目的 对于Cyclo (RGD)与R8肽共修饰麦角甾醇联合顺铂脂质体递药系统进行裸鼠体内靶向性及抗肺癌作用初步评价。方法 第一步,对造模成功的A549荷瘤裸鼠尾静脉注射包封有近红外DiR荧光染料的RGD环肽与R8肽修饰、单一RGD环肽修饰、单一R8肽修饰、不修饰麦角甾醇联合顺铂脂质体,在小动物活体成像仪下不同时间点下观察脂质体的体内分布并评价其靶向性。第二步,连续给药14 d,观测小鼠体重、肿瘤生长情况,于第14天处死动物,取血,并摘取各小鼠瘤组织、脾脏、肺组织,以瘤重、抑瘤率、血清转化生长因子-β1(TGF-β1)、组织金属蛋白酶抑制剂(TIMPs)、肿瘤坏死因子-α(TNF-α)水平、脾脏指数、瘤组织及肺脏的病理组织改变为指标,初步评价各脂质体在小鼠体内的抑瘤作用。结果 靶向性结果表明,RGD与R8共修饰脂质体在荷瘤裸鼠肿瘤部位的荧光强度最高,高浓度下靶向性最为明显,其他几组的靶向作用均较弱。初步药效学结果表明,各给药组对于小鼠体重无明显变化,RGD与R8共修饰脂质体高、中剂量组有明显抑瘤作用,其中,高剂量组抑瘤作用最为显著,且血清中高表达TNF-α细胞因子,RGD与R8共修饰脂质体中、低剂量组脾脏指数较阳性药组显著升高。结论 RGD环肽与R8肽共修饰麦角甾醇联合顺铂靶向脂质体递药系统,进一步提高了体内肿瘤靶向性及抗肺癌作用。
Abstract
OBJECTIVE To preliminarily evaluate the targeting and anti-lung cancer effect in vivo in nude mice induced by Cyclo (RGD) and R8 peptides modified ergosterol combined cisplatin liposomes. METHODS The first step, injected RGD cyclo peptide and R8 peptide-modified, single modified or no modified ergosterol combined cisplatin liposome in the caudal vein of nude mouse bearing the tumor, the body distribution and targeting of each group under the different time points through small animals living imager were observed. The second step, continuously, dose every other day for 14 d, observating the weight of mice and the tumor growth situation. The animals were drawed blood and then were put to death, removing the tumor, the spleen and the lung tissue of all the mice. As the index of the tumor weight, the tumor suppression effect, the level of TGF-β1, TIMPs and TNF-α in serum, the spleen index and changes of the tumor and lung tissue, investigate the tumor suppression effect in mice of the liposomes preliminary. RESULTS The targeting result of tumor-bearing nude mice displays that the fluorescence intensity of RGD and R8 peptides-modified liposome is the highest and the targeting is most obvious under high concentration and other group of liposome are weaker. Preliminary pharmacodynamics results show that each dosage group of mice have no obvious change in body weight and the high and middle dose group of RGD and R8 peptides-modified liposomes has tumor suppression effect obviously. The high dose group of RGD and R8 peptides-modified liposome is the most significant. It has high expression of cytokines (TNF-α) in serum. The spleen index of middle and low dose group of RGD and R8 peptides-modified liposomes significantly increased compared with positive medicine group. CONCLUSION RGD cyclo peptide and R8 peptide-modified ergosterol combined cisplatin targeting liposome drug delivery system further improves the tumor targeting and anti-lung cancer effect in vivo.
关键词
麦角甾醇 /
顺铂 /
脂质体 /
Cyclo /
R8肽 /
活体荧光成像 /
抑瘤作用
{{custom_keyword}} /
Key words
ergosterol /
cisplatin /
liposome /
RGD cyclopeptide /
R8 peptide /
in vivo fluorescence imaging /
tumor suppression effect
{{custom_keyword}} /
中图分类号：
R965
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] TU L X, XU Y H, TANG C Y, et al. In vivo imaging in tumor-bearing animals and pharmacokinetics of PEGylated liposomes modified with RGD cyclopeptide. Acta Pharm Sin(药学学报),2012,47(5):646-651.
