超声介导载多烯紫杉醇的聚乳酸—羟基乙酸微球治疗荷人肝癌裸鼠的实验研究
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摘要
目的制备一种载多烯紫杉醇的聚乳酸-羟基乙酸(PLGA)缓释微球,考察其理化性质、体外释放及药物稳定性,并探讨其在超声引导下瘤内注射对荷人肝癌裸鼠皮下移植瘤的治疗作用及相关机制。
方法
1.采用溶剂挥发法制备载多烯紫杉醇的PLGA缓释微球,应用扫描电镜(SEM)检测微球的表面形态、粒径,高效液相色谱(HPLC)法检测包封率、载药率及体外药物释放情况,气相色谱检测二氯甲烷的残留量,5、15、25kGy 60Co三种剂量辐照灭菌,改良寇氏法测定载药微球小鼠皮下注射的半数致死量。
2.建立人肝癌BEL-7404裸鼠皮下移植瘤模型,随机分为模型组、空白微球组、多帕菲腹腔内注射组、多帕菲瘤内注射组、多烯紫杉醇微球瘤内注射低剂量和高剂量组共6组,每组15只,在超声引导下给予相应的治疗;
3.治疗后每周超声观察各组肿瘤的大小、实质回声及血供情况;
4.给药3周后,每组随机抽取5只裸鼠行肿瘤超声造影,而后处死并剥离肿瘤称质量,计算抑瘤率;
5.肿瘤行病理组织学检查,免疫组织化学法检测微血管密度(MVD),实时荧光定量PCR检测血管内皮生长因子(VEGF)、血管生成素2(Ang2)和碱性成纤维生长因子(bFGF)基因表达的差异。
6.每组余下裸鼠继续观察荷瘤生存时间。
结果
1.采用溶剂挥发法可制备平均粒径为23.1μm的载药微球,PLGA与多烯紫杉醇的投料比为100mg/5mg时可获得较佳的包封率(96.3%)和载药率(4.82%)。载药微球在体外21天累积释放药物达82.5%,无明显突释效应,并且包裹在微球内的多烯紫杉醇稳定性明显提高。三种剂量60Co辐照后均未见短小芽孢杆菌生长。微球内二氯甲烷残留量为0.026%,符合国家药典规定。
2.多烯紫杉醇PLGA微球小鼠皮下注射的半数致死量为483.6mg/kg,明显高于多烯紫杉醇注射液的52.7mg/kg。
3.治疗3周后,模型组和空白微球组肿瘤持续生长,超声检查示肿瘤实质回声欠均匀,血流信号丰富;多烯紫杉醇治疗各组的肿瘤生长都受到不同程度的抑制,其中多烯紫杉醇微球瘤内注射高剂量组肿瘤生长抑制最显著,抑瘤率为66.01%,均明显高于多帕菲腹腔内注射组(34.65%)、多帕菲瘤内注射组(35.62%)和多烯紫杉醇微球瘤内注射低剂量组(48.37%)。
4.治疗3周后,超声造影示多烯紫杉醇微球瘤内注射高剂量组肿瘤仅见周边少许增强,实质大部分呈充盈缺损改变;其余各组实质内仍可见不同程度的增强。
5.多烯紫杉醇微球瘤内注射组病理学检查示组织大片坏死,MVD和VEGF、bFGF及Ang2表达均低于其余各组。
6.生存分析结果显示,治疗15周后载药微球组生存率(70%)高于多帕菲腹腔内注射组(30%)和瘤内注射组(30%)具有统计学显著性意义(P<0.05)。
结论
采用溶剂挥发法可制备粒径及分布适宜,分散良好的载多烯紫杉醇PLGA缓释微球,包封率高,释放周期可达3周,并能提高多烯紫杉醇的稳定性;超声引导瘤内注射载多烯紫杉醇PLGA微球,可明显提高多烯紫杉醇抗人肝癌疗效,抑制肿瘤组织血管生成相关基因VEGF、bFGF和Ang2的表达,减少肿瘤新生血管生成,提高生存率,具有潜在的临床应用价值。
Objective
To prepare sustained-release poly(lactic-co-glycolic acid)(PLGA) microspheres containing docetaxel, and investigate the physiochemical properties, in vitro release and drug stability; and to investigate the effect and mechanism in treatment of human hepatoma-bearing nude mice by ultrasound-guided intratumor injection of the drug-loaded microspheres.
