Research progress of microsphere formulations with narrow size distribution

doi:10.11949/0438-1157.20211117

Abstract

Abstract:

Microsphere preparation is a new type of drug delivery system, and its particle size uniformity is very important. It not only affects the repeatability of product batches, but also affects the application effect. Therefore, manufacture of microspheres with uniform and controlled size play key role in microsphere formulations. Our team has studied on membrane emulsification technology for more than 20 years and successfully prepared various polymer microspheres with uniform and controlled size, and applied them in formulation application. The uniform microsphere formulations have the advantages of green production, low cost, good batch-to-batch repeatability, beneficial to scale up. Furthermore, the uniform size of microsphere helps to study the structure–drug efficacy relationships. The drug-loaded microspheres prepared by our team have been successfully applied in sustained-release formulations, vaccines delivery and malignant tumor treatment.

Key words: uniform size, microsphere formulations, membrane emulsification technique

摘要：

微球制剂是新型的给药系统，其粒径均一性非常重要，不仅影响产品批次间制备重复性，还会影响应用效果。因此，尺寸均一、可控的微球产品是医药制剂的关键核心。本团队成功发展了微孔膜乳化技术，20年来在粒径均一、尺寸可控微球的制备和应用方面进行了系统性研究。均一的微球制剂的优势有：绿色环保、降低成本，利于规模放大，批次间重复性好，利于研究构效关系。本团队制备的均一载药微球已成功应用于缓释制剂、疫苗递送及恶性肿瘤治疗中。

关键词: 尺寸均一, 微球制剂, 膜乳化技术

CLC Number:

Q 944.9

Yi WEI, Guanghui MA. Research progress of microsphere formulations with narrow size distribution[J]. CIESC Journal, 2021, 72(12): 6176-6187.

韦祎, 马光辉. 尺寸均一微球制剂的研究进展[J]. 化工学报, 2021, 72(12): 6176-6187.

