羟基喜树碱亚微乳细胞内动力学及其抗肿瘤作用研究
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摘要
本课题在前期研究基础上,采用微射流技术制备了羟基喜树碱(HPCT)亚微乳,对HCPT亚微乳的细胞内动力学特征、细胞器的分布规律,细胞摄取机制和体内外抗肿瘤作用进行了探讨;研究了亚微乳中药物分布和其药物释放,以及HCPT-SAE克服肿瘤细胞多药耐药作用。本研究为亚微乳成为抗肿瘤药物载体的进一步研究开发提供了理论和实验依据。
本课题首先建立了羟基喜树碱的HPLC分析方法,测定其在水和正辛醇中的表观溶解度分别为2.98和47.06μg/mL,正辛醇/水中的表观分配系数为12.62,其脂溶性比水溶性好;考察HCPT在不同pH条件下的表观开环平衡常数,以及其在多种油中的溶解度,为设计处方确定工艺条件及建立体内分析方法提供了依据。
本课题以注射用大豆油、大豆磷脂、十八酰胺或胆固醇和维生素E为油相,Poloxamer188或(和)大豆磷脂和甘油为水相,采用微射流技术制备了两种HCPT亚微乳(HCPT-SAE和HCPT-LipoE)。HCPT亚微乳理化性质研究显示,HCPT-SAE和HCPT-LipoE经高压灭菌后,外观、乳滴粒径、粒径分布和Zeta电位均未发生显著改变;pH值有所下降,但符合注射液质量要求;药物含量略有下降,但仍占标示量的96%以上。HCPT亚微乳经高压灭菌后理化性质稳定。亚微乳中HCPT相分布研究表明,HCPT主要分布于O/W界面层构成的界面膜中,占亚微乳中药物总量80%以上,油相(14%以上)中分布高于水相;体外释放实验表明,HCPT-SAE和HCPT-LipoE两者体外释放行为相似,释药速度较慢,具有缓释作用,此作用可能与药物在乳剂中的相分配有关。稳定性研究表明,HCPT亚微乳减慢了其在血浆和细胞培养液中由内酯型向羧酸盐型的转化速率,增加其以内酯形式存的浓度。
采用建立的细胞内HCPT含量测定方法,研究HCPT亚微乳细胞内动力学和HCPT在细胞器的分布。摄取动力学结果表明,与对照制剂HCPT-I相比,相同药物量HCPT亚微乳与细胞孵育后,能显著提高细胞内和细胞核内药物量。
细胞内消除动力学研究表明,在SGC7901细胞中,HCPT-SAE和HCPT-LipoE的AUC显著高于HCPT-I(P＜0.01),分别为HCPT-I的9.88和7.69倍;t_(1/2)也显著比HCPT-I延长(P＜0.01),分别为HCPT-I的1.67和2.1倍。HCPT亚微乳细胞核AUC和t_(1/2)均显著高于HCPT-I(P＜0.01),HCPT-SAE细胞核AUC比HCPT-LipoE高1.76倍;细胞质中两亚微乳AUC也均显著高于HCPT-I(P＜0.01)。两亚微乳细胞核AUC均比细胞质低。
SGC7901/VCR细胞中HCPT-SAE和HCPT-LipoE的AUC显著高于HCPT-I(P＜0.01),分别为HCPT-I的29.16和8.54倍,HCPT-SAE为HCPT-LipoE的3.41倍;t_(1/2)也显著比HCPT-I长(P＜0.01),分别为HCPT-I的5.37和6.23倍。两亚微乳细胞核AUC均显著高于细胞质(P＜0.01),HCPT-LipoE细胞核内t_(1/2)比细胞质显著延长(P＜0.05);HCPT-SAE组细胞核和细胞质AUC均显著比HCPT-LipoE组高(P＜0.01),两亚微乳细胞核t_(1/2)无差异,而细胞质中HCPT-SAE比HCPT-LipoE显著延长(P＜0.05)。
HeLa细胞中HCPT-SAE和HCPT-LipoE的AUC显著高于HCPT-I(P＜0.01),分别为HCPT-I的35.26和15.44倍;t_(1/2)也显著比HCPT-I长(P＜0.05),分别为HCPT-I的1.67和1.75倍。两亚微乳细胞核AUC均显著高于细胞质(P＜0.05),HCPT-LipoE细胞核内t_(1/2)比细胞质显著延长(P＜0.05);HCPT-SAE组细胞核和细胞质AUC均显著比HCPT-LipoE组高(P＜0.01)。
HCPT亚微乳细胞摄取机理研究显示,在一定浓度范围内,细胞摄取HCPT量随HCPT亚微乳浓度升高而增加,表现出明显的浓度依赖性,高浓度时则表现为饱和性;细胞摄取HCPT亚微乳时呈现明显的温度依赖性,该过程需要消耗能量;内吞抑制剂(叠氮钠、甘露醇和氯喹)显著降低细胞内HCPT聚积。初步证实,细胞摄取HCPT亚微乳为能量依赖性的内吞方式。
HCPT亚微乳能增强对肿瘤细胞增殖的抑制作用,抑制作用呈时间和剂量依赖性;HCPT-SAE对SGC7901、SGC7901/VCR和HeLa细胞的增殖均有较显著的抑制作用,HCPT-LipoE和HCPT-I仅对敏感的细胞有较强抑制作用,而对耐药细胞(SGC7901/VCR细胞)的抑制作用很弱。肿瘤细胞增殖抑制、胞内药物聚积等实验确证,阳离子亚微乳(HCPT-SAE)可增强药物对肿瘤细胞抑制增殖作用,克服肿瘤细胞多药耐药性。
体内药动学研究结果表明,HCPT-SAE和HCPT-LipoE可以显著延长HCPT的体内循环时间,提高血浆中药物浓度,其消除半衰期分别为HCPT-I的5.75和3.72倍,AUC为HCPT-I的4.03和4.01倍。荷S180肿瘤小鼠体内分布研究结果表明,HCPT亚微乳可提高HCPT在肿瘤内的分布,HCPT-SAE的肿瘤靶向作用最明显,其AUC和峰浓度分别为HCPT-I组的11.57和1.91倍。
