包载紫杉醇的透明质酸功能化乳剂对卵巢癌治疗效果研究
|
摘要
目的:制备紫杉醇(paclitaxel,PTX)的透明质酸固体纳米乳剂(PTX-HSNs)用于递送PTX,以改善卵巢癌治疗效果。方法:采用高压均质设备制造PTX-HSNs,对PTX-HSNs进行材料表征,并在体内外评估其性能。结果:PTX-HSNs平均粒径<100 nm,PTX包载量3 mg·mL~(-1),包封率(EE)接近100%。通过PTXHSN和不含乙酰透明质酸的PTX固体纳米乳剂(PTX-SNs)对SK-OV-3(分化簇44[CD_(44)~+])细胞和OVCAR-3(CD_(44)~-)细胞的作用比较,表明PTX-HSN与SK-OV-3细胞的亲和能力比PTX-SNs高上百倍。PTX-HSNs的最大耐受剂量(MTD)>50 mg PTX·kg~(-1),比Taxol高2.5倍。小鼠肿瘤移植中显示,PTX-HSN治疗比Taxol治疗毒性小,PTX-HSN有效抑制体内肿瘤生长。PTX-HSN治疗后,PTX的循环时间延长,PTX在卵巢肿瘤组织中的滞留增加。结论:PTX-HSN是具有高MTD的高效纳米系统,用于递送PTX至卵巢癌,并具有对CD44过表达肿瘤靶向和低毒性的特征。
Objective: To fabricate paclitaxel-loaded hyaluronan solid nanoemulsions( PTX-HSNs) for the delivery of PTX to improve ovarian cancer treatment via active tumor targeting. Methods: PTX-HSNs were fabricated using high-pressure homogenization and were lyophilized with d-mannitol. The outside of the PTX-HSNs spheres were coated with hyaluronan. Results: The mean size of the PTX-HSNs was maintained to be less than 100 nm,with a relatively narrow size distribution. The PTX loading content was 3 mg·mL~(-1),and encapsulation efficiency( EE) was close to 100%. The effects of PTX-HSNs and hyaluronan-free PTX-loaded solid nanoemulsions( PTXSNs) on SK-OV-3( cluster of differentiation 44 [CD_(44)~+]) cells and OVCAR-3( CD_(44)~-) cells were compared,and it was shown that PTX-HSNs had hundreds of times higher affinity for SK-OV-3 cells than PTX-SNs. The maximum tolerated dose( MTD) of PTX-HSNs was greater than 50 mg PTX·kg~(-1),which was 2. 5-fold higher than that of Taxol when administered by injection. Less toxicities were observed in tumor-transplanted mice compared to Taxol.The pharmacokinetic parameters of PTX-HSNs were more desirable than those of Taxol. PTX-HSNs treatment effectively inhibited tumor growth in vivo. After PTX-HSNs administration,the circulation time of PTX wasprolonged and the retention of PTX in ovarian tumor tissues was increased. Conclusion: PTX-HSNs is a highly effective nanosystem with a high MTD for delivering PTX to ovarian cancers characterized by CD44 overexpression,enhanced active tumor targeting,and low toxicity.
Objective: To fabricate paclitaxel-loaded hyaluronan solid nanoemulsions( PTX-HSNs) for the delivery of PTX to improve ovarian cancer treatment via active tumor targeting. Methods: PTX-HSNs were fabricated using high-pressure homogenization and were lyophilized with d-mannitol. The outside of the PTX-HSNs spheres were coated with hyaluronan. Results: The mean size of the PTX-HSNs was maintained to be less than 100 nm,with a relatively narrow size distribution. The PTX loading content was 3 mg·mL~(-1),and encapsulation efficiency( EE) was close to 100%. The effects of PTX-HSNs and hyaluronan-free PTX-loaded solid nanoemulsions( PTXSNs) on SK-OV-3( cluster of differentiation 44 [CD_(44)~+]) cells and OVCAR-3( CD_(44)~-) cells were compared,and it was shown that PTX-HSNs had hundreds of times higher affinity for SK-OV-3 cells than PTX-SNs. The maximum tolerated dose( MTD) of PTX-HSNs was greater than 50 mg PTX·kg~(-1),which was 2. 5-fold higher than that of Taxol when administered by injection. Less toxicities were observed in tumor-transplanted mice compared to Taxol.The pharmacokinetic parameters of PTX-HSNs were more desirable than those of Taxol. PTX-HSNs treatment effectively inhibited tumor growth in vivo. After PTX-HSNs administration,the circulation time of PTX wasprolonged and the retention of PTX in ovarian tumor tissues was increased. Conclusion: PTX-HSNs is a highly effective nanosystem with a high MTD for delivering PTX to ovarian cancers characterized by CD44 overexpression,enhanced active tumor targeting,and low toxicity.