Figures/Tables 4

References 85

1	Johnson O L, Cleland J L, Lee H J, et al. A month–long effect from a single injection of microencapsulated human growth hormone[J]. Nature Medicine, 1996, 2(7): 795-799.
2	Anderson J M, Shive M S. Biodegradation and biocompatibility of PLA and PLGA microspheres[J]. Advanced Drug Delivery Reviews, 1997, 28(1): 5-24.
3	陈庆华, 瞿文. 多肽、蛋白质药物的微球给药系统研究进展[J]. 国外医学药学分册, 1997, 24(3): 129-133.
	Chen Q H, Qu W. Progress of microsphere drug delivery system for peptide and protein drugs [J]. Foreign Medical Sciences Section on Pharmacy, 1997, 24(3): 129-133.
4	马光辉. 高分子微球用于蛋白质药物给药系统: 策略、制备及应用[C]//2012年全国高分子材料科学与工程研讨会论文集. 武汉, 2012: 518-519.
	Ma G H. Application of polymer microspheres in protein drug delivery system: strategy, preparation and application [C]// Proceedings of 2012 National Symposium on Polymer Materials Science and Engineering.Wuhan, 2012: 518-519.
5	包文超, 周加祥, 罗九甫, 等. 蛋白质/多肽类药物的可降解缓释微球制备方法和应用相关问题[J]. 化学世界, 2005, 46(1): 50-53.
	Bao W C, Zhou J X, Luo J F, et al. Biodegradable microspheres: a review[J]. Chemical World, 2005, 46(1): 50-53.
6	Xia Y J, Ribeiro P F, Pack D W. Controlled protein release from monodisperse biodegradable double-wall microspheres of controllable shell thickness[J]. Journal of Controlled Release, 2013, 172(3): 707-714.
7	Yang Y Y, Chen Q L, Lin J Y, et al. Recent advance in polymer based microspheric systems for controlled protein and peptide delivery[J]. Current Medicinal Chemistry, 2019, 26(13): 2285-2296.
8	Liu B, Dong Q, Wang M, et al. Preparation, characterization, and pharmacodynamics of exenatide-loaded poly(DL-lactic-co-glycolic acid) microspheres[J]. Chemical & Pharmaceutical Bulletin, 2010, 58(11): 1474-1479.
9	Berkland C, King M, Cox A, et al. Precise control of PLG microsphere size provides enhanced control of drug release rate[J]. Journal of Controlled Release, 2002, 82(1): 137-147.
10	Rhee Y S, Sohn M, Woo B H, et al. Sustained-release delivery of octreotide from biodegradable polymeric microspheres[J]. AAPS PharmSciTech, 2011, 12(4): 1293-1301.
11	Ma G H. Microencapsulation of protein drugs for drug delivery: strategy, preparation, and applications[J]. Journal of Controlled Release, 2014, 193: 324-340.
12	Li X, Wei Y, Lv P, et al. Preparation of ropivacaine loaded PLGA microspheres as controlled-release system with narrow size distribution and high loading efficiency[J]. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2019, 562: 237-246.
13	Wei Y, Wang Y X, Wang W, et al. mPEG-PLA microspheres with narrow size distribution increase the controlled release effect of recombinant human growth hormone[J]. Journal of Materials Chemistry, 2011, 21(34): 12691.
14	Wei Y, Wang Y, Kang A, et al. A novel sustained-release formulation of recombinant human growth hormone and its pharmacokinetic, pharmacodynamic and safety profiles[J]. Molecular Pharmaceutics, 2012, 9(7): 2039-2048.
15	Niwa T, Takeuchi H, Hino T, et al. In vitro drug release behavior of D, L-lactide/glycolide copolymer (PLGA) nanospheres with nafarelin acetate prepared by a novel spontaneous emulsification solvent diffusion method[J]. Journal of Pharmaceutical Sciences, 1994, 83(5): 727-732.
16	Rosenblum D, Joshi N, Tao W, et al. Progress and challenges towards targeted delivery of cancer therapeutics[J]. Nature Communications, 2018, 9(1): 1410.
17	Zhu X J, Yu Z J, Feng L B, et al. Chitosan-based nanoparticle co-delivery of docetaxel and curcumin ameliorates anti-tumor chemoimmunotherapy in lung cancer[J]. Carbohydrate Polymers, 2021, 268: 118237.
18	Scheeren L E, Nogueira-Librelotto D R, Mathes D, et al. Multifunctional PLGA nanoparticles combining transferrin-targetability and pH-stimuli sensitivity enhanced doxorubicin intracellular delivery and in vitro antineoplastic activity in MDR tumor cells[J]. Toxicology in Vitro, 2021, 75: 105192.
