聚合物胶束载药系统的研究进展

摘要/Abstract

摘要： 聚合物胶束（polymeric micelles）通常由具有两亲性或带有反向电荷的共聚物在水中聚集而成。疏水性嵌段和亲水性嵌段构成胶束的核-壳结构。拥有亲水性外壳以及纳米级粒径（约为10-100nm）的聚合物胶束不仅能够使其不易被网状内皮系统（reticuloendothelial system，RES）识别吞噬，并且可以通过实体瘤的高通透性和滞留效应（enhanced permeability and retention effect，EPR效应）实现药物胶束对癌组织和炎性组织的被动靶向作用。聚合物胶束可以作为抗癌、抗炎、基因治疗药物的载体。本文总结并分析了聚合物胶束的研究进展，包括胶束的分类组成、制备、胶束的特征、药物胶束的释放以及聚合物胶束的应用。

关键词: 纳米, 聚合物胶束, 药物载体

Abstract: Polymeric micelles are composed by copolymers, which are amphiphilic or oppositely charged in the aqueous solution. The hydrophobic and hydrophilic blocks form core and shell structure of the polymeric micelles. The hydrophilic shell and nanoscale particle size (10-100nm) of the polymeric micelles not only escape recognizing and up taking by the reticuloendothelial system (RES), but also passively target cancer and inflammatory tissue by enhanced permeability and retention effect (EPR). Polymeric micelles are the carrier of anti-cancer, anti-inflammatory and gene therapy medicine. In this review, we summarized the progress of the polymeric micelles, including the classification of the polymeric micelles, micelles preparation, characteristics, drug release and the application of the polymeric micelles.

Key words: nanoscale, polymeric micelles, drug carrier

中图分类号:

R944.9

宗蕊, 沈丽霞. 聚合物胶束载药系统的研究进展[J]. 神经药理学报, 2015, 5(6): 21-29.

ZONG Rui, SHEN Li-xia. Polymeric Micelles for Drug Delivery[J]. Acta Neuropharmacologica, 2015, 5(6): 21-29.

参考文献

[1]Nobuhiro Nishiyama, Yasuhiro Matsumura, Kazunori Kataoka. Development of polymeric micelles for tageting intractable cancers[J]. Cancer Sci, 2016, 107(7): 867-874.

[2]Aya Aoki. Novel gene transfer using micellar nanovectors inhibits choroidal neovascularization[J]. Nippon Ganka Gakkai Zasshi, 2013, 117(11): 869-877.

[3]Nobuhiro Nishiyama, Souichiro Okazaki, Horacio Cabral, et al. Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice[J]. Cancer Res, 2003, 63(24), 8977-8983.

[4]Cheng Yi-long. Poly(ethylene glycol)-polypeptide copolymer micelles for therapeutic agent delivery[J]. Curr Pharm Biotechnol, 2016, 17(3): 212-26.

[5]沈丹, 吕娟丽, 李彦. 两亲性聚合物胶束作为药物载体研究进展[J]. 武警医学院学报, 2008, 17(3): 237-240.

[6]Avinash Gothwal, Iliyas Khan, Umesh Gupa. Polymeric micelles: recent advancements in the delivery of anticancer drugs[J]. Pharm Res, 2016, 33(1): 18-39.

[7]Daniel Bobo, Kye J Robinson, Jiaul Islam, et al. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date[J]. Pharm Res, 2016, 33(10): 2373-2387.

[8]Hu Fu-qiang, Zhao Meng-dan, Yuan Hong, et al. A novel chitosan oligosaccharide-stearic acid micelles for gene delivery: Properties and in vitro transfection studies[J]. Int J Pharm, 2006, 315(1-2): 158 -166.

[9]Anatoly N Lukyanov, Vladimir P Torchilin. Micelles from lipid derivatives of water-Soluble polymers as delivery systems for poorly soluble drugs[J]. Adv Drug Deliv Rev, 2004, 56(9): 1273 -1289.

[10]徐建平, 陈伟东, 计剑, 等. 新型仿生聚合物胶束用于纳米药物载体的研究[J].高等学校化学学报, 2007, 28(2): 394-396.

[11]Afsaneh Lavasanifar, John Samuel, Glen S Kwon. Poly(ethylene oxide)-block-poly(L-amino acid) micelles for drug delivery[J]. Adv Drug Deliv Rev, 2002, 54 (2): 169-190.

