纳米粒子吸附抗癌药物的载体效应及其药动学研究
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摘要
目的:本实验主要是观察了载体纳米粒子(NPC,nanoparticles)吸附抗癌药物(ANTC,anticancer drugs)即卡波霉素(CBMC)的载体效应并测定其在大鼠体内的药代动力学参数。方法:采用纳米粒度仪测定了靶向载体NPC的表征;根据NPC对ANTC的吸附特性研究结果设计了具有特定载药量的CBMC并进行了中试制备研究;使用HPLC法分析了CBMC的释药特性;采用改良寇式法分别测定了NPC、ANTC和CBMC经腹腔注射和静脉注射对小白鼠的急性毒性并比较了NPC、ANTC和CBMC的LD50;采用MTT法评价了CBMC对体外培养的6种人癌细胞的细胞生长抑制作用,并计算了CBMC对6种细胞的IC50;采用6种动物肿瘤模型评价了CBMC的体内抗肿瘤作用,运用电镜技术和组织病理学方法初步观察了NPC的肿瘤靶向作用;采用流式细胞术观察了NPC对人癌细胞的细胞周期的影响,探讨了NPC可能存在的对抗癌药物的增效机制;测定了CBMC及ANTC经腹腔注射后在大鼠体内的药代动力学特征及腹腔组织分布特点,并获得了药代动力学参数。结果:
1.经高精度CPS纳米粒度仪对NPC纳米粒子表征,本实验所用NPC平均粒径为319±111 nm;
2. NPC对ANTC有很强大的吸附作用,25℃时,NPC吸附ANTC约0.5h即可达到平衡,且达平衡时间与NPC:ANTC质量比无关。NPC吸附ANTC的量M与溶液中游离ANTC浓度C符合经公式172*C0.145(R=0.953,P<0.0001),单位质量NPC可吸附ANTC的量最高可达285mg/g。
3.根据NPC吸附ANTC特点,建立了CBMC中试生产配方,并进行了中试制备,获得3批次CBMC,共计954支混悬注射剂;
4.用改良寇式法测定了NPC、ANTC和CBMC腹腔注射及静脉注射急性毒性,结果显示,NPC腹腔注射后LD50﹥4000mg/kg;静脉注射LD50约为308.52mg/kg;ANTC腹腔LD50约为5.83mg/kg,静脉注射LD50约为4.79mg/kg;CBMC腹腔注射LD50约为122.91mg/kg,毒性比含药量相等的ANTC低约3.5倍。
5.采用MTT法评价了CBMC对体外培养的6人癌细胞的细胞生长抑制作用的结果显示,NPC对体外培养的人癌细胞无明显的抑制生长作用,CBMC对体外培养的多种人癌细胞均有较强的抑制生长作用,具有较好的剂量效应关系,且其作用均显著高于相等浓度的游离ANTC组。经计算,CBMC作用于人胃癌BGC-823细胞48h时IC50为41.8μg/mL、人肝癌HepG-2细胞48h时IC50为31.4μg/ mL、人肝癌7701细胞48h时IC50为97.08μg/ mL、人肺鳞癌H460细胞48h时IC50为256.14μg/ mL、人非小细胞肺癌H1299细胞48h时IC50为129.13μg/ mL、人胰腺癌JF305细胞48h时IC50为58.60μg/ mL。
6.建立了6种肿瘤移植模型,包括白血病移植模型、腹水瘤移植模型及实体瘤移植模型评价CBMC的体内抗肿瘤作用。体内实验结果显示,CBMC对6种动物肿瘤模型均有显著的治疗作用,且具有较好的剂量-效应关系。含ANTC量相等的6mg/kgCBMC组其生命延长率及抑瘤率均显著高于1mg/kgANTC组。低剂量CBMC(2mg/kg)组其生命延长率及抑瘤率与1mg/kgANTC组无显著性差异。结果提示NPC的载体效应,即NPC由于其局部滞留性、肿瘤附着性及淋巴趋向性,可将ANTC滞留于给药局部或经过淋巴系统导向肿瘤组织,在肿瘤局部形成药物高浓度并经过缓慢释放维持药物浓度,使药物直接作用于肿瘤组织。
7.部分肿瘤病灶的病理切片及TEM观察结果显示[0],NPC可附着于肿瘤组织并进入肿瘤病灶,进而进入肿瘤细胞释放药物并杀伤肿瘤细胞,其细胞内靶分子主要为细胞核、线粒体、溶酶体。
8. NPC对BGC-823细胞周期影响的结果显示,大剂量NPC可将肿瘤细胞抑制于S期,NPC可能具有对化疗药物的增效作用。
9.建立了CBMC的HPLC测定方法;获得了CBMC和ANTC经腹腔注射后在大鼠体内的药代动力学参数及腹腔组织分布特点,结果显示,CBMC腹腔注射与ANTC相比具有消除慢、血药浓度低、选择性好等特点,其组织药物浓度以肿瘤细胞较易附着的大网膜、胃、腹膜、膈肌、淋巴结最高。
OBJECTIVE: To study the development and research of CBMC that is ANTC adsorbed by NPC. METHODS: The size of targeting carrier(NPC) was characterized by NPC; Adsorption features of NPC for ANTC was investigated by uLtraviolet spectrophotometer; Design and prepare the CBMC, the drug loading of which was specified, according to the resuLts of adsorption features of NPC; The release characteristics of CBMC was studied by HPLC; The LD50 of NPC, ANTC and CBMC was determined and compared; The