表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒的研制及其对骨肉瘤靶向治疗
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摘要
目的：通过乳化聚合法制备出表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒(EPI-PBCA-MNPS),检测其理化表征,并检测药物在小鼠体内的靶向分布。通过体外肿瘤细胞实验研究其对MG-63及U2-OS两型人骨肉瘤细胞的作用,制作裸鼠移植肿瘤模型,观察表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒靶向治疗裸鼠移植性肿瘤的疗效。为骨肉瘤的靶向治疗提供一种新的可能性。
方法：(1)通过化学共沉淀和乳化聚合法,利用FeCl2-4H2O、FeCI3·6H2O、盐酸表阿霉素(EPI)、α-氰基丙烯酸正丁酯等试剂合成表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒。(2)用用电子透射显微镜镜下观测纳米粒的物理形态,用振动样品磁强计测定其饱和磁化强度,用紫外可见分光光度计检测其载药量、包封率,通过动物实验检测纳米粒在小鼠体内靶向分布。(3)通过CCK-8实验和Transwell实验检测表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒对MG-63及U2-OS两型人骨肉瘤细胞增殖和侵袭的影响。(4)制作裸鼠移植肿瘤模型,将表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒注射到裸鼠体内,观察纳米粒靶向治疗裸鼠移植性肿瘤的疗效。
结果：成功制备了性质稳定的磁性纳米胶体溶液,透射电镜测其平均粒径为184.6nm,振动样品磁强计测其饱和磁化强度为0.558emu/g,紫外可见分光光度计检测其包封率为90.73%,载药量为10.68%。磁性纳米粒在外加磁场的作用下富集于靶器官,非靶器官(血、心、肝、肺)中药物浓度显著降低。CCK-8实验表明磁性纳米粒对MG-63及U2-OS两型人骨肉瘤细胞增殖具有抑制作用,Transwell实验表明该药物能降低两型骨肉瘤细胞的侵袭能力。将磁性纳米药物通过尾静脉注射到裸鼠肿瘤模型体内,再在肿瘤部位施加一定强度的磁场,结果表明其抑瘤效果明显,其肿瘤体积抑制率为96.26%,肿瘤质量抑制率为88.82%。观察瘤体制作成的病理切片显示,肿瘤细胞坏死明显。
结论：该方法所制备的表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒制作上艺简单,性质稳定,药物包封率和载药量高,在磁场下具有较强的靶向性,毒副作用小,体外实验表明表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒对MG-63及U2-OS两型人骨肉瘤细胞的增殖和侵袭均具有抑制作用,肿瘤模型实验表明,表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒明显抑制裸鼠移植性骨肉瘤瘤体的生长率,且靶向性强。该药物有望成为一种新型的骨肉瘤化疗药物,为骨肉瘤的化疗提供新的可选方案。
Objective:to prepare the epirubicin-polybutylcyanoacrylate magnetic nanoparticles (EPI-PBCA-MNPS) by emulsion polymerization method,examine its physical and chemical properties,and inspect its targeted distribution in mice. Type MG-63and U2-OS human osteosarcoma cells by tumor cells in vitro experimental study, produced in nude mice transplanted tumor model, observe the targeted therapy efficacy of EPI-PBCA-MNPS by the transplanted tumor in nude mice. Provide a new possibility for the targeted treatment of osteosarcoma.
Methods:(1)we synthesis EPI-PBCA-MNPS by chemical co-precipitation and emulsion polymerization using FeCl2·4H2O、 FeCl3·6H2O、the epirubicin hydrochloride adriamycin (EPI)、a-polybutylcyanoacrylate.(2) observe its physical form by the transmission electron microscope,measure its saturation magnetization using a vibrating sample magnetometer (VSM), measure the drug envelopment rate and the quantity of drug load of EPI by ultraviolet-visible light spectrophotometer inspect its targeted distribution in mice.(3)observe the proliferation and invasion of type MG-63and U2-OS human osteosarcoma cell by CCK-8and Transwell experiment.(4) produce nude mice transplanted tumor model, inject EPI-PBCA-MNPS into the nude mice to observe the efficacy of targeted therapy in nude mice transplanted tumor.
Results:Successfully prepared stable colloidal solution, its average particle size was184.6nm in transmission electron microscopy, the saturation magnetization was0.558emu/g, the drug envelopment rate was90.73%, and the quantity of drug load was10.68%. The magnetic nanoparticles enriched in the target organ, and the drug concentration was lower in the non-target organs (blood, heart, liver, lung) by the role of the external magnetic field. CCK-8experiment showed that the magnetic nanoparticles inhibit the proliferation of type MG-63and U2-OS human osteosarcoma cells, Transwell experiments showed that the drug can reduce invasion of the two type cells. Injection the magnetic nanoparticle drug into the nude mice t umor model, a certain strength of the magnetic field is applied to the tumor site, results showed an obvious inhibitory effect, inhibition rate of tumor volume was96.26%, inhibition rate of tumor weight was88.82%. The tumor biopsy showed an obvious tumor necrosis.