Methods
1. Sustained-release PLGA microspheres containing docetaxel were prepared by solvent evaporation method, thereafter morphology and particle size were observed by scanning electron microscope, while drug loading, encapsulation efficiency, and in vitro release within 21days were examined by HPLC. The effect of irradiation steriliazation at three doses(5, 15 and 25kGy) was examined. Dichloromethane residue in microspheres was detected by gas chromatography. Post hypodermic administration on the mice back for 4 weeks, death of mice was recorded to calculate half-lethal dose by modified Karber’s method.
2. Established mude mice model of human heptoma cell line BEL-7407 transplanted subcutaneously. Ninety mice were randomly enrolled into a model(M), blank microspheres(BM), docetaxel intraperitoneal injection(DP), docetaxel intratumor injection(DT),low-dose(DMTL) and high-dose(DMTH) of docetaxel-loaded PLGA microspheres intratumor injection group with 15 animals in each group. Either group was given corresponding treatment under ultrasound guidance.
3. Tumor volume, parenchyma echo and blood supply between six groups were compared by regular ultrasound follow-up every week for consecutive 3 weeks.
4. At 3 weeks postinjection,5 nude mice randomly selected in each group were examined on contrast-enhanced ultrasound following by sacrification, and the tumors were excised, weighted to evaluate the inhibition rate.
5. tumor tissues were examined on histopathology by microscopy, on microvessel density by immunohistochemical method, and on the gene expression of vascular endothelial growth factor(VEGF), basic fibroblast growth factor(bFGF) and Angiopoietin-2(Ang2) by real-time fluorescence quantitative PCR.
6. Survival of remaining nude mice was observed for another 12 weeks.
Results
1. Mean diameter of drug-loaded microspheres were 23.1μm by solvent evaporation method; the optimal drug loading rate(4.82%) and encapsulation efficiency(96.3%) were gained when the feed ratio of PLGA to docetaxel was 100mg/5mg. Stably the cumulative release of docetaxel from microspheres was 82.5% within 21days without occurrence of burst release, and docetaxel encapsulated in microspheres, detected by HPLC, kept stability of structure. The limited amount of dichloromethane residue(0.026%) in microspheres accorded with general rule of Chinese Pharmacopoeia. No bacillus pumilus colony was cultured in microspheres after irradiation steriliazation at three doses.
2. Half-lethal dose calculated in docetaxel-loaded microspheres injection group (483.6mg/kg) was far higher than docetaxel injection group (52.7mg/kg).
3. The tumors of model and blank microspheres group were significantly increased after administration, with inhomogeneous internal echo and relatively rich blood flow signal on ultrasonography. The tumor growth was slower in the other docetaxel group, especially for DMTH group which inhibited tumor growth markedly with a little flow signal around tumors detected by color Doppler ultrasonography. DMTH displayed a potent antitumor effect on human hepatoma with a tumor inhibitory rate 66.01%, higher than that of DP(34.65%), DT(35.62%), and DMTL group(48.37%) significantly.
4. At 3 weeks postinjection,contrast-enhanced ultrasound was founded that a mass of tumors parenchyma showed filling defect except slight enhancement in paratumor parenchyma in DMTH group, but tumors parenchyma of all the other groups was enhanced in various degrees.
5. Extensive necrosis of tumor tissue was found in the histopathologic examination of docetaxel-loaded microspheres injection group. And the expression of MVD, as well as VEGF, bFGF and Ang2, decreased compared with the other groups.
6. For Survival analysis, survival rate in drug-loaded microspheres group(70%) was higher than DP group(30%), as well as DT group(30%) significantly(P<0.05).
Conclusion : Sustained-release PLGA microspheres containing docetaxel were successfully prepared by solvent evaporation method with optimal particle size, distribution, dispersion, encapsulation efficiency and low drug degradation, whose release period was about 3 weeks; the effect of docetaxel in treatment of human hepatoma-bearing nude mice was promoted by ultrasound-guided intratumor injection of PLGA microspheres containing docetaxel, which depressed the gene expression of VEGF, bFGF and Ang2 resulting in inhibition of tumor angiogenesis and also developed survival rate of nude mice. This new method of hepatoma treatment has potential clinical value.