HCPT-I的抗肿瘤活性最差,在4 mg/kg时其抑瘤率为31.03%,同剂量的HCPT-SAE和HCPT-LipoE抑瘤效率分别为90.75%和70.21%;2 mg/kg的HCPT-SAE的抑瘤率为64.31%,为HCPT-I(4 mg/kg)的两倍,对小鼠体重无显著影响;肿瘤病理切片显示,HCPT-SAE对肿瘤细胞抑制作用也较其他制剂显著。结果表明,HCPT-SAE毒性低,抗肿瘤作用强。
Hydrocamptothecin (HCPT) submicroemulsions were prepared by microfluid technology. The physicochemical characteristics, intracellular kinetics, subcellular biodistribution, mechanism of cellular uptake and antitumor effect of HCPT submicroemulsions (HCPT-SE) were studied. The relation between phase distribution and in vitro release of HCPT submicroemulsions, and overcoming multidrug resistance were also investigated. In the present work we provide some academic and experimental data for submicroemulsions as carrier of anticacer agents.
The method of high performance liquid chromatography (HPLC) was set up to determine the concentration of HCPT. The apparent solubility of HCPT in distilled water and octanol was 2.98μg/mL and 47.06μg/mL, respectively. The apparent partition coefficient of HCPT in octanol/distilled water was 12.62. Lipophilicity of HCPT is more than hydrophilicity. The pKa was calculated from the process of carboxylate form of HCPT into lactones form in diferent pH solution. The solubility of HCPT in different oil was also determined.
HCPT-SE containing HCPT, soybean oil, lecithin, stearylamine cholesterol and vitamine E as oily phase and Poloxamer188 and (or) as lecithin emulsifier were prepared by microfluid technology. As a result, HCPT-SE of different charge, cationic submicroemulsion (HCPT-SAE) and anionic charged submicroemulsion (HCPT-LipoE) were prepared. The HCPT-SE were characterized in terms of physical appearance, droplet size, polydispersity and zeta potential. The result showed that the characterizations of HCPT-SE were not significantly affected by autoclaving. HCPT-SE accorded with the quality standards of injections, although the pH value and content of HCPT were slight decrease. The HCPT in submicroemulsions mainly distributed in oil/water interface (～80%). Distribution of HCPT in oil phase (～14%) was more than that in water phase. In vitro, the release of HCPT from HCPT-SAE and HCPT-LipoE were similar. The release pattern of HCPT was slow and related to distribution of HCPT in submicroemulsions. HCPT-SE significantly decreased the conversion of lactone to carboxylate and enhanced proportion of the serum HCPT with the lactone fragment.