Conclusion:The magnetic nanoparticle we prepared showed some good characteristics such as good stability, strong targeting, high drug envelopment rate and quantity of drug load and simple preparative method. The vitro experiments showed EPI-PBCA-MNPS inhibited the proliferation and invasion of type MG-63and U2-OS human osteosarcoma cell. Tumor model experiment showed that, EPI-PBCA-MNPS significantly inhibited the growth rate of nude mice transplanted osteosarcoma tumor with a strong target. The drug was expected to become a new type of osteosarcoma chemotherapy drugs, and to provide new options for osteosarcoma chemotherapy.
方法：(1)通过化学共沉淀和乳化聚合法,利用FeCl2-4H2O、FeCI3·6H2O、盐酸表阿霉素(EPI)、α-氰基丙烯酸正丁酯等试剂合成表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒。(2)用用电子透射显微镜镜下观测纳米粒的物理形态,用振动样品磁强计测定其饱和磁化强度,用紫外可见分光光度计检测其载药量、包封率,通过动物实验检测纳米粒在小鼠体内靶向分布。(3)通过CCK-8实验和Transwell实验检测表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒对MG-63及U2-OS两型人骨肉瘤细胞增殖和侵袭的影响。(4)制作裸鼠移植肿瘤模型,将表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒注射到裸鼠体内,观察纳米粒靶向治疗裸鼠移植性肿瘤的疗效。
结果：成功制备了性质稳定的磁性纳米胶体溶液,透射电镜测其平均粒径为184.6nm,振动样品磁强计测其饱和磁化强度为0.558emu/g,紫外可见分光光度计检测其包封率为90.73%,载药量为10.68%。磁性纳米粒在外加磁场的作用下富集于靶器官,非靶器官(血、心、肝、肺)中药物浓度显著降低。CCK-8实验表明磁性纳米粒对MG-63及U2-OS两型人骨肉瘤细胞增殖具有抑制作用,Transwell实验表明该药物能降低两型骨肉瘤细胞的侵袭能力。将磁性纳米药物通过尾静脉注射到裸鼠肿瘤模型体内,再在肿瘤部位施加一定强度的磁场,结果表明其抑瘤效果明显,其肿瘤体积抑制率为96.26%,肿瘤质量抑制率为88.82%。观察瘤体制作成的病理切片显示,肿瘤细胞坏死明显。
结论：该方法所制备的表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒制作上艺简单,性质稳定,药物包封率和载药量高,在磁场下具有较强的靶向性,毒副作用小,体外实验表明表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒对MG-63及U2-OS两型人骨肉瘤细胞的增殖和侵袭均具有抑制作用,肿瘤模型实验表明,表阿霉素聚氰基丙烯酸正丁酯磁性纳米粒明显抑制裸鼠移植性骨肉瘤瘤体的生长率,且靶向性强。该药物有望成为一种新型的骨肉瘤化疗药物,为骨肉瘤的化疗提供新的可选方案。
Objective:to prepare the epirubicin-polybutylcyanoacrylate magnetic nanoparticles (EPI-PBCA-MNPS) by emulsion polymerization method,examine its physical and chemical properties,and inspect its targeted distribution in mice. Type MG-63and U2-OS human osteosarcoma cells by tumor cells in vitro experimental study, produced in nude mice transplanted tumor model, observe the targeted therapy efficacy of EPI-PBCA-MNPS by the transplanted tumor in nude mice. Provide a new possibility for the targeted treatment of osteosarcoma.
Methods:(1)we synthesis EPI-PBCA-MNPS by chemical co-precipitation and emulsion polymerization using FeCl2·4H2O、 FeCl3·6H2O、the epirubicin hydrochloride adriamycin (EPI)、a-polybutylcyanoacrylate.(2) observe its physical form by the transmission electron microscope,measure its saturation magnetization using a vibrating sample magnetometer (VSM), measure the drug envelopment rate and the quantity of drug load of EPI by ultraviolet-visible light spectrophotometer inspect its targeted distribution in mice.(3)observe the proliferation and invasion of type MG-63and U2-OS human osteosarcoma cell by CCK-8and Transwell experiment.(4) produce nude mice transplanted tumor model, inject EPI-PBCA-MNPS into the nude mice to observe the efficacy of targeted therapy in nude mice transplanted tumor.
Results:Successfully prepared stable colloidal solution, its average particle size was184.6nm in transmission electron microscopy, the saturation magnetization was0.558emu/g, the drug envelopment rate was90.73%, and the quantity of drug load was10.68%. The magnetic nanoparticles enriched in the target organ, and the drug concentration was lower in the non-target organs (blood, heart, liver, lung) by the role of the external magnetic field. CCK-8experiment showed that the magnetic nanoparticles inhibit the proliferation of type MG-63and U2-OS human osteosarcoma cells, Transwell experiments showed that the drug can reduce invasion of the two type cells. Injection the magnetic nanoparticle drug into the nude mice t umor model, a certain strength of the magnetic field is applied to the tumor site, results showed an obvious inhibitory effect, inhibition rate of tumor volume was96.26%, inhibition rate of tumor weight was88.82%. The tumor biopsy showed an obvious tumor necrosis.