19	Matsumoto S, Nakata K, Sagara A, et al. Efficient pre-treatment for pancreatic cancer using chloroquine-loaded nanoparticles targeting pancreatic stellate cells[J]. Oncology Letters, 2021, 22(2): 633.
20	Almoustafa H A, Alshawsh M A, Chik Z. Targeted polymeric nanoparticle for anthracycline delivery in hypoxia-induced drug resistance in metastatic breast cancer cells[J]. Anti-Cancer Drugs, 2021, 32(7): 745-754.
21	Tansık G, Yakar A, Gündüz U. Tailoring magnetic PLGA nanoparticles suitable for doxorubicin delivery[J]. Journal of Nanoparticle Research, 2013, 16(1): 1-13.
22	Wu P, Zhou Q, Zhu H, et al. Enhanced antitumor efficacy in colon cancer using EGF functionalized PLGA nanoparticles loaded with 5-fluorouracil and perfluorocarbon[J]. BMC Cancer, 2020, 20(1): 354.
23	Guo T, Li X K, Lin M, et al. Mucosal adjuvant activity of chitosan encapsulated nanoparticles as Helicobacter pylori epitope vaccine carrier[J]. Nanoscience and Nanotechnology Letters, 2016, 8(12): 1106-1111.
24	Xia Y F, Wu J, Wei W, et al. Exploiting the pliability and lateral mobility of Pickering emulsion for enhanced vaccination[J]. Nature Materials, 2018, 17(2): 187-194.
25	Gu P, Wusiman A, Zhang Y, et al. Rational design of PLGA nanoparticle vaccine delivery systems to improve immune responses[J]. Molecular Pharmaceutics, 2019, 16(12): 5000-5012.
26	Ebrahimian M, Hashemi M, Maleki M, et al. Co-delivery of dual toll-like receptor agonists and antigen in poly(lactic-co-glycolic) acid/polyethylenimine cationic hybrid nanoparticles promote efficient in vivo immune responses[J]. Frontiers in Immunology, 2017, 8: 1077.
27	Clawson C, Huang C T, Futalan D, et al. Delivery of a peptide via poly(d, l-lactic-co-glycolic) acid nanoparticles enhances its dendritic cell-stimulatory capacity[J]. Nanomedicine: Nanotechnology, Biology and Medicine, 2010, 6(5): 651-661.
28	Zhang W F, Wang L Y, Yang T Y, et al. Immunopotentiator-loaded polymeric microparticles as robust adjuvant to improve vaccine efficacy[J]. Pharmaceutical Research, 2015, 32(9): 2837-2850.
29	Luo L, Qin T, Huang Y F, et al. Exploring the immunopotentiation of Chinese yam polysaccharide poly(lactic-co-glycolic acid) nanoparticles in an ovalbumin vaccine formulation in vivo[J]. Drug Delivery, 2017, 24(1): 1099-1111.
30	岳华, 马光辉. 高分子纳微球在工程疫苗中的新应用[J]. 高分子学报, 2020, 51(2): 125-135.
	Yue H, Ma G H. Applications of polymeric micro/nanoparticles in engineered vaccines[J]. Acta Polymerica Sinica, 2020, 51(2): 125-135.
31	胡运玖, 左奕, 邬均, 等. 聚己内酯载药微球的制备及释药性能研究[J]. 材料导报, 2015, 29(2): 29-32, 56.
	Hu Y J, Zuo Y, Wu J, et al. Preparation and release study of drug loaded poly(ε-caprolactone)microspheres[J]. Materials Review, 2015, 29(2): 29-32, 56.
32	Sollohub K, Cal K. Spray drying technique (Ⅱ):. Current applications in pharmaceutical technology[J]. Journal of Pharmaceutical Sciences, 2010, 99(2): 587-597.
33	Arpagaus C. PLA/PLGA nanoparticles prepared by nano spray drying[J]. Journal of Pharmaceutical Investigation, 2019, 49(4): 405-426.
34	Zhang D L, Li X N, Hao D X, et al. Systematic purification of polydatin, resveratrol and anthraglycoside B from Polygonum cuspidatum Sieb. et Zucc[J]. Separation and Purification Technology, 2009, 66(2): 329-339.
35	Li X, Wei Y, Wen K, et al. Novel insights on the encapsulation mechanism of PLGA terminal groups on ropivacaine[J]. European Journal of Pharmaceutics and Biopharmaceutics, 2021, 160: 143-151.
36	Wang W C, Zhou W Q, Li J, et al. Comparison of covalent and physical immobilization of lipase in gigaporous polymeric microspheres[J]. Bioprocess and Biosystems Engineering, 2015, 38(11): 2107-2115.
