platinum adducts resulted from an increase in cellular accumulation of the drug. Surprisingly, FRT carboplatin liposomes showed significantly lower levels of DNA-platinum adducts in comparison to free drug. To elucidate this discrepancy, activation of extracellular signal-regulated protein kinase (ERK) was probed, which has been suggested as an alternative mechanism of carboplatin action. FRT liposomes loaded with carboplatin exhibited the highest level of ERK phosphorylation, and the cytotoxic effect of FRT carboplatin liposomes could be reversed by the MEK/ERK inhibitors, U0126 and PD98059. Importantly, empty FRT liposomes could significantly increase ERK phosphorylation in a concentration-dependent manner without causing toxicity to cells. For the first time, increased potency of carboplatin delivered by FRT liposomes was found to be associated with other molecular targets in addition to DNA-platinum adduct formation. Collectively, the current study suggests a novel mechanism by which FRT liposomes could sensitize cancer cells to drug treatment via modulation of ERK-related cell survival signals. 相似文献
17.
Ichiro Uyama Koichiro Kumai Tatsuji Yasuda Toshiaki Tagawa Kyuya Ishibiki Masaki Kitajima Takushi Tadakuma 《Cancer science》1994,85(4):434-440
To improve the therapeutic efficiency adriamycin entrapped in antibody-conjugated liposomes, Fab' fragment was used instead of the whole antibody molecule. The murine monoclonal antibody, 21B2, against human carcinoembryonic antigen (CEA) was digested with pepsin, and the thiol residue of intra-heavy chain produced by reduction of F(ab')2 with dithiothreitol was conjugated to liposomes containing adriamycin. The tissue distribution of adriamycin delivered with these liposomes was studied in BALB/c nu/nu female mice bearing CEA-positive human gastric cancer strain MKN-45. An increase in delivery of adriamycin to the tumor was observed in the mice given liposomes with Fab' fragment as compared to those given liposomes with whole antibody. However, the preferential distribution of adriamycin in liposomes to the reticuloendothelial cells remained the same regardless of the use of Fab' fragment. For investigation of in vivo therapeutic effect, three i.v. injections of free adriamycin or adriamycin in liposomes equivalent to 5 mg/kg were given, and adriamycin in Fab' fragment-conjugated liposomes was found most effective in the inhibition of tumor growth. This was confirmed in terms of actual tumor weights excised and CEA concentration in the blood, as well as by pathological observations. The advantages of using Fab' fragment instead of whole antibody are discussed. 相似文献
18.
Tana Shinobu Watarai Misao Onuma Yoko Aida Hitoshi Kakidani Hiroshi Kodama Tatsuji Yasuda 《Cancer science》1998,89(11):1202-1211
Monoclonal antibody c143 against tumor-associated antigen (TAA) expressed on bovine leukemia cells was conjugated to cationic liposomes carrying a plasmid pLTR-DT which contained a gene for diphtheria toxin A-chain (DT-A) under the control of the long terminal repeat (LTR) of bovine leukemia virus (BLV) in the multicloning site of pUC-18. The specificity and antitumor effects of the conjugates were examined in vitro and in vivo using TAA-positive bovine B-cell lymphoma line as the target tumor. In vitro studies with the TAA-positive cell line indicated that luciferase genecontaining cationic liposomes associated with the c143 anti-TAA monoclonal antibody caused about 2-fold increase in luciferase activity compared with cationic liposomes having no antibody, and also that the c143-conjugated cationic liposomes containing pLTR-DT exerted selective growth-inhibitory effects on the TAA-positive B-cell line. Three injections of pLTR-DT-containing cationic liposomes coupled with c143 into tumor-bearing nude mice resulted in significant inhibition of the tumor growth. The antitumor potency of the c143-conjugated cationic liposomes containing pLTR-DT was far greater than that of normal mouse IgG-coupled cationic liposomes containing pLTR-DT as assessed in terms of tumor size. These results suggest that cationic liposomes bearing c143 are an efficient transfection reagent for BLV-infected B-cell lymphoma cells, and that the delivery of the pLTR-DT gene into BLV-infected B-cells by the use of such liposomes may become a useful technique for gene therapy of bovine leukosis. 相似文献
19.
A new tumor model is described that is suitable for the evaluation of antibody-directed drug-delivery protocols and a modification in the procedure for covalently coupling antibody to the surface of drug-containing liposomes is presented. These immunospecific liposomes containing cytosine arabinonucleoside (Ara-C) have been tested in vitro and in vivo for their ability to kill a B-cell tumor. The target of the immunospecific-Ara-C liposomes is the idiotype associated with an antigen-specific immunoglobulin receptor on the cell surface of a murine B-cell hybrid (2C3). Affinity-purified antibodies specific for the idiotype were covalently coupled to modified lipid on the surface of the large unilamelar liposomes containing drug. These liposomes were shown to kill idiotype-positive 2C3 cells in vitro, but not idiotype-negative variants of this same cell line. It was also established in vitro that the drug-containing liposomes were at least 40 times more efficient than free Ara-C in the killing of the tumor cells. The 2C3 tumor was also propagated in vivo following the i.p. administration of tumor cells. The tumor grew initially as multiple foci within the peritoneum and subsequently spread to the spleen. Tumor-bearing mice were treated either with free Ara-C or with immunospecific liposomes containing Ara-C. Tumor growth in the primary tumor nodules and in the spleen was monitored by the administration of bromodeoxyuridine to the tumor-bearing animals followed by the immunofluorescent staining of cells with a monoclonal anti-bromodeoxyuridine antibody to estimate the proportion of cells in S phase. Our data from five out of seven animal experiments shows that the immunospecific-Ara-C liposomes, but not free drug, reduced tumor growth in the spleen. However, neither the liposomes containing drug nor the free drug were able to alter the growth of the primary tumor nodules growing in the peritoneal cavity. These results suggest that immunospecific-Ara-C containing liposomes may be useful in conjunction with other cytoreductive protocols in controlling tumor growth or preventing the spread of the tumor to other sites, but that immunospecific-Ara-C containing liposomes by themselves are not likely to eliminate an established tumor in vivo. We also demonstrate here that the administration of immunospecific-Ara-C containing liposomes in an animal having high levels of circulating tumor-associated antigen (i.e., IgG containing the idiotype) represents a potential clinically relevant hazard which must be considered when designing antibody-directed drug-delivery protocols. 相似文献
20.
Liposome entrapment of doxorubicin has been shown to reduce its cardiotoxicity in vivo and increase its therapeutic index. A further improvement in therapeutic index could be achieved through targeting of liposome-entrapped drug selectively to cancer cells. Monoclonal antibodies against the squamous lung cancer cell line KLN-205 have been ligated to the surface of long-circulating (Stealth) and conventional liposomes. The antibody-bearing liposomes showed specific, competitive uptake by KLN-205 cells as compared to liposomes bearing nonspecific isotype-matched antibodies or antibody-free liposomes. Doxorubicin-containing antibody-liposomes resulted in as much as a 15-fold decrease in the 50% inhibitory concentration for doxorubicin against KLN-205 cells as compared to free doxorubicin or doxorubicin entrapped in antibody-free liposomes. 相似文献