方法
1.采用溶剂挥发法制备载多烯紫杉醇的PLGA缓释微球,应用扫描电镜(SEM)检测微球的表面形态、粒径,高效液相色谱(HPLC)法检测包封率、载药率及体外药物释放情况,气相色谱检测二氯甲烷的残留量,5、15、25kGy 60Co三种剂量辐照灭菌,改良寇氏法测定载药微球小鼠皮下注射的半数致死量。
2.建立人肝癌BEL-7404裸鼠皮下移植瘤模型,随机分为模型组、空白微球组、多帕菲腹腔内注射组、多帕菲瘤内注射组、多烯紫杉醇微球瘤内注射低剂量和高剂量组共6组,每组15只,在超声引导下给予相应的治疗;
3.治疗后每周超声观察各组肿瘤的大小、实质回声及血供情况;
4.给药3周后,每组随机抽取5只裸鼠行肿瘤超声造影,而后处死并剥离肿瘤称质量,计算抑瘤率;
5.肿瘤行病理组织学检查,免疫组织化学法检测微血管密度(MVD),实时荧光定量PCR检测血管内皮生长因子(VEGF)、血管生成素2(Ang2)和碱性成纤维生长因子(bFGF)基因表达的差异。
6.每组余下裸鼠继续观察荷瘤生存时间。
结果
1.采用溶剂挥发法可制备平均粒径为23.1μm的载药微球,PLGA与多烯紫杉醇的投料比为100mg/5mg时可获得较佳的包封率(96.3%)和载药率(4.82%)。载药微球在体外21天累积释放药物达82.5%,无明显突释效应,并且包裹在微球内的多烯紫杉醇稳定性明显提高。三种剂量60Co辐照后均未见短小芽孢杆菌生长。微球内二氯甲烷残留量为0.026%,符合国家药典规定。
2.多烯紫杉醇PLGA微球小鼠皮下注射的半数致死量为483.6mg/kg,明显高于多烯紫杉醇注射液的52.7mg/kg。
3.治疗3周后,模型组和空白微球组肿瘤持续生长,超声检查示肿瘤实质回声欠均匀,血流信号丰富;多烯紫杉醇治疗各组的肿瘤生长都受到不同程度的抑制,其中多烯紫杉醇微球瘤内注射高剂量组肿瘤生长抑制最显著,抑瘤率为66.01%,均明显高于多帕菲腹腔内注射组(34.65%)、多帕菲瘤内注射组(35.62%)和多烯紫杉醇微球瘤内注射低剂量组(48.37%)。
4.治疗3周后,超声造影示多烯紫杉醇微球瘤内注射高剂量组肿瘤仅见周边少许增强,实质大部分呈充盈缺损改变;其余各组实质内仍可见不同程度的增强。
5.多烯紫杉醇微球瘤内注射组病理学检查示组织大片坏死,MVD和VEGF、bFGF及Ang2表达均低于其余各组。
6.生存分析结果显示,治疗15周后载药微球组生存率(70%)高于多帕菲腹腔内注射组(30%)和瘤内注射组(30%)具有统计学显著性意义(P<0.05)。
结论
采用溶剂挥发法可制备粒径及分布适宜,分散良好的载多烯紫杉醇PLGA缓释微球,包封率高,释放周期可达3周,并能提高多烯紫杉醇的稳定性;超声引导瘤内注射载多烯紫杉醇PLGA微球,可明显提高多烯紫杉醇抗人肝癌疗效,抑制肿瘤组织血管生成相关基因VEGF、bFGF和Ang2的表达,减少肿瘤新生血管生成,提高生存率,具有潜在的临床应用价值。
Objective
To prepare sustained-release poly(lactic-co-glycolic acid)(PLGA) microspheres containing docetaxel, and investigate the physiochemical properties, in vitro release and drug stability; and to investigate the effect and mechanism in treatment of human hepatoma-bearing nude mice by ultrasound-guided intratumor injection of the drug-loaded microspheres.
Methods
1. Sustained-release PLGA microspheres containing docetaxel were prepared by solvent evaporation method, thereafter morphology and particle size were observed by scanning electron microscope, while drug loading, encapsulation efficiency, and in vitro release within 21days were examined by HPLC. The effect of irradiation steriliazation at three doses(5, 15 and 25kGy) was examined. Dichloromethane residue in microspheres was detected by gas chromatography. Post hypodermic administration on the mice back for 4 weeks, death of mice was recorded to calculate half-lethal dose by modified Karber’s method.
2. Established mude mice model of human heptoma cell line BEL-7407 transplanted subcutaneously. Ninety mice were randomly enrolled into a model(M), blank microspheres(BM), docetaxel intraperitoneal injection(DP), docetaxel intratumor injection(DT),low-dose(DMTL) and high-dose(DMTH) of docetaxel-loaded PLGA microspheres intratumor injection group with 15 animals in each group. Either group was given corresponding treatment under ultrasound guidance.