[12]Hugo Almeida, Maria Helena Amaral, Paulo Lobao, et al. Applications of poloxamers in ophthalmic pharmaceutical formulations: an overview[J]. Expert Opin Drug Deliv, 2013, 10(9): 1223-1237.

[13]孙晓利. 新型载基因自组装聚离子复合物胶束的研究[D].济南：山东大学, 2011.

[14]Marie-Helene Dufresne, Jean-Christophe Leroux. Study of the micellization behavior of different order amino block copolymers with heparin[J]. Pharm Res, 2004, 21 (1): 160-169.

[15]Makoto Oba. Study on development of polymeric micellar gene carrier and evaluation of its functionality[J]. Bio Pharm Bull, 2013, 36(7): 1045-1051.

[16]Atsushi Harada, Kazunori Kataoka. Pronounced activity of enzymes through the incorporation into the core of polyion complex micelles made from charged block copolymers[J]. J Control Release, 2001, 72 (1-3): 85-91.

[17]刘佳, 姜同英, 王思玲. 聚离子复合物胶束的制备及其载药性质研究[J].中国药剂学杂志: 网络版, 2008, 6: 341-348.

[18]Lu Ying, Kinam Park. Polymeric micelles and alternative nanonized delivery vehicles for poorly soluble drugs[J]. Int J Pharm, 2013, 453(1): 198-214.

[19]张晓君, 王东凯, 韩晓. 聚合物胶束作为药物传递系统的研究进展[J].中国药剂学杂志: 网络版, 2009, 3: 177-183.

[20]Tian Ye, Mao Shi-rui. Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of pooly soluble anticancer drugs[J]. Expert Opinion on Drug Delivery, 2012, 9(6): 687-700.

[21]Eun Kyoung Park, So Yeon Kim, Sang Bong Lee, et al. Folate-conjugated methoxy poly(ethylene glycol) /poly(vepsiln-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery[J]. Controlled Release, 2005, 109(1-3): 158-168.

[22]Madhu Gupta, Govind P Agrawal, Suresh P Vyas. Polymeric nanomedicines as a promising vehicle for solid tumor therapy and targeting[J]. Curr Mol Med, 2013, 13(1): 179-204.

[23]Cho Heui Kyoung, Cho Jin Hun, Seong Hoon Jeong, et al. Polymeric vehicles for topical delivery and related analytical methods[J]. Archives of Pharmacal Research, 2014, 37(4): 432-434.

[24]Chloe Matin, Noorjahan Aibani, John F Callan, et al. Recent advances in amphiphilic polymers for simultaneous delivery of hydrophobic and hydrophilic drugs[J]. Ther Deliv, 2016, 7(1): 15-31.

[25]Vinayak P Sant, Damon Smith, Jean-Christophe Leroux. Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: prepatation and characterization[J]. Controlled Release, 2004, 97(2): 301-312.

[26]杜松, 左建国, 邓英杰. 叔丁醇-水共溶剂冷冻干燥工艺及其在药剂学中的应用[J].中国药剂学杂志: 网络版, 2006, 3: 116-121.

[27]Elvire Fournier, Marie-Helene Dufresne, Damon C Smith, et al. A novel one-step drug-loading procedure for watersoluble amphiphilic nanocarriers[J]. Pharm Res, 2004, 21(6): 962– 968.

[28]Gao Guang-hui, Li Yi, Lee Doo Sung. Enviromental pH-sensitive polymeric micelles for cancer diagnosis and targeted therapy[J]. J Control Release, 2013, 169(3): 180-184.

[29]Younsoo Bae, Nobuhiro Nishiyama, Shigeto Fukushima, et al. Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy[J]. Bioconjug Chem, 2005, 16(1): 122-130.

[30]Amaud E Felber, Marie-Helene Durfresne, Jean-Christophe Leroux. pH-sensitive vesicles, polymeric micelles, and nanospheres prepard with polycarboxylates[J]. Adv Drug Deliv Rev, 2012, 64(11): 979-992.

[31]Jun Akimoto, Masamichi Nakayama, Teruo Okano. Temperature-responsive polymeric micelles for optimizing drug targeting to solid tumors[J]. J Control Release, 2014, 193: 2-8.