anti-cancer effect of CBMC was studied by MTT; Then measured the dose-effect relationship and calcuLated the IC50 based on the MTT resuLts. The anti-cancer action of CBMC in vivo was studied by observing its effect on the animal tumor model. Meanwhile, the guiding effect of the CBMC to NPC is observed by conventional dye and TEM. The cell cycle was distinguished by PI staining was detected flow cytometer in order to explore the synergistic action of NPC for anti-cancer drugs. The peritoneal and plasma distribution in rats was studied by HPLC, then the corresponding pharmacokinetic parameters based on the time process of blood drug concentration were calcuLated.
RESULTS:
1. The average particle size was 319±111 nm for NPC.
2. NPC can absorb ANTC effectively and the absorption curve is consistent with exponential form 172*C0.145(R=0.953,P<0.0001) at 25℃. Reached equilibrium time of NPC for ANTC was about 0.5h, which was unrelated to the mass ratio of NPC to ANTC. The quantity of ANTC adsorbed by Per unit mass NPC was 285mg/g.
3. The production formuLa of CBMC was established according to the adsorption features of NPC for ANTC. 3 batches, totally 954 branches, CBMC injection was obtained by middle test.
4. LD50 of mice received intraperitoneal injection of NPC was more than 4000mg/kg. LD50 of mice received intravenous injection of NPC was about 308.52mg/kg. LD50 of mice received intraperitoneal and intravenous injections of NPC were 5.83 and 4.97mg/kg. LD50 of mice received intraperitoneal injection of CBMC was about 122.91mg/kg. Toxicity of CBMC was 3.5 times that of ANTC.
5. CBMC exhibits advanced function of anticancer, which displays better dose-effect relationship. The inhibitory concentration 50%(IC50) of CBMC in BGC-823, HepG-2, 7701, H460, H1299 and JF305 were 41.8, 31.4, 97.08, 256.14, 129.13 and 58.60μg/ mL, respectively.
6. In vivo CBMC can inhibit the growth of solid tumor in and prolong the life span of ascetic tumor mice. CBMC exhibits advanced function of anticancer, which displays better dose-effect relationship; CBMC with the better postponed life property and the inhibition the growth of tumor shows much higher than the dissociated MMC with equivalent quantities. The resuLts suggest that ANTC can stay on the local or can been guided to tumor tissues because of carrier effect of NPC, then high-concentration was formed at the local and ANTC was released.