3. Tumor volume, parenchyma echo and blood supply between six groups were compared by regular ultrasound follow-up every week for consecutive 3 weeks.
4. At 3 weeks postinjection,5 nude mice randomly selected in each group were examined on contrast-enhanced ultrasound following by sacrification, and the tumors were excised, weighted to evaluate the inhibition rate.
5. tumor tissues were examined on histopathology by microscopy, on microvessel density by immunohistochemical method, and on the gene expression of vascular endothelial growth factor(VEGF), basic fibroblast growth factor(bFGF) and Angiopoietin-2(Ang2) by real-time fluorescence quantitative PCR.
6. Survival of remaining nude mice was observed for another 12 weeks.
Results
1. Mean diameter of drug-loaded microspheres were 23.1μm by solvent evaporation method; the optimal drug loading rate(4.82%) and encapsulation efficiency(96.3%) were gained when the feed ratio of PLGA to docetaxel was 100mg/5mg. Stably the cumulative release of docetaxel from microspheres was 82.5% within 21days without occurrence of burst release, and docetaxel encapsulated in microspheres, detected by HPLC, kept stability of structure. The limited amount of dichloromethane residue(0.026%) in microspheres accorded with general rule of Chinese Pharmacopoeia. No bacillus pumilus colony was cultured in microspheres after irradiation steriliazation at three doses.
2. Half-lethal dose calculated in docetaxel-loaded microspheres injection group (483.6mg/kg) was far higher than docetaxel injection group (52.7mg/kg).
3. The tumors of model and blank microspheres group were significantly increased after administration, with inhomogeneous internal echo and relatively rich blood flow signal on ultrasonography. The tumor growth was slower in the other docetaxel group, especially for DMTH group which inhibited tumor growth markedly with a little flow signal around tumors detected by color Doppler ultrasonography. DMTH displayed a potent antitumor effect on human hepatoma with a tumor inhibitory rate 66.01%, higher than that of DP(34.65%), DT(35.62%), and DMTL group(48.37%) significantly.
4. At 3 weeks postinjection,contrast-enhanced ultrasound was founded that a mass of tumors parenchyma showed filling defect except slight enhancement in paratumor parenchyma in DMTH group, but tumors parenchyma of all the other groups was enhanced in various degrees.
5. Extensive necrosis of tumor tissue was found in the histopathologic examination of docetaxel-loaded microspheres injection group. And the expression of MVD, as well as VEGF, bFGF and Ang2, decreased compared with the other groups.
6. For Survival analysis, survival rate in drug-loaded microspheres group(70%) was higher than DP group(30%), as well as DT group(30%) significantly(P<0.05).
Conclusion : Sustained-release PLGA microspheres containing docetaxel were successfully prepared by solvent evaporation method with optimal particle size, distribution, dispersion, encapsulation efficiency and low drug degradation, whose release period was about 3 weeks; the effect of docetaxel in treatment of human hepatoma-bearing nude mice was promoted by ultrasound-guided intratumor injection of PLGA microspheres containing docetaxel, which depressed the gene expression of VEGF, bFGF and Ang2 resulting in inhibition of tumor angiogenesis and also developed survival rate of nude mice. This new method of hepatoma treatment has potential clinical value.
引文
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[1] Sipos EP and Brem H. Local anti-angiogenic brain tumor therapies[J]. Journal of Neuro-Oncology, 2000, 50(1-2): 181–188.
[2] Brem H, Mahaley S Jr, Vick NA, et al. Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas[J]. J Neurosurg,1991,74(3):441-446.
[3] Tamargo RJ, Myseros JS,Epstein JI,et al.Interstitial chemotherapy of the 9L gliosarcoma:controlled release polymers for drug delivery in the brain[J].Cancer Res,1993,53(2):329-333.
[4]张灵芝.脂质体制备及其在生物医学中的应用[M].北京:北京大学医学出版社, 1998: 128.
[5] Glavas-Dodov M, Fredro-Kumbaradzi E, Goracinova K, et al. 5-Fluorouracil in topical liposome gels for anticancer treatment-Formulation and evaluation[J]. Acta Pharm, 2003(53): 241-250.
[6] Liu JJ, Hong RL, Cheng WF, et al. Simple and efficient liposomel encapsulation of topotecan by ammonium sulfate gradient: stability, pharmacokinetic and therapeutic evaluation[J]. Anticancer Drugs, 2002, 13(7): 709-717.