Conclusion:The magnetic nanoparticle we prepared showed some good characteristics such as good stability, strong targeting, high drug envelopment rate and quantity of drug load and simple preparative method. The vitro experiments showed EPI-PBCA-MNPS inhibited the proliferation and invasion of type MG-63and U2-OS human osteosarcoma cell. Tumor model experiment showed that, EPI-PBCA-MNPS significantly inhibited the growth rate of nude mice transplanted osteosarcoma tumor with a strong target. The drug was expected to become a new type of osteosarcoma chemotherapy drugs, and to provide new options for osteosarcoma chemotherapy.
引文
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[4]D, Uster P, Working P. Tumour uptake of doxorubicin in polyethylene glycol-coated liposomes and therapeutic effect against a xenografted human pancreatic carcinoma. [J].Cancer., 1997,75(4):482-6.
[5]Couvreur P, Kante B, Roland M, et al.[J].pharm.Pharmacol,1979,31:331.
[6]Brasseur F, Couvreur P, Kante B, et al. Eur.J.Cancer 1980,16:1441.
[7]Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles:theory to particle.[J] Pharmacol Rcv.2001,53:283-318.
[8]Lee JII, Jung SW, Kim IS, et al. Polymeric nanoparticle composed of fatty acids and poly (ethylene glycol) as a drug carrier.[J]Int J Pharm,2003,251:23-32.
[9]Davis CM, Boyett TM.Renal artery embolization:application and success in patients with renal cell carcinoma and angiomyolipoma. seminars in interventional radiology[J]. Case-Based Intcrventional Radiol,2007,24(1):111-116.
[10]Thomas DG, Giordano TJ, Sanders D, et al. Absence of HER2/neu gene expression in ostcosarcoma and Skeletal ewing's sarcoma[J].Clin Cancer Res,2002,8(3):788-793.
[11]Bielack S, Casali PG. Osteosarcoma:ESMO clinical recommendations for diagnosis, treatment and follow-up. Annals Of Oncology,2009,20:137-139.
[12]Bajpai J, Gamnagatti S, Kumar R, et al. Role of MRI in osteosarcoma for evaluation and prediction of chemotherapy response:correlation with histological necrosis. Pediatric Radiology,2011,41:441-450.
[13]Shin KH, Moon SI I, Suh JS, et al. Tumor volume change as a predictor of chemotherapeutic response in osteosarcoma. Clin Orthop Relat Res,2000:200-208.
[14]Ochi K, Daigo Y, Katagiri T, et al. Prediction of response to neoadjuvant chemotherapy for osteosarcoma by gene-expression profiles[J]. Int J Oncol 2004,24(3):647-655.
[15]Szekeres T, Novotuy L. New targets and drugs in cancer chemotherapy[]]. Med Princ Pract,2002,11(3):117-125.
[16]Patel SJ, Lynchjw Jr, Johnson T, et al. Dose-intense ifosfamide/doxorubicirdcisplafin based chemotherapy for osteosarcoma in adults[]]. Am J Clin Oncol,2002,25(5):489-495.
[17]Ek E, Dass C, Chconq P. Commonly used mouse models of osteosarcoma [J]. Crit Rev Oncol Hematol,2006,60(1):l-8.
[18]Dow S, Elmslie R, Kurzman I, et al. Phase I study of liposome-DNA complexes encoding the interleukin-2 gene in dogs with osteosarcoma lung metastasos[J]. Hum Gene Ther,2005, 16(8):937-946.
[19]Dobson J. Magnetic nanopartiicles for dmg delivery[J]. Drug Dev Res,2006,67(1):55-60.
[20]Huh Y M, Jun Y W, Song H T, et al. In ivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals [J]. J Amer Chem Soc,2005,127(35):12387-12391.
[21]Pumshotham S, Ramanujan R V. Thermore sponsive magnetic composite nanomaterials for multimodal cancer therapy [J]. Acta Biomater,2010,6(2):502-510.
[1]Langer R.Drug delivery and targeting. Nature.1998;392(6679):5-10.
[2]Archakov AI, Ivanov YD. Analytical nanobiotechnology for medicine diagnostics. Mol Biosyst. 2007;3(5):336-342.
[3]Goldberg M, Langer R, Jia X. Nanostructured materials for applications in drug delivery and tissue engineering. J Biomater Sci Polym Ed.2007; 18(3):241-268.
[4]Man M, He CX, Fang QL,et al. A Novel Camptothecin Derivative Incorporated in Nano-Carrier Induced Distinguished Improvement in Solubility, Stability and Anti-tumor Activity Both In Vitro and In Vivo. Phann Res.2009;26(4):926-935.
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