摘要
背景：将难溶性药物改善为药物治疗是药剂师面临的主要问题。纳米悬浮液可以通过提高溶解度，化学稳定性和减少添加剂的使用来提高不溶性药物的可药性，为不溶性药物制剂的开发和应用提供了新的途径。紫杉醇（PTX）是众所周知的BCS IV类药物，具有差的溶解性和渗透性。此外，许多研究已经证明紫杉醇是膜结合药物外排泵P-糖蛋白（P-gp）的底物，因此它通常对抗性肿瘤和口服吸收或摄取显示出有限的功效。 目的：制备增强型PTX纳米悬浮液（PTX-Nanos），并评价其体内理化性质，药代动力学和组织分布以及体外细胞毒作用。 方法：采用微量沉淀 - 高压均质法制备PTX-Nanos，以良好的生物相容性两亲性嵌段共聚物聚（L-苯丙氨酸）-b-聚（L-天冬氨酸）（PPA-PAA）为稳定剂。 结果：与PTX注射相比，PTX-Nanos具有持续溶出方式，可有效降低血浆峰浓度，延长血浆循环时间，显着被动靶向MPS相关器官，如肝脏和脾脏。这种独特的性质可以增强这些组织中癌症的治疗并减少其他正常组织中的副作用。此外，杂合稳定剂可以增强PTX-Nanos中PTX对多药耐药细胞的渗透。 结论：总之，我们的结果表明，最佳配方可以提高PTX的溶解度和产品的稳定性。在该研究中开发的PTX-Nanos将是癌症治疗中有前景的递送平台。
关键词: 紫杉醇，纳米悬浮液，药代动力学，细胞毒性，增强渗透，药物外排泵P-糖蛋白（P-gp）。
图形摘要
[1]
Yang, R.; Chen, J.B.; Xiao, C.F.; Liu, Z.C.; Gao, Z.Y.; Yan, S.J.; Zhang, J.H.; Zhang, H.B.; Lin, J. Inclusion complex of GA-13316 with β-cyclodextrin: preparation, characterization, molecular modeling, and in vitro evaluation. Carbohydr. Polym., 2014, 111, 655.
[2]
Efiana, N.A.; Phan, T.N.Q.; Wicaksono, A.J.; Bernkop-Schnurch, A. Mucus permeating self-emulsifying drug delivery systems (SEDDS): About the impact of mucolytic enzymes. Colloids Surf. B Biointerfaces, 2017, 161, 228-235.
[3]
Chaudhury, A.; Das, S. Folate receptor targeted liposomes encapsulating anti-cancer drugs. Curr. Pharm. Biotechnol., 2015, 16(4), 333-343.
[4]
Deng, H.; Liu, J.; Zhao, X.; Zhang, Y.; Liu, J.; Xu, S.; Deng, L.; Dong, A.; Zhang, J. PEG-b-PCL copolymer micelles with the ability of pH-controlled negative-to-positive charge reversal for intracellular delivery of doxorubicin. Biomacromolecules, 2014, 15(11), 4281-4292.
[5]
Zhang, T.; Luo, J.; Fu, Y.; Li, H.; Ding, R.; Gong, T.; Zhang, Z. Novel oral administrated paclitaxel micelles with enhanced bioavailability and antitumor efficacy for resistant breast cancer. Colloids Surf. B Biointerfaces, 2016, 150, 89-97.
[6]
Dousa, M.; Meca, L.; Gibala, P.; Jirman, J.; Tkadlecova, M.; Srbek, J.; Salandova, J.; Kovalcikova, E.; Brichac, J. Esterification of ibuprofen in soft gelatin capsules formulations-identification, synthesis and liquid chromatography separation of the degradation products. J. Chromatogr. Sci., 2017, 55(8), 790-797.
[7]
Stephenson, G.A.; Aburub, A.; Woods, T.A. Physical stability of salts of weak bases in the solid-state. J. Pharm. Sci., 2011, 100(5), 1607-1617.
[8]
Schultheiss, N.; Newman, A. Pharmaceutical cocrystals and their physicochemical properties. Cryst. Growth Des., 2009, 9(6), 2950-2967.
[9]
Serajuddin, A.T.M. Salt formation to improve drug solubility. Adv. Drug Deliv. Rev., 2007, 59(7), 603-616.
[10]
Zhao, B.; Gu, S.; Du, Y.; Shen, M.; Liu, X.; Shen, Y. Solid lipid nanoparticles as carriers for oral delivery of hydroxysafflor yellow A. Int. J. Pharm., 2017, 535(1-2), 164-171.
[11]
Edwards, F.; Tsakmaka, C.; Mohr, S.; Fielden, P.R.; Goddard, N.J.; Booth, J.; Tam, K.Y. Using droplet-based microfluidic technology to study the precipitation of a poorly water-soluble weakly basic drug upon a pH-shift. The Analyst , 2013, 138(1), 339-345.
[12]
Pu, X.H.; Sun, J.; Li, M.; He, Z.G. Formulation of nanosuspensions as a new approach for the delivery of poorly soluble drugs. Curr. Nanosci., 2009, 5(4), 417-427.
