目的 制备一种癌细胞膜修饰的仿生纳米靶向药物,并探讨其在乳腺癌治疗中的作用。方法 采用薄膜水化法制备药物乳糖多柔比星包载多柔比星(lac-DOX/DOX),同时提取小鼠乳腺癌细胞4T1的细胞膜,通过超声法将细胞膜包覆在lac-DOX/DOX外面,制备出lac-DOX/DOX@4T1m。测量其粒径、电位并通过透射电子显微镜观察lac-DOX/DOX@4T1m的形貌;通过凝胶电泳对4T1细胞膜上蛋白质成分进行分析;通过体外细胞摄取实验和小动物活体成像实验评价药物在体内外对同源癌细胞的靶向性;构建4T1荷瘤Balb/c小鼠模型,对lac-DOX/DOX@4T1的抗肿瘤效果及生物安全性做出评价。结果 成功制备lac-DOX/DOX@4T1m仿生纳米药物,平均粒径为(204.8±13.0)nm,在电镜下呈规则球状结构,且蛋白质完好地保留在细胞膜表面;细胞摄取实验和小动物活体成像实验结果显示,lac-DOX/DOX@4T1m对4T1细胞有靶向性;药效实验结果显示,lac-DOX/DOX@4T1m能更有效地抑制肿瘤生长,同时对肝功能的损伤显著降低。结论 本实验成功制备了一种仿生纳米药物,提高了对肿瘤的靶向性及治疗效果,降低了多柔比星的毒副作用,提高了用药安全性。
Abstract
OBJECTIVE To investigate a biomimetic nano-targeted drug modifide by cancer cell membrane and to discuss its efficiency in breast cancer. METHODS The lac-DOX/DOX was prepared by filming-rehydration method, and the 4T1 cell membrane was extracted at the same time. The lac-DOX /DOX@4T1m was prepared by sonication method.. The morphology of lac-DOX /DOX@4T1m was observed by a transmission electron microscopy. The protein on 4T1 cell membrane was analyzed by gel electrophoresis. The targeting of drugs to homologous cancer cells in vivo and in vitro were evaluated by cell uptake experiments and imaging experiments of small animals. 4T1 tumor-bearing Balb/c mice were built, the anti-tumor efficacy and biosafety of lac-DOX/ DOX@4t1m were evaluated . RESULTS The prepared lac-DOX /DOX@4T1m have a regular spherical shape with an average particle diameter of (204.8±13.0)nm, and the protein entirety remained on the cell membrane. The results of cell uptake experiments and in vivo imaging experiments of mice showed that lac-DOX/DOX@4T1m can target 4T1 cells. Antitumor test results showed that lac-DOX/ DOX@4T1m could inhibit tumor growth more effectively and significantly reduce the damage to liver function. CONCLUSION In this study, a bionic nano-drug is successfully prepared, which improve the tumor targeting and therapeutic effect, reduce the toxic effects of adriamycin, and improve the drug safety.
关键词
癌细胞膜 /
多柔比星 /
乳腺癌 /
纳米胶束 /
靶向性
{{custom_keyword}} /
Key words
cancer cell membrane /
doxorubicin /
breast cancer /
nano-micelle /
target
{{custom_keyword}} /
中图分类号：
R944
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] SHAH S N, COPE L, POH W, et al. HMGA1:a master regulator of tumor progression in triple-negative breast cancer cells[J]. PLoS One, 2013, 8(5):e63419.
[2] FAN L, STRASSER-WEIPPL K, ST LOUIS J, et al. Breast cancer in China[J]. Lancet Oncol,2014, 5(7):279-289.
[3] JENNIFER C R. Cancer cancer immunotherapy[J]. Science, 2013, 342(6165):1432-1433.
[4] XU Y,LUO Y,WANG Z Y, et al. MRTF-A can activate Nrf2 to increase the resistance to doxorubicin[J]. Oncotarget, 2017, 8(5):8436-8446.