7. The resuLts of pathological section and TEM showed that NPC can adhere on and entere into tumor tissues. Then, NPC can enter into tumor cells. The target molecuLes of NPC were cell nuclear, mitochondria and lysosome.
8. In vitro high dose of NPC can block the BGC-823 cell cycle in S phase which suggested that he synergistic action of NPC for anti-cancer drugs.
9. HPLC of CBMC in rats was established. Then the corresponding pharmacokinetic parameters were calcuLated. The resuLts showed that CBMC was eliminated slower, blood drug concentration lower and selectivity better than that of rats received intraperitoneal injection. The tissue drug concentration of ANTC in great epiploon, stomach , peritoneum, diaphragmatic and lymph was high than that of other tissues.
1.经高精度CPS纳米粒度仪对NPC纳米粒子表征,本实验所用NPC平均粒径为319±111 nm;
2. NPC对ANTC有很强大的吸附作用,25℃时,NPC吸附ANTC约0.5h即可达到平衡,且达平衡时间与NPC:ANTC质量比无关。NPC吸附ANTC的量M与溶液中游离ANTC浓度C符合经公式172*C0.145(R=0.953,P<0.0001),单位质量NPC可吸附ANTC的量最高可达285mg/g。
3.根据NPC吸附ANTC特点,建立了CBMC中试生产配方,并进行了中试制备,获得3批次CBMC,共计954支混悬注射剂;
4.用改良寇式法测定了NPC、ANTC和CBMC腹腔注射及静脉注射急性毒性,结果显示,NPC腹腔注射后LD50﹥4000mg/kg;静脉注射LD50约为308.52mg/kg;ANTC腹腔LD50约为5.83mg/kg,静脉注射LD50约为4.79mg/kg;CBMC腹腔注射LD50约为122.91mg/kg,毒性比含药量相等的ANTC低约3.5倍。
5.采用MTT法评价了CBMC对体外培养的6人癌细胞的细胞生长抑制作用的结果显示,NPC对体外培养的人癌细胞无明显的抑制生长作用,CBMC对体外培养的多种人癌细胞均有较强的抑制生长作用,具有较好的剂量效应关系,且其作用均显著高于相等浓度的游离ANTC组。经计算,CBMC作用于人胃癌BGC-823细胞48h时IC50为41.8μg/mL、人肝癌HepG-2细胞48h时IC50为31.4μg/ mL、人肝癌7701细胞48h时IC50为97.08μg/ mL、人肺鳞癌H460细胞48h时IC50为256.14μg/ mL、人非小细胞肺癌H1299细胞48h时IC50为129.13μg/ mL、人胰腺癌JF305细胞48h时IC50为58.60μg/ mL。
6.建立了6种肿瘤移植模型,包括白血病移植模型、腹水瘤移植模型及实体瘤移植模型评价CBMC的体内抗肿瘤作用。体内实验结果显示,CBMC对6种动物肿瘤模型均有显著的治疗作用,且具有较好的剂量-效应关系。含ANTC量相等的6mg/kgCBMC组其生命延长率及抑瘤率均显著高于1mg/kgANTC组。低剂量CBMC(2mg/kg)组其生命延长率及抑瘤率与1mg/kgANTC组无显著性差异。结果提示NPC的载体效应,即NPC由于其局部滞留性、肿瘤附着性及淋巴趋向性,可将ANTC滞留于给药局部或经过淋巴系统导向肿瘤组织,在肿瘤局部形成药物高浓度并经过缓慢释放维持药物浓度,使药物直接作用于肿瘤组织。
7.部分肿瘤病灶的病理切片及TEM观察结果显示[0],NPC可附着于肿瘤组织并进入肿瘤病灶,进而进入肿瘤细胞释放药物并杀伤肿瘤细胞,其细胞内靶分子主要为细胞核、线粒体、溶酶体。
8. NPC对BGC-823细胞周期影响的结果显示,大剂量NPC可将肿瘤细胞抑制于S期,NPC可能具有对化疗药物的增效作用。
9.建立了CBMC的HPLC测定方法;获得了CBMC和ANTC经腹腔注射后在大鼠体内的药代动力学参数及腹腔组织分布特点,结果显示,CBMC腹腔注射与ANTC相比具有消除慢、血药浓度低、选择性好等特点,其组织药物浓度以肿瘤细胞较易附着的大网膜、胃、腹膜、膈肌、淋巴结最高。
OBJECTIVE: To study the development and research of CBMC that is ANTC adsorbed by NPC. METHODS: The size of targeting carrier(NPC) was characterized by NPC; Adsorption features of NPC for ANTC was investigated by uLtraviolet spectrophotometer; Design and prepare the CBMC, the drug loading of which was specified, according to the resuLts of adsorption features of NPC; The release characteristics of CBMC was studied by HPLC; The LD50 of NPC, ANTC and CBMC was determined and compared; The anti-cancer effect of CBMC was studied by MTT; Then measured the dose-effect relationship and calcuLated the IC50 based on the MTT resuLts. The anti-cancer action of CBMC in vivo was studied by observing its effect on the animal tumor model. Meanwhile, the guiding effect of the CBMC to NPC is observed by conventional dye and TEM. The cell cycle was distinguished by PI staining was detected flow cytometer in order to explore the synergistic action of NPC for anti-cancer drugs. The peritoneal and plasma distribution in rats was studied by HPLC, then the corresponding pharmacokinetic parameters based on the time process of blood drug concentration were calcuLated.
