用于治疗非小细胞肺癌的阿法替尼脂质体的制备与包封率的测定
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摘要
背景与目的阿法替尼是针对非小细胞肺癌及继发性耐药研发的第二代不可逆表皮生长因子受体抑制剂,目前仅停留在口服给药方式,其生物利用度低,不良反应较多。本研究旨在制备新型药物传递系统-阿法替尼脂质体,并建立包封率的测定方法。方法 4种不同方法制备阿法替尼脂质体,通过对比包封率和粒径确定最佳制备工艺。结果经验证可采用葡聚糖凝胶微柱离心法纯化脂质体,并通过紫外分光光度法测定脂质体的包封率。不同制备方法中硫酸铵梯度法制备的脂质体,包封率约为90.73%,平均粒径为108.6 nm。结论硫酸铵梯度法制备阿法替尼脂质体包封率高、粒径小,紫外分光光度法用来测定脂质体的包封率简单易行、准确度高。
Background and objective Afatinib, a second-generation irreversible epidermal growth factor inhibitor receptor for the development of non-small cell lung cancer and secondary drug resistance, has low bioavailability and adverse reactions due to current oral administration. The aim of this study was to prepare a novel drug delivery system, afatinib liposome, and to establish a method for the determination of encapsulation efficiency. Methods Four different preparation methods were used to prepare afatinib liposomes, and the optimal preparation process was determined by comparing the encapsulation efficiency and particle size. Results It has been verified that sephadex microcolumn centrifugation can be used to purify afatinib liposomes, and UV spectrophotometry can be employed to determine the entrapment efficiency of liposomes. Among different preparation methods, the encapsulation efficiency of afatinib liposomes prepared by ammonium sulfate gradient method was 90.73% and the average particle size was 108.6 nm. Conclusion Ammonium sulfate gradient method can be successfully applied to prepare afatinib liposomes that performed higher encapsulation efficiency and smaller particle size. The UV spectrophotometry employed to determine the liposome encapsulation efficiency was easy operation and with high accuracy.
Background and objective Afatinib, a second-generation irreversible epidermal growth factor inhibitor receptor for the development of non-small cell lung cancer and secondary drug resistance, has low bioavailability and adverse reactions due to current oral administration. The aim of this study was to prepare a novel drug delivery system, afatinib liposome, and to establish a method for the determination of encapsulation efficiency. Methods Four different preparation methods were used to prepare afatinib liposomes, and the optimal preparation process was determined by comparing the encapsulation efficiency and particle size. Results It has been verified that sephadex microcolumn centrifugation can be used to purify afatinib liposomes, and UV spectrophotometry can be employed to determine the entrapment efficiency of liposomes. Among different preparation methods, the encapsulation efficiency of afatinib liposomes prepared by ammonium sulfate gradient method was 90.73% and the average particle size was 108.6 nm. Conclusion Ammonium sulfate gradient method can be successfully applied to prepare afatinib liposomes that performed higher encapsulation efficiency and smaller particle size. The UV spectrophotometry employed to determine the liposome encapsulation efficiency was easy operation and with high accuracy.