[5] CHU C Y,JIN Y T,ZHANG W, et al. CAIX is upregulated in CoCl 2-induced hypoxia and associated with cell invasive potential and a poor prognosis of breast cancer[J]. Int J Oncol,2016,48 (1):271-280.
[6] HORN C F, OSHIYO C, MARSH S, et al. Doxorubicin pathways:pharmacodynamics and adverse effects[J]. Pharmacogenet Genomics,2011,21(7):440-446.
[7] MOHEBBATI R, SHAFEI M N, SOUKHTANLOO M, et al. Adriamycin-induced oxidative stress is prevented by mixed hydro-alcoholic extract of nigella sativa and curcuma longain rat kidney[J]. Avicenna J Phytomed,2016,6(1):86-94.
[8] CREMERS H F M,VERRIJK R,NOTEBORN H P J M, et al. Adriamycin loading and release characteristics of albumin-heparin conjugate microspheres[J]. J Controlled Release,2017,29(1-2):143-155.
[9] ZHANG C Y, PAN D Y, LUO K, et al. Peptide dendrimer-doxorubicin conjugate-based nanoparticles as an enzyme-responsive drug delivery systerm for cancer therapy[J]. Adv Healthcare Mater, 2014, 3(8):1299-1308.
[10] MOU Q B, MA Y, ZHU X Y, et al. A small molecule nanodrug consisting of amphiphilic targeting ligand-chemotherapy drug conjugate for targeted cancer therapy[J]. J Controlled Release, 2016, 230:34-44.
[11] DENG G, SUN Z, LI S, et al. Cell-membrane immunotherapy based on natural killer cell membrane coated nanoparticles for the effective inhibition of primary and abscopal tumor growth[J]. ACS Nano, 2018, 12:12096-12108.
[12] YING M, ZHUANG J, WEI X K, et al. Remote-loaded platelet vesicles for disease-targeted delivery of therapeutics[J]. Adv Funct Mater, 2018,28(22):1801032.
[13] CAO H Q, DAN Z L, HE X Y, et al. Liposomes coated with isolated macrophage membrane can target lung metastasis of breast cancer[J]. ACS Nano, 2016, 10:7738-7748.
[14] PORAND C D, AMLEIDA PORAND G. Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery[J]. Adv Drug Deliv Rev, 2010, 62(12):1156-1166.
[15] DIANA DEHAINI, WEI X L, RONNIE H, et al. Erythrocyte-platelet hybrid membrane coating for enhanced nanoparticle functionalization[J]. Adv Mater, 2017, 29(16):1-18.
[16] SU J H, SUN H P, MENG Q S, et al. Long circulation red-blood-cell-mimetic nanoparticles with peptide-enhanced tumor penetration for simultaneously inhibiting growth and lung metastasis of breast cancer[J]. Adv Funct Mater, 2016, 26:1243-1252.
[17] SUN H, SU J, MENG Q, et al. Cancer-cell-biomimetic nanoparticles for targeted therapy of homotypic tumors[J]. Adv Mater, 2016, 28(43):9581-9588.
[18] ZHU J Y, ZHENG D W, ZHANG M K, et al. Preferential cancer cell self-recognition and tumor self-targeting by coating nanoparticles with homotypic cancer cell membranes[J]. Nano Lett, 2016, 16(9):5895-5901.
[19] ZHAO X Z. Cancer cell membrane-coated upconversion nanoprobes for highly specific tumor imaging[J]. Adv Mater, 2016, 28:3460-3466.
[20] HU C M J, ZHANG L, SANTOSH A, et al. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform[J]. PNAS, 2011, 108(27):10980-10985.
[21] FIDLER I J. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis[J]. Eur J Cancer, 1975, 9:223-227.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
国家重点研发计划纳米科技重点专项资助(2016YFA0201503)
{{custom_fund}}
PDF(7740 KB)