[7] Firth G, Oliver AS, McKeran RO. Studies on the intracerebral injection of bleomycin free and entrapped within liposomes in the rat[J]. J Neurol Neurosurg Psychiatry. 1984, 47(6): 585-9.
[8]刘占川,闫世军,刘莉,等.卡氮芥脂质体对鼠C6胶质细胞瘤内化疗的研究[J].白求恩医科大学学报,2000,26(2): 152-153.
[9]张自强,覃斌,李战,等.mPEG-DSPE修饰的紫杉醇脂质体的制备及其药动学研究[J].中国药学杂志,2008,43(3):l99-202.
[10] Liang W, Levchenko T, Khaw BA, et al. ATP-Containing Immunoliposomes Specific for Cardiac Myosin [J]. Current Drug Delivery,2004,1(1):1-7.
[11] Ruel-Gariepy E, Leclair G, Hildgen P, et al. Thermosensitive chitosan-based hydrogel containing liposomes for the delivery of hydrophilic molecules[J]. J Control Release,2002,82 (2-3): 373-83.
[12] Li W, Huang Z, MacKay JA, et al. Low-pH-sensitive poly(ethylene glycol)(PEG)-stabilized plasmid nanolipoparticles: effects of PEG chain length, lipid composition and assembly conditions on gene delivery[J]. Gene Med,2005,7(1): 67-79.
[13] Seong H,An TK,Khang G,et a1.BCNU-loaded poly(D,L-lactic-co-glycolide) wafer and antitumor activity against XF-498 human CNS tumor cells in vitro[J].Int J Pharm,2003,251(1-2):1-12.
[14] Roullin VG,Deverre JR,Lemaire L,et a1.Anti-cancer drug diffusion within living rat brain tissue:an experimental study using [3H](6)-5-fiuorouracil-loaded PLGA microspheres[J].Eur J Pharm Biopharm,2002,53(3):293-299.
[15] Bodell WJ,Bodell AP,Giannini DD,et a1.Levels and distribution of BCNU in GBM tumors following intratumoral injection of DTI-015(BCNU-ethanol)[J].Neuro oncol,2007,9(1):l2-19.
[16]李井泉,赵平,王世亮,等.吉西他滨缓释微球间质化疗治疗胰腺癌的实验研究[J].癌症进展杂志,2008,6(6): 601-606.
[17] Menei P , Montero-Menei C , Venier MC , et a1 . Drug delivery into the brain using poly(lactide-co-glycolide) microspheres[J].Expert Opin Drug Deliv,2005,2(2):363-76.
[18] Zhu GZ , Schwendemen SP . Stabilization of proteins encapsulated in cylindrical poly(1actied-co-glycolide) implants:mechanism of stablization by basic additives[J].Pharm Res,2000,17(3):351-357.
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[1] Sipos EP and Brem H. Local anti-angiogenic brain tumor therapies[J]. Journal of Neuro-Oncology, 2000, 50(1-2): 181–188.
[2] Brem H, Mahaley S Jr, Vick NA, et al. Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas[J]. J Neurosurg,1991,74(3):441-446.
[3] Tamargo RJ, Myseros JS,Epstein JI,et al.Interstitial chemotherapy of the 9L gliosarcoma:controlled release polymers for drug delivery in the brain[J].Cancer Res,1993,53(2):329-333.
[4]张灵芝.脂质体制备及其在生物医学中的应用[M].北京:北京大学医学出版社, 1998: 128.
[5] Glavas-Dodov M, Fredro-Kumbaradzi E, Goracinova K, et al. 5-Fluorouracil in topical liposome gels for anticancer treatment-Formulation and evaluation[J]. Acta Pharm, 2003(53): 241-250.
[6] Liu JJ, Hong RL, Cheng WF, et al. Simple and efficient liposomel encapsulation of topotecan by ammonium sulfate gradient: stability, pharmacokinetic and therapeutic evaluation[J]. Anticancer Drugs, 2002, 13(7): 709-717.
[7] Firth G, Oliver AS, McKeran RO. Studies on the intracerebral injection of bleomycin free and entrapped within liposomes in the rat[J]. J Neurol Neurosurg Psychiatry. 1984, 47(6): 585-9.
[8]刘占川,闫世军,刘莉,等.卡氮芥脂质体对鼠C6胶质细胞瘤内化疗的研究[J].白求恩医科大学学报,2000,26(2): 152-153.