[13]
Bergstrom, C.A.; Wassvik, C.M.; Johansson, K.; Hubatsch, I. Poorly soluble marketed drugs display solvation limited solubility. J. Med. Chem., 2007, 50(23), 5858-5862.
[14]
Shah, S.M.; Ullah, F.; Khan, S.; Shah, S.M.; de Matas, M.; Hussain, Z.; Minhas, M.U. AbdEl-Salam, N.M.; Assi, K.H.; Isreb, M. Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation. Drug Des. Devel. Ther., 2016, 10, 3837-3850.
[15]
Liu, C.Z.; Chang, J.H.; Zhang, L.; Xue, H.F.; Liu, X.G.; Liu, P.; Fu, Q. Preparation and evaluation of diosgenin nanocrystals to improve oral bioavailability. AAPS PharmSciTech, 2016, 1-10.
[16]
Kassem, M.A.; ElMeshad, A.N.; Fares, A.R. Enhanced solubility and dissolution rate of lacidipine nanosuspension: formulation via antisolvent sonoprecipitation technique and optimization using box-behnken design. AAPS PharmSciTech, 2016, 1-14.
[18]
Pu, X.; Sun, J.; Wang, Y.; Wang, Y.; Liu, X.; Zhang, P.; Tang, X.; Pan, W.; Han, J.; He, Z. Development of a chemically stable 10-hydroxycamptothecin nanosuspensions. Int. J. Pharm., 2009, 379(1), 167-173.
[19]
Moschwitzer, J.; Achleitner, G.; Pomper, H.; Muller, R.H. Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology. Eur. J. Pharm. Biopharm., 2004, 58(3), 615-619.
[20]
Gao, L.; Liu, G.; Wang, X.; Liu, F.; Xu, Y.; Ma, J. Preparation of a chemically stable quercetin formulation using nanosuspension technology. Int. J. Pharm., 2011, 404(1-2), 231-237.
[21]
Bi, C.; Miao, X.Q.; Chow, S.F.; Wu, W.J.; Yan, R.; Liao, Y.H.; Chow, A.H.; Zheng, Y. Particle size effect of curcumin nanosuspensions on cytotoxicity, cellular internalization, in vivo pharmacokinetics and biodistribution. Nanotechnol. Biol. Med., 2017, 13(3), 943-953.
[22]
Müller, R.H.; Peters, K.; Becker, R.; Kruss, B. Nanosuspensions, A novel formulation for the i.v. administration of poorly soluble drugs.In; APGI, 1995, pp. 491-492.
[23]
Kumar, M.P.; Rao, Y.M.; Apte, S. Formulation of nanosuspensions of albendazole for oral administration. Curr. Nanosci., 2008, 4(1), 53-58.
[24]
Peters, K.; Leitzke, S.; Diederichs, J.E.; Borner, K.; Hahn, H.; Muller, R.H.; Ehlers, S. Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection. J. Antimicrob. Chemother., 2000, 45(1), 77-83.
[25]
Pu, X.H.; Sun, J.; Qin, Y.M.; Zhang, X.; Zhang, P.; Yan, Z.T.; He, Z.G. The passive targeting and the cytotoxicity of intravenous 10-HCPT nanosuspension. Curr. Nanosci., 2012, 8(5), 762-766.
[26]
Boistelle, R.; Astier, J.P. Crystallization mechanisms in solution. J. Cryst. Growth, 1988, 90(1-3), 14-30.
[27]
Florence, A.T.; Attwood, D. Physicochemical principles of pharmacy. Am. J. Pharm. Educ., 1998, 70(5), 122.
[28]
Liu, P.; Rong, X.; Laru, J.; van Veen, B.; Kiesvaara, J.; Hirvonen, J.; Laaksonen, T.; Peltonen, L. Nanosuspensions of poorly soluble drugs: preparation and development by wet milling. Int. J. Pharm., 2011, 411(1-2), 215-222.
[29]
Merisko-Liversidge, E.; Liversidge, G.G. Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology. Adv. Drug Deliv. Rev., 2011, 63(6), 427-440.
[30]
Zhao, D.; Zhang, H.; Yang, S.; He, W.; Luan, Y. Redox-sensitive mPEG-SS-PTX/TPGS mixed micelles: An efficient drug delivery system for overcoming multidrug resistance. Int. J. Pharm., 2016, 515(1-2), 281-292.
[31]
Gao, L.; Liu, G.; Kang, J.; Niu, M.; Wang, Z.; Wang, H.; Ma, J.; Wang, X. Paclitaxel nanosuspensions coated with P-gp inhibitory surfactants: I. Acute toxicity and pharmacokinetics studies. Colloids Surf. B Biointerfaces, 2013, 111, 277-281.
[32]
Malingre, M.M.; Terwogt, J.M.; Beijnen, J.H.; Rosing, H.; Koopman, F.J.; van Tellingen, O.; Duchin, K.; Huinink, W.W.; Swart, M.; Lieverst, J.; Schellens, J.H. Phase I and pharmacokinetic study of oral paclitaxel. J. Clin. Oncol., 2000, 18(12), 2468-2475.