37	Sun L J, Xiong Z D, Zhou W Q, et al. Novel konjac glucomannan microcarriers for anchorage-dependent animal cell culture[J]. Biochemical Engineering Journal, 2015, 96: 46-54.
38	Qi F, Wu J, Yang T Y, et al. Mechanistic studies for monodisperse exenatide-loaded PLGA microspheres prepared by different methods based on SPG membrane emulsification[J]. Acta Biomaterialia, 2014, 10(10): 4247-4256.
39	马光辉, 苏志国. 微球材料尺寸和结构控制的过程工程[J]. 化工学报, 2014, 65(7): 2574-2587.
	Ma G H, Su Z G. Process engineering for size and structure control of microspheres[J]. CIESC Journal, 2014, 65(7): 2574-2587.
40	李小青, 巩方玲, 马光辉. 旋转膜乳化法制备均一魔芋葡苷聚糖凝胶微球[J]. 过程工程学报, 2014, 14(2): 296-303.
	Li X Q, Gong F L, Ma G H. Preparation of uniform konjac glucomannan gel microspheres by rotating membrane emulsification[J]. The Chinese Journal of Process Engineering, 2014, 14(2): 296-303.
41	何帆, 齐峰, 吴颉, 等. 快速膜乳化法制备载生长激素释放肽-6的PLGA微球[J]. 过程工程学报, 2013, 13(3): 458-465.
	He F, Qi F, Wu J, et al. Preparation of growth hormone-releasing peptide-6 loaded PLGA microspheres by premix membrane emulsification[J]. The Chinese Journal of Process Engineering, 2013, 13(3): 458-465.
42	张慧霞, 韦祎, 王玉霞, 等. 快速膜乳化法制备尺寸均一PELA多孔微球及其孔径调控[J]. 过程工程学报, 2013, 13(3): 466-473.
	Zhang H X, Wei Y, Wang Y X, et al. Preparation of uniform-sized porous PELA microspheres and their pore size control[J]. The Chinese Journal of Process Engineering, 2013, 13(3): 466-473.
43	Ma G H, Yue H. Advances in uniform polymer microspheres and microcapsules: preparation and biomedical applications[J]. Chinese Journal of Chemistry, 2020, 38(9): 911-923.
44	包谢茹, 吴颉, 马光辉. 用于细菌生物膜感染治疗的Pickering乳液制备[J]. 过程工程学报, 2021, 21(5): 594-600.
	Bao X R, Wu J, Ma G H. Preparation of a Pickering emulsion for treatment of bacterial biofilm infection[J]. The Chinese Journal of Process Engineering, 2021, 21(5): 594-600.
45	Hao D X, Gong F L, Hu G H, et al. Controlling factors on droplets uniformity in membrane emulsification: experiment and modeling analysis[J]. Industrial & Engineering Chemistry Research, 2008, 47(17): 6418-6425.
46	郝冬霞. 膜乳化法结合悬浮聚合制备均一多孔聚苯乙烯微球的过程研究[D]. 北京:中国科学院研究生院(过程工程研究所), 2009.
	Hao D X. Preparation of homogeneous porous polystyrene microspheres by membrane emulsification combined with suspension polymerization [D]. Beijing: Graduate University of Chinese Academy of Sciences (Institute of Process Engineering), 2009.
47	Wang L Y, Gu Y H, Zhou Q Z, et al. Preparation and characterization of uniform-sized chitosan microspheres containing insulin by membrane emulsification and a two-step solidification process[J]. Colloids and Surfaces B: Biointerfaces, 2006, 50(2): 126-135.
48	Wu J, Wei W, Wang L Y, et al. Preparation of uniform-sized pH-sensitive quaternized chitosan microsphere by combining membrane emulsification technique and thermal-gelation method[J]. Colloids and Surfaces B: Biointerfaces, 2008, 63(2): 164-175.
49	Liu R, Huang S S, Wan Y H, et al. Preparation of insulin-loaded PLA/PLGA microcapsules by a novel membrane emulsification method and its release in vitro[J]. Colloids and Surfaces B: Biointerfaces, 2006, 51(1): 30-38.
50	Zhou Q Z, Wang L Y, Ma G H, et al. Preparation of uniform-sized agarose beads by microporous membrane emulsification technique[J]. Journal of Colloid and Interface Science, 2007, 311(1): 118-127.
51	刘艳, 王月琦, 范清泽, 等. 快速膜乳化与热固化法制备粒径均一的pH敏感壳聚糖季铵盐凝胶微球[J]. 过程工程学报, 2015, 15(3): 473-481.
	Liu Y, Wang Y Q, Fan Q Z, et al. Preparation of uniform-sized pH-sensitive HTCC hydrogel microspheres by premix membrane emulsification and thermal gelation[J]. The Chinese Journal of Process Engineering, 2015, 15(3): 473-481.
52	Xu J H, Luo G S, Chen G G, et al. Experimental and theoretical approaches on droplet formation from a micrometer screen hole[J]. Journal of Membrane Science, 2005, 266(1/2): 121-131.