RESULTS:
1. The average particle size was 319±111 nm for NPC.
2. NPC can absorb ANTC effectively and the absorption curve is consistent with exponential form 172*C0.145(R=0.953,P<0.0001) at 25℃. Reached equilibrium time of NPC for ANTC was about 0.5h, which was unrelated to the mass ratio of NPC to ANTC. The quantity of ANTC adsorbed by Per unit mass NPC was 285mg/g.
3. The production formuLa of CBMC was established according to the adsorption features of NPC for ANTC. 3 batches, totally 954 branches, CBMC injection was obtained by middle test.
4. LD50 of mice received intraperitoneal injection of NPC was more than 4000mg/kg. LD50 of mice received intravenous injection of NPC was about 308.52mg/kg. LD50 of mice received intraperitoneal and intravenous injections of NPC were 5.83 and 4.97mg/kg. LD50 of mice received intraperitoneal injection of CBMC was about 122.91mg/kg. Toxicity of CBMC was 3.5 times that of ANTC.
5. CBMC exhibits advanced function of anticancer, which displays better dose-effect relationship. The inhibitory concentration 50%(IC50) of CBMC in BGC-823, HepG-2, 7701, H460, H1299 and JF305 were 41.8, 31.4, 97.08, 256.14, 129.13 and 58.60μg/ mL, respectively.
6. In vivo CBMC can inhibit the growth of solid tumor in and prolong the life span of ascetic tumor mice. CBMC exhibits advanced function of anticancer, which displays better dose-effect relationship; CBMC with the better postponed life property and the inhibition the growth of tumor shows much higher than the dissociated MMC with equivalent quantities. The resuLts suggest that ANTC can stay on the local or can been guided to tumor tissues because of carrier effect of NPC, then high-concentration was formed at the local and ANTC was released.
7. The resuLts of pathological section and TEM showed that NPC can adhere on and entere into tumor tissues. Then, NPC can enter into tumor cells. The target molecuLes of NPC were cell nuclear, mitochondria and lysosome.
8. In vitro high dose of NPC can block the BGC-823 cell cycle in S phase which suggested that he synergistic action of NPC for anti-cancer drugs.
9. HPLC of CBMC in rats was established. Then the corresponding pharmacokinetic parameters were calcuLated. The resuLts showed that CBMC was eliminated slower, blood drug concentration lower and selectivity better than that of rats received intraperitoneal injection. The tissue drug concentration of ANTC in great epiploon, stomach , peritoneum, diaphragmatic and lymph was high than that of other tissues.
引文
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