To study the intracellular kinetics behavior and distribution of HCPT-SE, reversed-phase HPLC mothod was established to determine intracellular HCPT concentration. The cellular uptake kinetics study showed that HCPT-SE could significantly increase intracellular accumulation and nuclear delivery of HCPT compared with HCPT-I at same dose.
The intracellular elimination kinetics study in SGC7901 cells showed that the AUC of HCPT-SAE and HCPT-LipoE were 9.88 and 7.69 folds higher than that of HCPT-I, when half-life was enhanced by 1.67 and 3.1 folds, respectively. The AUC and halt-life of HCPT-SE in nuclei and cytoplasm were significantly higher than that of HCPT-I (P < 0.01), whereas the AUC of HCPT-SAE extended the AUC of HCPT-LipoE by 1.76 times. The AUC of HCPE-SE in nuclei was lower than that in cytoplasm.
In SGC7901/VCR cells, the AUC of HCPT-SAE and HCPT-LipoE were 29.16 and 8.54 folds higher than that of HCPT-I, when half-life was enhanced by 5.37 and 6.23 folds, respectively. The AUC of HCPT-SE in nuclei were significantly higher than that in cytoplasm (P< 0.01), whereas the half-life of HCPT-LipoE in nuclei was longer than that in cytoplasm. The AUC of HCPT-SAE in nuclei and cytoplasm was significantly higher than that of HCPT-LipoE (P < 0.01). The half-life of HCPT-SE in nuclei was no difference although the half-life of HCPT-SAE in cytoplasm was significently longer than that of HCPT-LipoE (P < 0.01).
The AUC of HCPT-SAE and HCPT-LipoE were 35.26 and 15.44 folds higher than that of HCPT-I in HeLa cells, when half-life was enhanced by 1.67 and 1.75 folds, respectively. The AUC of HCPT-SE in nuclei were significantly higher than that in cytoplasm (P<0.01), whereas the half-life of HCPT-LipoE in nuclei was longer than that in cytoplasm. The AUC of HCPT-SAE in nuclei and cytoplasm was significantly higher than that of HCPT-LipoE (P < 0.01).
The cellular uptake of HCPT-SE was in proportion to the concentrtion, and the pathway was saturable in high concentrtion (1.0μg/mL). The uptake of HCPT-SE was energy-dependent and was influenced by temperature. Endocytosis inhibitors (sodium azide, mannitol and chloroquine) decreased significantly accumulation of HCPT (p<0.01). The result revealed that HCPT-SE was uptaken through the endocytosis of energy-dependent.
HCPT-SE showed higher antiproliferative activity than HCPT-Injection (HCPT-I), and the antiproliferative activity of HCPT-SE was in proportion to the incubation time and HCPT concentration. The proliferation of SGC7901cells, SGC7901/VCR cells and HeLa cells were signifcantly inhibited by HCPT-SAE (p<0.01). Whereas HCPE-LipoE only inhibited proliferation of SGC7901cells and HeLa cells and did not show significantly cytotoxicity in SGC7901/VCR (multidrug resistance cells). HCPT-SAE was suggested to overcome multidrug resistance in SGC7901/VCR cells by many approaches, such as fluorescence microscopy, flow cytometric ananlysis and HPLC, etc.
After IV administration of HCPT-SE and HCPT-I to rat, pharmacokinetics parameters were calculated. It turned out that HCPT-SE significantly prolonged half-life of HCPT, and ehanced bioavailability. HCPT-SAE and HCPT-LipoE could extend the half-life of HCPT-I by 5.75 and 3.72 times, when AUC was enhanced by 4.03 and 4.01folds, respectively.The biodistribution test was carried out on S-180 tumor bearing mice. HCPT-SAE enhanced HCPT content of tumor, and had significantly tumor targeting effects. The AUC and C_(max) of HCPT-SAE in tumor were 11.57 and 1.91 folds higher than that of HCPT-I, respectively.