[2] CHOI N, KIM S M, HONG K S, et al. The use of the fusion protein RGD-HAS-TIMP2 as a tumor targeting imaging probe for SPECT and PET. Biomaterials,2011, 32(29): 7151-7158.
[3] LI Z S, ZHOU R H, WANG L L, et al. Anti-cancer metastasis effect of RGD-based peptide-bound long-circulating liposome. Chin Pharm J(中国药学杂志),2002,37(6):422-424.
[4] ROBINSON S D, HODIVALA-DILKE K M. The role of β3-integrins in tumor angiogenesis: context is everything. Curr Opin Cell Biol,2011,23(5):630-637.
[5] IYER A K, KHALED G, FANG J, et al. Exploiting the enhanced perm eability and retention effect for tum or targeting. Drug Discov Today, 2006,11(17-18):812-818.
[6] ZHANG L, WANG P, LI Y H, et al. Cholesterol-PEG modified vinorelbine tartar liposomes. Chin Pharm J(中国药学杂志), 2010,45(24):1930-1932.
[7] MENG H, XUE M, XIA T, et al. Use of size and a copolymer design feature to improve the biodistrihution and the enhanced permeability and retention effect of doxorubicin-loaded mesoporous silica nanoparticles in a murine xenograft tumor model. Acs Nano,2011,5(5):4131-4144.
[8] JI Y H, YANG X Y, WANG L N, et al. Liposome particles modified with transferrin and arginine-glycine-aspartic acid peptide:laboratory preparation therapeutic potential against lung cancer. Chin J Cancer Biother(中国肿瘤生物治疗杂志),2015,22(3):299-303.
[9] YE Q S, LOU L G, LIU W P, et al. Research progress in targeted drug delivery of platinum antitumor drugs. Chin Pharm J(中国药学杂志),2008,43(20):1521-1529.
[10] KLARA S, CHEN J, ZHENG G. Using molecular beacons for cancer imaging and treatment. Front Biosci, 2007, 12(9):4709-4721.
[11] LIANG B, WANG Y, QIU Y Y, et al. Tumor-targeting efficiency of bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles in hepatocellular carcinoma-bearing nude mice. J Med Res,2013,42(8):37-39.
[12] WEI P P, ZHANG Z H, JIN X, et al. Preparation and antitumor activity of luteolin mixed micelles. Chin Pharm J(中国药学杂志), 2015,50(15):1330-1334.
[13] QIAN B Z, POLLARD J W. Macrophage diversity enhances tumor progression and metastasis. Cell,2010, 141(1):39-51.
[14] ZHAO C G, HUANG W H, WANG Z Y, et al. New progress in the study of transforming growth factor-β in idiopathic pulmonary fibrosis. Chin Pharm J(中国药学杂志), 2016, 51(5): 341-345.
[15] HUA S,DAN G N,SHEN J X, et al. TGF-β1 induces erlotinib resistance in non-small cell lung cancer by down-regulating PTEN. Biomed Pharmacother, 2015,77:1-6.
[16] YOKO T I, TOSHI Y, TOHRU O, et al. Up-regulation of syndecan-4 contributes to TGF-β1 induced epithelial to mesenchymal transition in lung adenocarcinoma A549 cells. Biochem Biophys Reports, 2016, 5(C):1-7.
[17] XIE M, HE C S, WEI S H. Relationship between expression of TGF-β1,Smad2,Smad4 and prognosis of patients with resected non-small cell lung cancer. Chin J Lung Cancer(中国肺癌杂志),2015, 18(9):543-548.
[18] SHAO B, NIE Q H. The current basic and clinical research situation of matrix metallopro- teinases tissue inhibitor (TIMPs). J Clin Hepatol(实用肝脏病杂志),2005,8(3):182-186.
[19] TIAN C Y. The status of TAMs and the expression of TNF-α and EGFR in NSCLC. Chengde: Chengde Med Coll,2014.
[20] MA M, ZHANG Y, GUO L H, et al. Study on the mechanism of inhibition of tumor necrosis factor-α by compound 1487B. Chin Pharm J(中国药学杂志),2015,50(20):1806-1810.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
国家自然科学基金项目资助(81473361);浙江省自然科学基金项目资助(LY16H280010)
{{custom_fund}}
PDF(6751 KB)