[32]Alexander V Kabanov, Elena V Batrakova, Valery Yu Alakhov. An essential relationship between ATPdepletion and chemosensitizing activity ofPluronic block copolymers[J].J Control Release, 2003, 91(1-2): 75-83.

[33]Roubeena Jeetah, Archana Bhaw-Luximon, Dhanjay Jhurry. Polymeric nanomicelles for sustained delivery of anti-cancer drug[J]. Mutat Res, 2014, 768: 47-59.

[34]Ana C Silva, Carla Martins Lopes, J M Lobo. Delivery systems for biopharmaceuticas. Part Ⅱ: liposomes, micelles, microemulsions, and dendrimers[J]. Curr Pharm Biotechnol, 2015, 16(11): 955-65.

[35]Tatsuhiro Yamamoto, Masayuki Yokoyama, Praneet Opanasopit, et al. What are determining factors for stable drug incorporation into polymeric micelle carriers? Consideration on physical and chemical characters of the micelle inner core[J]. J Control Release, 2007, 123(1): 11-18.

[36]Daria Y Alakhova, Alexander V Kabanov. Pluronics and MDR reversal an update[J]. Mol Pharm, 2014, 11(8): 2566-2578.

[37]Wang Chun-yan, Jaya Mallela, Subhra Mohapatra. Pharmacokinetics of polymeric micelles for cancer treatment[J]. Curr Drug Metab, 2013, 14(8): 900-909.

[38]Mohammad Mahmoudzadeh, Afshin Fassihi, Jaber Emani, et al. Physicochemical, pharmaceutical and biological approaches toward designing optimized and efficient hydrophobically modified chitosan-based polymeric micelles as a nanocarrier system for targeted delivery of anticancer drugs[J]. J Drug Target, 2013, 21(8): 693-709.

[39]Xu He-lin, Yao Qing, Cai Cui-fang, et al. Amphiphilic poly(amino acid) based micelles applied to drug delivery: the in vitro and in vivo challenges and the corresponding potential strategies[J]. J Control Release, 2015, 199: 84-97.

[40]Yasuo Mizumura, Yasuhiro Matsumura, Masayuki Yokoyama, et al. Incorporation of the anticancer agent KRN 5500 into polymeric micelles diminishes the pulmonary toxicity[J]. Jpn J Cancer Res, 2002, 93(11): 1237-1243.

[41]Chu Zong-lin, Cecile A Dreiss, Feng Yu-jun. Smart wormlike micelles[J]. Chem Soc Rev, 2013, 42(17): 7174-7203.

[42]Rajesh Thipparaboina, Rahul B Chavan, Dinesh Kumar, et al. Micellar carrriers for the delivery of multiple therapeutic agents[J].Colloids Surf B Biointerfaces, 2015, 135: 291-308.

[43]Anupama Mittal, Deepak Chitkara. Structural modifications in polymeric micelles to impart multifunctionality for improved drug delivery[J]. Ther Deliv, 2016, 7(2):73-87.

[44]Afsaneh Lavasanifar, John Samuel, Glen S Kwon. Poly(ethylene oxide)-block-poly(L-amino acid)micelles for drug delivery[J]. Adv Drug Deliv Rev, 2002, 54(2): 169-190.

[45]Susana MN Simoes, Ana R Figueiras, Francisco Veiga, et al. Polymeric micelles for oral durg administration enabling locoregional and systemic treatments[J]. Expert Opin Drug Deliv, 2015, 12(2): 297-318.

[46]M S Muthu, David Tai Leong, Mei Lin, et al. Nanotheranostics-application and further development of nanomedicine strategies for advanced theranostics[J]. Theranostics, 2014, 4(6): 660-677.

[47]Elvire Fournier, Marie-Helene Dufresne, Damon C Smith, et al. A novel one-step drug-loading procedure for water-soluble amphiphilic nanocarriers[J]. Pharm Res, 2004, 21(6): 962-968.

[48]Diego A Chiappetta, Alejandro Sosnik. Poly(ethylene oxide)-poly(propylene oxide) block copolymer micelles as drug delivery agent: improved hydrosolubility, stability and bioavailability of drugs[J]. Eur J Pharm Biopharm, 2007, 66(3): 303-317.

[49]Li Zi-biao, Loh Xian Jun. Recent advances of using polyhydroxyalkanoate-based nanovehicles as therapeutic delivery carriers[J]. Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology, 2016, 10: 1002.