53	Suzuki K, Hayakawa K, Hagura Y. Preparation of high concentration O/W and W/O emulsions by the membrane phase inversion emulsification using PTFE membranes[J]. Food Science and Technology Research, 1999, 5(2): 234-238.
54	韦祎, 巩方玲, 崔一民, 等. 微孔膜乳化技术制备缓释微球的研究进展[J]. 中国医药工业杂志, 2018, 49(10): 1341-1352.
	Wei Y, Gong F L, Cui Y M, et al. Research progress of sustained-release microspheres prepared by membrane emulsification technique[J]. Chinese Journal of Pharmaceuticals, 2018, 49(10): 1341-1352.
55	Jin H J, Chong H H, Zhu Y M, et al. Preparation and evaluation of amphipathic lipopeptide-loaded PLGA microspheres as sustained-release system for AIDS prevention[J]. Engineering in Life Sciences, 2020, 20(11): 476-484.
56	文康, 韦祎, 马光辉. 基于响应面法对制备高包埋率ROP-PLGA微球的影响因素分析[J]. 过程工程学报, 2021, 21(1): 83-91.
	Wen K, Wei Y, Ma G H. Analysis of preparation factors of ROP-PLGA microspheres with high encapsulation efficiency based on response surface method[J]. The Chinese Journal of Process Engineering, 2021, 21(1): 83-91.
57	Na X M, Guo J J, Li T, et al. Double emulsion-templated single-core PLGA microcapsules with narrow size distribution and controllable structure by using premix membrane emulsification[J]. ChemNanoMat, 2020, 6(7): 1059-1062.
58	Qi F, Wu J, Hao D X, et al. Comparative studies on the influences of primary emulsion preparation on properties of uniform-sized exenatide-loaded PLGA microspheres[J]. Pharmaceutical Research, 2014, 31(6): 1566-1574.
59	Mi Y C, Li J, Zhou W Q, et al. Improved stability of emulsions in preparation of uniform small-sized konjac glucomanna (KGM) microspheres with epoxy-based polymer membrane by premix membrane emulsification[J]. Polymers, 2016, 8(3): 53.
60	Zhang H, Zhao L, Huang Y, et al. Uniform polysaccharide composite microspheres with controllable network by microporous membrane emulsification technique[J]. Analytical and Bioanalytical Chemistry, 2018, 410(18): 4331-4341.
61	Wright S G, Christenson T, Yeah T Y, et al. Polymer-based sustained release device: US7456254[P]. 2008-11-25.
62	刘琳娜, 李欣, 张琰, 等. 胰高血糖素样肽-2/聚乳酸-羟基乙酸微球的制备及其体外释药性质研究[J]. 中国药房, 2010, 21(29): 2755-2757.
	Liu L N, Li X, Zhang Y, et al. Preparation and in vitro release property of glucagon-like peptide-2/PLGA microspheres[J]. China Pharmacy, 2010, 21(29): 2755-2757.
63	冯子雄, 徐建昌, 章莉娟. 溶剂挥发法制备大孔聚合物微球[J]. 高校化学工程学报, 2019, 33(6): 1509-1515.
	Feng Z X, Xu J C, Zhang L J. Preparation of macroporous polymer microspheres by a solvent evaporation method[J]. Journal of Chemical Engineering of Chinese Universities, 2019, 33(6): 1509-1515.
64	Wang H N, Wang F, Li X Q, et al. Preparation and performance investigation of polydimethylsiloxane microsphere/polyvinyl alcohol composite hydrogel[J]. Materials Letters, 2018, 228: 399-402.
65	Wei Y, Wang Y X, Wang L Y, et al. Fabrication strategy for amphiphilic microcapsules with narrow size distribution by premix membrane emulsification[J]. Colloids and Surfaces B: Biointerfaces, 2011, 87(2): 399-408.
66	Ma G H, Nagai M, Omi S. Study on preparation and morphology of uniform artificial polystyrene-poly(methyl methacrylate) composite microspheres by employing the SPG (shirasu porous glass) membrane emulsification technique[J]. Journal of Colloid and Interface Science, 1999, 214(2): 264-282.
67	马光辉, 韦祎, 王玉霞, 等. 重组人生长激素rhGH长效缓释微囊及其制备方法: 102370630A[P]. 2012-03-14.
	Ma G H, Wei Y, Wang Y X, et al. Recombinant human growth hormone (rhGH) long-acting sustained-release microcapsule and preparation method thereof: 102370630A[P]. 2012-03-14.
68	王玉霞, 马光辉, 王宁, 等. 一种包埋小分子亲水性药物缓释微囊及其制备方法: 104224753B[P]. 2017-02-08.
	Wang Y X, Ma G H, Wang N, et al. Small molecule hydrophilic drug-<wbr>embedded sustained-release capsule and preparation method thereof: 104224753B[P]. 2017-02-08.
69	曾烨婧, 王连艳, 马光辉, 等. 快速膜乳化法制备载紫杉醇聚乳酸类微球[J]. 过程工程学报, 2010, 10(3): 568-575.