引文
[1]JOURNO-GERSHFELD G,KAPP D,SHAMAY Y,et al.Hyaluronan oligomers-HPMA copolymer conjugates for targeting paclitaxel to CD44-overexpressing ovarian carcinoma[J].Pharm Res,2012,29(4):1121-1133.
[2]韩锐,何小庆,刘红岩,等.紫杉醇的抗肿瘤作用、药理及药代动力学研究[J].中国新药杂志,1996,5(4):10.
[3]杨秀丽,羊波,李承乐.HPLC测定紫杉醇纳米脂质体凝胶剂在小鼠皮肤中的含量[J].中国现代应用药学,2017,34(3):375-377.
[4]徐佳茗,夏学军,刘玉玲.紫杉醇新型制剂及临床研究进展[J].实用药物与临床,2016,19(4):510-517.
[5]LIEBMANN J,COOK J,MITCHELL J.Cremophor EL,solvent for paclitaxel,and toxicity[J].Lancet,1993,342(8884):1428.
[6]张超锋,高岩.分析纳米技术在药物制剂研究中的应用[J].临床医药文献电子杂志,2015,2(4):785-789.
[7]李树学,李德林,李志杰,等.纳米制剂研究进展[J].北方药学,2014,11(6):61-62.
[8]罗智琳,李娟.肿瘤靶向纳米递药系统的研究进展[J].医学信息,2010,23(6):1705-1706.
[9]孔晓龙,郭梅红,范颖,等.纳米靶向制剂的研究进展[J].广西医科大学学报,2015,32(4):682-685.
[10]ZHAO P,WANG H,YU M,et al.Paclitaxel loaded folic acid targeted nanoparticles of mixed lipid-shell and polymer-core:in vitro and in vivo evaluation[J].Eur J Pharm Biopharm,2012,81(2):248-256.
[11]孟路华,王驰.透明质酸及其衍生物在药物递送系统中的研究进展[J].中国新药杂志,2012,21(18):2165-2167.
[12]BATTISTINI FD,FLORES-MARTIN J,OLIVERA ME,et al.Hyaluronan as drug carrier.The in vitro efficacy and selectivity of Hyaluronan-Doxorubicin complexes to affect the viability of overexpressing CD44 receptor cells[J].Eur J Pharm Sci,2014,65:122-129.
[13]ZHAO D,GONG T,FU Y,et al.Lyophilized Cheliensisin A submicron emulsion for intravenous injection:characterization,in vitro and in vivo antitumor effect[J].Int J Pharm,2008,357(1):139-147.
[14]YANG XY,LI YX,LI M,et al.Hyaluronic acid-coated nanostructured lipid carriers for targeting paclitaxel to cancer[J].Cancer Lett,2013,334(2):338-345.
[15]PARK JH,CHO HJ,YOON HY,et al.Hyaluronic acid derivative-coated nanohybrid liposomes for cancer imaging and drug delivery[J].J Control Release,2014,174:98-108.
[16]LIU P,SITU JQ,LI WS,et al.High tolerated paclitaxel nanoformulation delivered by poly(lactic-co-glycolic acid)-g-dextran micelles to efficient cancer therapy[J].Nanomedicine,2015,11(4):855-866.
[17]LIU D,LIU F,LIU Z,et al.Tumor specific delivery and therapy by double-targeted nanostructured lipid carriers with anti-vegfr-2 antibody[J].Mol Pharm,2011,8(6):2291-2301.
[18]DAVIS ME,CHEN ZG,SHIN DM.Nanoparticle therapeutics:an emerging treatment modality for cancer[J].Nat Rev Drug Discov,2008,7(9):771-782.
[19]FANG J,NAKAMURA H,MAEDA H.The EPR effect:unique features of tumor blood vessels for drug delivery,factors involved,and limitations and augmentation of the effect[J].Adv Drug Deliv Rev,2011,63(3):136-151.