[50]Kevin Letchford, Helen Burt. A review of the formation and classification of amphiphilic block copolymer nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes[J]. Eur J Pharm Biopharm, 2007, 65(3): 259-269.

[51]Jana Drbohlavova, Jana Chomoucka, Vojtech Adam, et al. Nanocarriers for anticancer drugs-new trends in nanomedicine[J]. Curr Drug Metab, 2013, 14(5), 547-564.

[52]Tatsuhiro Yamamoto, Masayuki Yokoyama, Praneet Opanasopit, et al. What are determining factors for stable drug incorporation into polymeric micelle carriers? Consideration on physical and chemical characters of the micelle inner core[J]. Control Release, 2007, 123(1): 11-18.

[53]Masayuki Yokoyama. Polymeric micelles as drug carriers: their lights and shadows[J]. Drug Target, 2014, 22(7): 576-583.

[54]Der-Zen Liu, Jui-Hsiang Hsieh, Xian-Chan Fa, et al. Synthesis, characterization and drug delivery behaviors of new PCP polymeric micelles[J]. Carbohydrate Polym, 2007, 68: 544-554.

[55]Ramanathan Nagarajan. “Non-equilibrium” block copolymer micelles with glassy cores: a predictive approach based on theory of equilibrium micelles[J]. J Colloid Interface Sci, 2015, 449: 416-27.

[56]Fabienne Danhier, Pierre Danhier, Christophe J De Saedeleer, et al. Paclitaxel-loaded micelles enhance transvascular permeability and retention of nanomedicine in tumors[J]. Int J Pharm, 2015, 479(2): 399-407.

[57]Hadi Khodabandeholl, Hamid Zahednasab, Asghar Ashrafi Hafez. Nanocarriers usage for drug delivery in Cancer Therapy[J]. Iran J Cancer Prev, 2016, 24: 9(2).

[58]Eun Seong Lee, Hyun Joon Shin, Na Kun, et al. Poly(L-histidine) 2 PEG block copolymer micelles and pH-induced destabilization [J]. Cont rolled Release, 2003, 90(3): 363-374.

[59]Nobuhiro Nishiyama, Souichiro Okazaki, Horacio Cabral, et al. Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice[J]. Cancer Res, 2003, 63(24): 8977–8983.

[60]Hee Kyung Ahn, Minkyu Jung, Sun Jin Sym, et al. A phase Ⅱ trial of cremorphor EL-free paclitaxel(Genexol-PM) and gemcitabine in patients with advanced non-small cell lung cancer[J]. Cancer Chemother Pharmacol, 2014, 74(2): 277-282.

[61]Gelderblom H, Verweij J, Nooter K, et al. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation[J]. Eur J Cancer, 2001, 37(13): 1590–1598.

[62]Ghareb M Soliman, Angela O Choi, Dusica Maysinger, et al. Minocycline block copolymer micelles and their anti-inflammatory effects on microglia[J]. Macormol Biosic, 2010, 10(3): 278-288.

[63]Toru Yoshitomi, Sha Sha, Long Vong, et al. Indomethacin-loaded redox nanoparticles improve oral bioavailability of indomethacin and suppress its small intestinal inflammation[J]. Ther Deliv, 2014, 5(1): 29-38.

[64]Wu Wei, He Zhi-fen, Zhang Zhao-liang, et al. Intravitreal injection of rapamycin-loaded polymeric micelles for inhibition of ocular inflammation in rat model[J]. Int J Pharm, 2016, 513(1-2): 238-246.

[65]Wang Qin, Jiang Hao, Li Yan, et al. Targeting NF-κB signaling with polymeric hybrid micelles that co-deliver siRNA and dexamethasone for arthritis therapy[J]. Biomaterials, 2017, 122: 10-22.

[66]Chen Qi-xian, Kensuke Osada, Matthew Pennisi, et al. A tadpote-shaped gene carrier with distinct phase segregation in a ternary micelle[J]. Soft Matter, 2015, 11(14): 2718-2722.

[67]Han-Nah Kim, Jin Lee, Hae-Yeong Kim, et al. Enzymatic synthesis of a drug delivery system based on polyhydroxyalkanoate-protein block copolymers[J]. Chem Commun(Camb), 2009, 14(46): 7104-7106.