[9]张自强,覃斌,李战,等.mPEG-DSPE修饰的紫杉醇脂质体的制备及其药动学研究[J].中国药学杂志,2008,43(3):l99-202.
[10] Liang W, Levchenko T, Khaw BA, et al. ATP-Containing Immunoliposomes Specific for Cardiac Myosin [J]. Current Drug Delivery,2004,1(1):1-7.
[11] Ruel-Gariepy E, Leclair G, Hildgen P, et al. Thermosensitive chitosan-based hydrogel containing liposomes for the delivery of hydrophilic molecules[J]. J Control Release,2002,82 (2-3): 373-83.
[12] Li W, Huang Z, MacKay JA, et al. Low-pH-sensitive poly(ethylene glycol)(PEG)-stabilized plasmid nanolipoparticles: effects of PEG chain length, lipid composition and assembly conditions on gene delivery[J]. Gene Med,2005,7(1): 67-79.
[13] Seong H,An TK,Khang G,et a1.BCNU-loaded poly(D,L-lactic-co-glycolide) wafer and antitumor activity against XF-498 human CNS tumor cells in vitro[J].Int J Pharm,2003,251(1-2):1-12.
[14] Roullin VG,Deverre JR,Lemaire L,et a1.Anti-cancer drug diffusion within living rat brain tissue:an experimental study using [3H](6)-5-fiuorouracil-loaded PLGA microspheres[J].Eur J Pharm Biopharm,2002,53(3):293-299.
[15] Bodell WJ,Bodell AP,Giannini DD,et a1.Levels and distribution of BCNU in GBM tumors following intratumoral injection of DTI-015(BCNU-ethanol)[J].Neuro oncol,2007,9(1):l2-19.
[16]李井泉,赵平,王世亮,等.吉西他滨缓释微球间质化疗治疗胰腺癌的实验研究[J].癌症进展杂志,2008,6(6): 601-606.
[17] Menei P , Montero-Menei C , Venier MC , et a1 . Drug delivery into the brain using poly(lactide-co-glycolide) microspheres[J].Expert Opin Drug Deliv,2005,2(2):363-76.
[18] Zhu GZ , Schwendemen SP . Stabilization of proteins encapsulated in cylindrical poly(1actied-co-glycolide) implants:mechanism of stablization by basic additives[J].Pharm Res,2000,17(3):351-357.
[19] Mok TS,Kanekal S,Lin XR, et al.Pharmacokinetic study of intralesional cisplatin for the treatment of hepatocellular carcinoma[J].Cancer,2001,91(12):2369-77.
[20] Harbord M,Dawes RF,Barr H,et a1.Palliation of patients with dysphagia due to advanced esophageal cancer by endoscopic injection of cisplatin/epinephrine injectable gel[J].Gastrointest Endosc,2002,56(5):644-51.
[21] Leung TW,Yu S,Johnson PJ,et a1.Phase II study of the efficacy and safety of cisplatin/epinephrine injectable gel administered to patients with unresectable hepatocellular carcinoma[J].Clin Oncol,2003,21(4):652-8.
[22] Engelmann K,Mack MG,Straub R,et a1.CT-guided percutaneous intratumoral chemotherapy with a novel eisplatin/epinephrine injectable gel for the treatment of inoperable malignant liver tumors [J].Rofo,2000,172(12):1020-7.
[23] Vogl TJ,Engelmann K,Mack MG,et a1. CT-guided intratumoural administration of cisplatin/epinephrine gel for treatment of malignant liver tumours[J].Br J Cancer,2002,86(4):524-9.
[24] Jeong B, Bae YH and Kim SW. Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers[J].J Control Release, 2000;63(1-2):l55-163.
[25] Ghahremankhani AA, Dorkoosh F and Dinarvand R.PLGA-PEG-PLGA Tri-Block Copolymers as in situ gel forming peptide delivery system: effect of formulation properties on peptide release[J].Pharm Dev Technol, 2008, 13(1):49-55.
[26] Duvvuri S,Janoria KG,Pal D, et al.Controlled delivery of ganciclovir to the retina with drug-loaded Poly(D,L-lactide-co-glycolide)(PLGA) microspheres dispersed in PLGA-PEG-PLGA Gel:a novel intravitreal delivery system for the treatment of cytomegalovirus retinitis[J].J Ocul Pharmacol Ther, 2007, 23(3):264-274.
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