	Zeng Y J, Wang L Y, Ma G H, et al. Preparation of microspheres of paclitaxel-loaded PLA, PLGA and PELA by premix membrane emulsification[J]. The Chinese Journal of Process Engineering, 2010, 10(3): 568-575.
70	刘雁南, 王连艳, 杨婷媛, 等. 白油佐剂粒径均一性与炎症和免疫学效应的相关性[J]. 过程工程学报, 2015, 15(4): 653-658.
	Liu Y N, Wang L Y, Yang T Y, et al. Particle size uniformity of white oil adjuvant and its related inflammation and immunological effect[J]. The Chinese Journal of Process Engineering, 2015, 15(4): 653-658.
71	Oyewumi M O, Kumar A, Cui Z R. Nano-microparticles as immune adjuvants: correlating particle sizes and the resultant immune responses[J]. Expert Review of Vaccines, 2010, 9(9): 1095-1107.
72	Shah R R, O'Hagan D T, Amiji M M, et al. The impact of size on particulate vaccine adjuvants[J]. Nanomedicine (London, England), 2014, 9(17): 2671-2681.
73	付寒, 温新国, 典灵辉, 等. 粒径均一单分散载药微球的制备技术及其应用[J]. 中国医药工业杂志, 2011, 42(11): 856-862, 870.
	Fu H, Wen X G, Dian L H, et al. Methods for preparation of uniform-sized and monodisperse drug-loaded microspheres and their applications[J]. Chinese Journal of Pharmaceuticals, 2011, 42(11): 856-862, 870.
74	Wei W, Wang L Y, Yuan L, et al. Bioprocess of uniform-sized crosslinked chitosan microspheres in rats following oral administration[J]. European Journal of Pharmaceutics and Biopharmaceutics, 2008, 69(3): 878-886.
75	Qi F, Yang L Q, Wu J, et al. Microcosmic mechanism of dication for inhibiting acylation of acidic peptide[J]. Pharmaceutical Research, 2015, 32(7): 2310-2317.
76	杨柳青, 王丽秋, 吴颉, 等. 快速膜乳化法制备胸腺法新长效缓释微球[J]. 过程工程学报, 2014, 14(6): 994-999.
	Yang L Q, Wang L Q, Wu J, et al. Preparation of thymalfasin loaded PLGA microspheres by premix membrane emulsification as long-term effective formulation[J]. The Chinese Journal of Process Engineering, 2014, 14(6): 994-999.
77	Zhang Y L, Wei W, Lv P, et al. Preparation and evaluation of alginate-chitosan microspheres for oral delivery of insulin[J]. European Journal of Pharmaceutics and Biopharmaceutics, 2011, 77(1): 11-19.
78	Wei Y, Wang Y X, Wang W, et al. Microcosmic mechanisms for protein incomplete release and stability of various amphiphilic mPEG-PLA microspheres[J]. Langmuir, 2012, 28(39): 13984-13992.
79	Liu Y, Wang L Y, Zhang Y, et al. Uniform-sized water-in-oil vaccine formulations enhance immune response against Newcastle disease and avian influenza in chickens[J]. International Immunopharmacology, 2014, 23(2): 603-608.
80	Liu Q, Chen X, Jia J, et al. PH-Responsive poly(D, L-lactic-co-glycolic acid) nanoparticles with rapid antigen release behavior promote immune response[J]. ACS Nano, 2015, 9(5): 4925-4938.
81	Longo F, Mansueto G, Lapadula V, et al. Combination of aprepitant, palonosetron and dexamethasone as antiemetic prophylaxis in lung cancer patients receiving multiple cycles of cisplatin-based chemotherapy[J]. International Journal of Clinical Practice, 2012, 66(8): 753-757.
82	Wei W, Lv P P, Chen X M, et al. Codelivery of mTERT siRNA and paclitaxel by chitosan-based nanoparticles promoted synergistic tumor suppression[J]. Biomaterials, 2013, 34(15): 3912-3923.
83	Fu Q, Lv P, Chen Z K, et al. Programmed co-delivery of paclitaxel and doxorubicin boosted by camouflaging with erythrocyte membrane[J]. Nanoscale, 2015, 7(9): 4020-4030.
84	马宇峰, 吕丕平, 岳占国, 等. 以壳聚糖为基质的智能电荷翻转体系用于紫杉醇的高效输送[J]. 过程工程学报, 2012, 12(3): 460-465.
	Ma Y F, Lv P P, Yue Z G, et al. Chitosan-based intelligent charge-reversed system for high efficiency delivery of paclitaxel[J]. The Chinese Journal of Process Engineering, 2012, 12(3): 460-465.
85	Lv P P, Ma Y F, Yu R, et al. Targeted delivery of insoluble cargo (paclitaxel) by PEGylated chitosan nanoparticles grafted with Arg-Gly-Asp (RGD)[J]. Molecular Pharmaceutics, 2012, 9(6): 1736-1747.