Pharmacological test showed that HCPT-I at 4 mg/kg induced a 31.03% tumor inhibition rate. Compared with HCPT-I, HCPT-SAE and HCPT-LipoE showed tumor inhibiton rate of 90.75% and 70.21%, respectively. HCPT-SAE had tumor inhibiton rate of 64.31% at 2 mg/kg, which was 2 folds higher than that of HCPT-I at 4 mg/kg. Pathologic slice of tumor tissue also showed the effect of antitumor was higher than that of HCPT-LipoE and HCPT-I.
本课题首先建立了羟基喜树碱的HPLC分析方法,测定其在水和正辛醇中的表观溶解度分别为2.98和47.06μg/mL,正辛醇/水中的表观分配系数为12.62,其脂溶性比水溶性好;考察HCPT在不同pH条件下的表观开环平衡常数,以及其在多种油中的溶解度,为设计处方确定工艺条件及建立体内分析方法提供了依据。
本课题以注射用大豆油、大豆磷脂、十八酰胺或胆固醇和维生素E为油相,Poloxamer188或(和)大豆磷脂和甘油为水相,采用微射流技术制备了两种HCPT亚微乳(HCPT-SAE和HCPT-LipoE)。HCPT亚微乳理化性质研究显示,HCPT-SAE和HCPT-LipoE经高压灭菌后,外观、乳滴粒径、粒径分布和Zeta电位均未发生显著改变;pH值有所下降,但符合注射液质量要求;药物含量略有下降,但仍占标示量的96%以上。HCPT亚微乳经高压灭菌后理化性质稳定。亚微乳中HCPT相分布研究表明,HCPT主要分布于O/W界面层构成的界面膜中,占亚微乳中药物总量80%以上,油相(14%以上)中分布高于水相;体外释放实验表明,HCPT-SAE和HCPT-LipoE两者体外释放行为相似,释药速度较慢,具有缓释作用,此作用可能与药物在乳剂中的相分配有关。稳定性研究表明,HCPT亚微乳减慢了其在血浆和细胞培养液中由内酯型向羧酸盐型的转化速率,增加其以内酯形式存的浓度。
采用建立的细胞内HCPT含量测定方法,研究HCPT亚微乳细胞内动力学和HCPT在细胞器的分布。摄取动力学结果表明,与对照制剂HCPT-I相比,相同药物量HCPT亚微乳与细胞孵育后,能显著提高细胞内和细胞核内药物量。
细胞内消除动力学研究表明,在SGC7901细胞中,HCPT-SAE和HCPT-LipoE的AUC显著高于HCPT-I(P＜0.01),分别为HCPT-I的9.88和7.69倍;t_(1/2)也显著比HCPT-I延长(P＜0.01),分别为HCPT-I的1.67和2.1倍。HCPT亚微乳细胞核AUC和t_(1/2)均显著高于HCPT-I(P＜0.01),HCPT-SAE细胞核AUC比HCPT-LipoE高1.76倍;细胞质中两亚微乳AUC也均显著高于HCPT-I(P＜0.01)。两亚微乳细胞核AUC均比细胞质低。
SGC7901/VCR细胞中HCPT-SAE和HCPT-LipoE的AUC显著高于HCPT-I(P＜0.01),分别为HCPT-I的29.16和8.54倍,HCPT-SAE为HCPT-LipoE的3.41倍;t_(1/2)也显著比HCPT-I长(P＜0.01),分别为HCPT-I的5.37和6.23倍。两亚微乳细胞核AUC均显著高于细胞质(P＜0.01),HCPT-LipoE细胞核内t_(1/2)比细胞质显著延长(P＜0.05);HCPT-SAE组细胞核和细胞质AUC均显著比HCPT-LipoE组高(P＜0.01),两亚微乳细胞核t_(1/2)无差异,而细胞质中HCPT-SAE比HCPT-LipoE显著延长(P＜0.05)。
HeLa细胞中HCPT-SAE和HCPT-LipoE的AUC显著高于HCPT-I(P＜0.01),分别为HCPT-I的35.26和15.44倍;t_(1/2)也显著比HCPT-I长(P＜0.05),分别为HCPT-I的1.67和1.75倍。两亚微乳细胞核AUC均显著高于细胞质(P＜0.05),HCPT-LipoE细胞核内t_(1/2)比细胞质显著延长(P＜0.05);HCPT-SAE组细胞核和细胞质AUC均显著比HCPT-LipoE组高(P＜0.01)。
HCPT亚微乳细胞摄取机理研究显示,在一定浓度范围内,细胞摄取HCPT量随HCPT亚微乳浓度升高而增加,表现出明显的浓度依赖性,高浓度时则表现为饱和性;细胞摄取HCPT亚微乳时呈现明显的温度依赖性,该过程需要消耗能量;内吞抑制剂(叠氮钠、甘露醇和氯喹)显著降低细胞内HCPT聚积。初步证实,细胞摄取HCPT亚微乳为能量依赖性的内吞方式。
HCPT亚微乳能增强对肿瘤细胞增殖的抑制作用,抑制作用呈时间和剂量依赖性;HCPT-SAE对SGC7901、SGC7901/VCR和HeLa细胞的增殖均有较显著的抑制作用,HCPT-LipoE和HCPT-I仅对敏感的细胞有较强抑制作用,而对耐药细胞(SGC7901/VCR细胞)的抑制作用很弱。肿瘤细胞增殖抑制、胞内药物聚积等实验确证,阳离子亚微乳(HCPT-SAE)可增强药物对肿瘤细胞抑制增殖作用,克服肿瘤细胞多药耐药性。
体内药动学研究结果表明,HCPT-SAE和HCPT-LipoE可以显著延长HCPT的体内循环时间,提高血浆中药物浓度,其消除半衰期分别为HCPT-I的5.75和3.72倍,AUC为HCPT-I的4.03和4.01倍。荷S180肿瘤小鼠体内分布研究结果表明,HCPT亚微乳可提高HCPT在肿瘤内的分布,HCPT-SAE的肿瘤靶向作用最明显,其AUC和峰浓度分别为HCPT-I组的11.57和1.91倍。