[20]MERCEALR,CARRERA LCM,ROMANHOLI LKS,et al.Aqueous and solid complexes of iron(III)with hyaluronic acid:potentiometric titrations and infrared spectroscopy studies[J].J Inorg Biochem,2002,89(3):212-218.
[21]KIM JE,PARK YJ.High paclitaxel-loaded and tumor cell-targeting hyaluronan-coated nanoemulsions[J].Colloids Surf B Biointerfaces,2017,150:362-372.
[2]韩锐,何小庆,刘红岩,等.紫杉醇的抗肿瘤作用、药理及药代动力学研究[J].中国新药杂志,1996,5(4):10.
[3]杨秀丽,羊波,李承乐.HPLC测定紫杉醇纳米脂质体凝胶剂在小鼠皮肤中的含量[J].中国现代应用药学,2017,34(3):375-377.
[4]徐佳茗,夏学军,刘玉玲.紫杉醇新型制剂及临床研究进展[J].实用药物与临床,2016,19(4):510-517.
[5]LIEBMANN J,COOK J,MITCHELL J.Cremophor EL,solvent for paclitaxel,and toxicity[J].Lancet,1993,342(8884):1428.
[6]张超锋,高岩.分析纳米技术在药物制剂研究中的应用[J].临床医药文献电子杂志,2015,2(4):785-789.
[7]李树学,李德林,李志杰,等.纳米制剂研究进展[J].北方药学,2014,11(6):61-62.
[8]罗智琳,李娟.肿瘤靶向纳米递药系统的研究进展[J].医学信息,2010,23(6):1705-1706.
[9]孔晓龙,郭梅红,范颖,等.纳米靶向制剂的研究进展[J].广西医科大学学报,2015,32(4):682-685.
[10]ZHAO P,WANG H,YU M,et al.Paclitaxel loaded folic acid targeted nanoparticles of mixed lipid-shell and polymer-core:in vitro and in vivo evaluation[J].Eur J Pharm Biopharm,2012,81(2):248-256.
[11]孟路华,王驰.透明质酸及其衍生物在药物递送系统中的研究进展[J].中国新药杂志,2012,21(18):2165-2167.
[12]BATTISTINI FD,FLORES-MARTIN J,OLIVERA ME,et al.Hyaluronan as drug carrier.The in vitro efficacy and selectivity of Hyaluronan-Doxorubicin complexes to affect the viability of overexpressing CD44 receptor cells[J].Eur J Pharm Sci,2014,65:122-129.
[13]ZHAO D,GONG T,FU Y,et al.Lyophilized Cheliensisin A submicron emulsion for intravenous injection:characterization,in vitro and in vivo antitumor effect[J].Int J Pharm,2008,357(1):139-147.
[14]YANG XY,LI YX,LI M,et al.Hyaluronic acid-coated nanostructured lipid carriers for targeting paclitaxel to cancer[J].Cancer Lett,2013,334(2):338-345.
[15]PARK JH,CHO HJ,YOON HY,et al.Hyaluronic acid derivative-coated nanohybrid liposomes for cancer imaging and drug delivery[J].J Control Release,2014,174:98-108.
[16]LIU P,SITU JQ,LI WS,et al.High tolerated paclitaxel nanoformulation delivered by poly(lactic-co-glycolic acid)-g-dextran micelles to efficient cancer therapy[J].Nanomedicine,2015,11(4):855-866.
[17]LIU D,LIU F,LIU Z,et al.Tumor specific delivery and therapy by double-targeted nanostructured lipid carriers with anti-vegfr-2 antibody[J].Mol Pharm,2011,8(6):2291-2301.
[18]DAVIS ME,CHEN ZG,SHIN DM.Nanoparticle therapeutics:an emerging treatment modality for cancer[J].Nat Rev Drug Discov,2008,7(9):771-782.
[19]FANG J,NAKAMURA H,MAEDA H.The EPR effect:unique features of tumor blood vessels for drug delivery,factors involved,and limitations and augmentation of the effect[J].Adv Drug Deliv Rev,2011,63(3):136-151.
[20]MERCEALR,CARRERA LCM,ROMANHOLI LKS,et al.Aqueous and solid complexes of iron(III)with hyaluronic acid:potentiometric titrations and infrared spectroscopy studies[J].J Inorg Biochem,2002,89(3):212-218.
[21]KIM JE,PARK YJ.High paclitaxel-loaded and tumor cell-targeting hyaluronan-coated nanoemulsions[J].Colloids Surf B Biointerfaces,2017,150:362-372.