引文
1Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. J CA Cancer J Clin, 2016, 66(2):115-132. doi:10.3322/caac.21338
2 HottaK,Sasak iJ,Saek iS,etal.Gefitinibcombinedwithstandard chemoradiotherapy in eg fr-mutant locally advanced non-small-cell lung cancer:the logik0902/olcsg0905 intergroup study protocol. J Clin Lung Cancer, 2016, 17(1):75-79. doi:10.1016/j.cllc.2015.08.004
3 Janjigian Y Y, Smit EF, Groen HJM, et al. Dual Inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. J Caner Discov, 2014, 4(9):1036-1045. doi:10.1158/2159-8290.CD-14-0326
4 Pirazzoli V, Ayeni D, Meador CB, et al. Afatinib plus cetuximab delays resistance compared to single agent erlotinib or afatinib in mouse models of TKI-naive EGFR L858R-induced lung adenocarcinoma. J Clin Cancer Res, 2016, 22(2):426-435. doi:10.1158/1078-0432.CCR-15-0620
5 Brückl W, Tufman A, Huber R M. Advanced non-small cell lung cancer(NSCLC)with activating EGFR mutations:First-line treatment with afatinib and other EGFR TK Is. J Expert Rev Anticanc, 2016, 17(2):143 -155. doi:10.1080/14737140.2017.1266265
6 Stopfer P, Marzin K, Narjes H,et al. A fatinib pharmacokinetics and metabolismaf teroraladministrationtohealthymalevolunteers.JCancerChemothPharm,2012,69(4):1051-1061.doi:10.10 07/s00280-011-1803-9
7 Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3:a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol, 2013, 31(27):3342-3350. doi:10.1200/JCO.2012.46.1764
8 KatakamiN,AtagiS,GotoK,etal.LUX-Lung4:aphaseIItrialof afatinibinpatientswithadvancednon-small-celllungcancerwho progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol, 2013, 31(27):3335-3341. doi:10.1200/JCO.2012.45.0981
9 Harbeck N, Huang CS, Hurvitz S, et al. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment(LUX-Breast 1):an open-label, randomised,phase3 trial.J Lancet Oncol,2016,17(3):357-366.doi:10.1016/S1470-2045(15)00540-9
10 Uchibori K, Inase N, Araki M,et al.Brigatinib combined with antiEGFR antibody overcomes osimertinib resistance inEGFR-mutated non-small-cell lung cancer. J Nat Commun, 2017, 87:1468. doi:10.1038/ncomms14768
2 HottaK,Sasak iJ,Saek iS,etal.Gefitinibcombinedwithstandard chemoradiotherapy in eg fr-mutant locally advanced non-small-cell lung cancer:the logik0902/olcsg0905 intergroup study protocol. J Clin Lung Cancer, 2016, 17(1):75-79. doi:10.1016/j.cllc.2015.08.004
3 Janjigian Y Y, Smit EF, Groen HJM, et al. Dual Inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. J Caner Discov, 2014, 4(9):1036-1045. doi:10.1158/2159-8290.CD-14-0326
4 Pirazzoli V, Ayeni D, Meador CB, et al. Afatinib plus cetuximab delays resistance compared to single agent erlotinib or afatinib in mouse models of TKI-naive EGFR L858R-induced lung adenocarcinoma. J Clin Cancer Res, 2016, 22(2):426-435. doi:10.1158/1078-0432.CCR-15-0620
5 Brückl W, Tufman A, Huber R M. Advanced non-small cell lung cancer(NSCLC)with activating EGFR mutations:First-line treatment with afatinib and other EGFR TK Is. J Expert Rev Anticanc, 2016, 17(2):143 -155. doi:10.1080/14737140.2017.1266265
6 Stopfer P, Marzin K, Narjes H,et al. A fatinib pharmacokinetics and metabolismaf teroraladministrationtohealthymalevolunteers.JCancerChemothPharm,2012,69(4):1051-1061.doi:10.10 07/s00280-011-1803-9
7 Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3:a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol, 2013, 31(27):3342-3350. doi:10.1200/JCO.2012.46.1764
8 KatakamiN,AtagiS,GotoK,etal.LUX-Lung4:aphaseIItrialof afatinibinpatientswithadvancednon-small-celllungcancerwho progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol, 2013, 31(27):3335-3341. doi:10.1200/JCO.2012.45.0981
9 Harbeck N, Huang CS, Hurvitz S, et al. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment(LUX-Breast 1):an open-label, randomised,phase3 trial.J Lancet Oncol,2016,17(3):357-366.doi:10.1016/S1470-2045(15)00540-9
10 Uchibori K, Inase N, Araki M,et al.Brigatinib combined with antiEGFR antibody overcomes osimertinib resistance inEGFR-mutated non-small-cell lung cancer. J Nat Commun, 2017, 87:1468. doi:10.1038/ncomms14768