HCPT-I的抗肿瘤活性最差,在4 mg/kg时其抑瘤率为31.03%,同剂量的HCPT-SAE和HCPT-LipoE抑瘤效率分别为90.75%和70.21%;2 mg/kg的HCPT-SAE的抑瘤率为64.31%,为HCPT-I(4 mg/kg)的两倍,对小鼠体重无显著影响;肿瘤病理切片显示,HCPT-SAE对肿瘤细胞抑制作用也较其他制剂显著。结果表明,HCPT-SAE毒性低,抗肿瘤作用强。
Hydrocamptothecin (HCPT) submicroemulsions were prepared by microfluid technology. The physicochemical characteristics, intracellular kinetics, subcellular biodistribution, mechanism of cellular uptake and antitumor effect of HCPT submicroemulsions (HCPT-SE) were studied. The relation between phase distribution and in vitro release of HCPT submicroemulsions, and overcoming multidrug resistance were also investigated. In the present work we provide some academic and experimental data for submicroemulsions as carrier of anticacer agents.
The method of high performance liquid chromatography (HPLC) was set up to determine the concentration of HCPT. The apparent solubility of HCPT in distilled water and octanol was 2.98μg/mL and 47.06μg/mL, respectively. The apparent partition coefficient of HCPT in octanol/distilled water was 12.62. Lipophilicity of HCPT is more than hydrophilicity. The pKa was calculated from the process of carboxylate form of HCPT into lactones form in diferent pH solution. The solubility of HCPT in different oil was also determined.
HCPT-SE containing HCPT, soybean oil, lecithin, stearylamine cholesterol and vitamine E as oily phase and Poloxamer188 and (or) as lecithin emulsifier were prepared by microfluid technology. As a result, HCPT-SE of different charge, cationic submicroemulsion (HCPT-SAE) and anionic charged submicroemulsion (HCPT-LipoE) were prepared. The HCPT-SE were characterized in terms of physical appearance, droplet size, polydispersity and zeta potential. The result showed that the characterizations of HCPT-SE were not significantly affected by autoclaving. HCPT-SE accorded with the quality standards of injections, although the pH value and content of HCPT were slight decrease. The HCPT in submicroemulsions mainly distributed in oil/water interface (～80%). Distribution of HCPT in oil phase (～14%) was more than that in water phase. In vitro, the release of HCPT from HCPT-SAE and HCPT-LipoE were similar. The release pattern of HCPT was slow and related to distribution of HCPT in submicroemulsions. HCPT-SE significantly decreased the conversion of lactone to carboxylate and enhanced proportion of the serum HCPT with the lactone fragment.
To study the intracellular kinetics behavior and distribution of HCPT-SE, reversed-phase HPLC mothod was established to determine intracellular HCPT concentration. The cellular uptake kinetics study showed that HCPT-SE could significantly increase intracellular accumulation and nuclear delivery of HCPT compared with HCPT-I at same dose.
The intracellular elimination kinetics study in SGC7901 cells showed that the AUC of HCPT-SAE and HCPT-LipoE were 9.88 and 7.69 folds higher than that of HCPT-I, when half-life was enhanced by 1.67 and 3.1 folds, respectively. The AUC and halt-life of HCPT-SE in nuclei and cytoplasm were significantly higher than that of HCPT-I (P < 0.01), whereas the AUC of HCPT-SAE extended the AUC of HCPT-LipoE by 1.76 times. The AUC of HCPE-SE in nuclei was lower than that in cytoplasm.
In SGC7901/VCR cells, the AUC of HCPT-SAE and HCPT-LipoE were 29.16 and 8.54 folds higher than that of HCPT-I, when half-life was enhanced by 5.37 and 6.23 folds, respectively. The AUC of HCPT-SE in nuclei were significantly higher than that in cytoplasm (P< 0.01), whereas the half-life of HCPT-LipoE in nuclei was longer than that in cytoplasm. The AUC of HCPT-SAE in nuclei and cytoplasm was significantly higher than that of HCPT-LipoE (P < 0.01). The half-life of HCPT-SE in nuclei was no difference although the half-life of HCPT-SAE in cytoplasm was significently longer than that of HCPT-LipoE (P < 0.01).
The AUC of HCPT-SAE and HCPT-LipoE were 35.26 and 15.44 folds higher than that of HCPT-I in HeLa cells, when half-life was enhanced by 1.67 and 1.75 folds, respectively. The AUC of HCPT-SE in nuclei were significantly higher than that in cytoplasm (P<0.01), whereas the half-life of HCPT-LipoE in nuclei was longer than that in cytoplasm. The AUC of HCPT-SAE in nuclei and cytoplasm was significantly higher than that of HCPT-LipoE (P < 0.01).
The cellular uptake of HCPT-SE was in proportion to the concentrtion, and the pathway was saturable in high concentrtion (1.0μg/mL). The uptake of HCPT-SE was energy-dependent and was influenced by temperature. Endocytosis inhibitors (sodium azide, mannitol and chloroquine) decreased significantly accumulation of HCPT (p<0.01). The result revealed that HCPT-SE was uptaken through the endocytosis of energy-dependent.
HCPT-SE showed higher antiproliferative activity than HCPT-Injection (HCPT-I), and the antiproliferative activity of HCPT-SE was in proportion to the incubation time and HCPT concentration. The proliferation of SGC7901cells, SGC7901/VCR cells and HeLa cells were signifcantly inhibited by HCPT-SAE (p<0.01). Whereas HCPE-LipoE only inhibited proliferation of SGC7901cells and HeLa cells and did not show significantly cytotoxicity in SGC7901/VCR (multidrug resistance cells). HCPT-SAE was suggested to overcome multidrug resistance in SGC7901/VCR cells by many approaches, such as fluorescence microscopy, flow cytometric ananlysis and HPLC, etc.
After IV administration of HCPT-SE and HCPT-I to rat, pharmacokinetics parameters were calculated. It turned out that HCPT-SE significantly prolonged half-life of HCPT, and ehanced bioavailability. HCPT-SAE and HCPT-LipoE could extend the half-life of HCPT-I by 5.75 and 3.72 times, when AUC was enhanced by 4.03 and 4.01folds, respectively.The biodistribution test was carried out on S-180 tumor bearing mice. HCPT-SAE enhanced HCPT content of tumor, and had significantly tumor targeting effects. The AUC and C_(max) of HCPT-SAE in tumor were 11.57 and 1.91 folds higher than that of HCPT-I, respectively.
Pharmacological test showed that HCPT-I at 4 mg/kg induced a 31.03% tumor inhibition rate. Compared with HCPT-I, HCPT-SAE and HCPT-LipoE showed tumor inhibiton rate of 90.75% and 70.21%, respectively. HCPT-SAE had tumor inhibiton rate of 64.31% at 2 mg/kg, which was 2 folds higher than that of HCPT-I at 4 mg/kg. Pathologic slice of tumor tissue also showed the effect of antitumor was higher than that of HCPT-LipoE and HCPT-I.
引文
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