[33]
Huizing, M.T.; Misser, V.H.S.; Pieters, R.C.; ten Bokkel Huinink, W.W.; Veenhof, C.H.N.; Vermorken, J.B.; Pinedo, H.M.; Beijnen, J.H. Taxanes: A new class of antitumor agents. Cancer Invest., 1995, 13(4), 381-404.
[34]
Lee, J.; Lee, S.J.; Choi, J.Y.; Yoo, J.Y.; Ahn, C.H. Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion. Eur. J. Pharm. Sci., 2005, 24(5), 441-449.
[35]
Hong, J.; Li, Y.; Xiao, Y.; Li, Y.; Guo, Y.; Kuang, H.; Wang, X. Annonaceous acetogenins (ACGs) nanosuspensions based on a self-assembly stabilizer and the significantly improved anti-tumor efficacy. Colloids Surf. B Biointerfaces, 2016, 145, 319-327.
[36]
Wang, Y.; Zheng, Y.; Zhang, L.; Wang, Q.; Zhang, D. Stability of nanosuspensions in drug delivery. J. Control. Release, 2013, 172(3), 1126-1141.
[37]
Ghosh, I.; Bose, S.; Vippagunta, R.; Harmon, F. Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth. Int. J. Pharm., 2011, 409(1-2), 260-268.
[38]
Lauro, M.R.; Carbone, C.; Sansone, F.; Ruozi, B.; Chillemi, R.; Sciuto, S.; Aquino, R.P.; Puglisi, G. Innovative oral spray-dried Idebenone systems to improve patient compliance. Drug Development and Industrial Pharmacy,, 2016, 42(7), 1127-1136.
[39]
Kumar, G.; Sharma, S.; Shafiq, N.; Pandhi, P.; Khuller, G.K.; Malhotra, S. Pharmacokinetics and tissue distribution studies of orally administered nanoparticles encapsulated ethionamide used as potential drug delivery system in management of multi-drug resistant tuberculosis. Drug Deliv., 2011, 18(1), 65-73.
[40]
Ghosh, I.; Schenck, D.; Bose, S.; Ruegger, C. Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: Effect of Vitamin E TPGS and nanocrystal particle size on oral absorption. Eur. J. Pharm. Sci., 2012, 47(4), 718-728.
[41]
Mirshafiee, V.; Kim, R.; Park, S.; Mahmoudi, M.; Kraft, M.L. Impact of protein pre-coating on the protein corona composition and nanoparticle cellular uptake. Biomaterials, 2016, 75, 295-304.
[42]
Kari, O.K.; Rojalin, T.; Salmaso, S.; Barattin, M.; Jarva, H.; Meri, S.; Yliperttula, M.; Viitala, T.; Urtti, A. Multi-parametric surface plasmon resonance platform for studying liposome-serum interactions and protein corona formation. Drug Deliv. Transl. Res., 2016, 7(2), 228-240.
[43]
Caracciolo, G.; Palchetti, S.; Colapicchioni, V.; Digiacomo, L.; Pozzi, D.; Capriotti, A.L.; La Barbera, G.; Lagana, A. Stealth effect of biomolecular corona on nanoparticle uptake by immune cells. Langmuir, 2015, 31(39), 10764-10773.
[44]
Manjunath, K.; Venkateswarlu, V. Pharmacokinetics, tissue distribution and bioavailability of clozapine solid lipid nanoparticles after intravenous and intraduodenal administration. J. Drug Target., 2006, 14(9), 632-645.
[45]
Wang, Y.; Li, X.; Wang, L.; Xu, Y.; Cheng, X.; Wei, P. Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery. Int. J. Nanomed, 2011, 6, 1497-1507.
[46]
Wei, L.; Ji, Y.; Gong, W.; Kang, Z.; Meng, M.; Zheng, A.; Zhang, X.; Sun, J. Preparation, physical characterization and pharmacokinetic study of paclitaxel nanocrystals. Drug Dev. Ind. Pharm., 2015, 41(8), 1343-1352.
[47]
Yin, T.; Cai, H.; Liu, J.; Cui, B.; Wang, L.; Yin, L.; Zhou, J.; Huo, M. Biological evaluation of PEG modified nanosuspensions based on human serum albumin for tumor targeted delivery of paclitaxel. Eur. J. Pharm. Sci., 2016, 83, 79-87.
Related Books
Frontiers in Clinical Drug Research - Anti-Cancer Agents
NEOPLASIA and FERTILITY
Breast Cancer: Current Trends in Molecular Research
The Evolution of Radionanotargeting towards Clinical Precision Oncology: A Festschrift in Honor of Kalevi Kairemo
Nanotherapeutics for the Treatment of Hepatocellular Carcinoma
Topics in Anti-Cancer Research
Frontiers in Clinical Drug Research - Anti-Cancer Agents
Modern Cancer Therapies and Traditional Medicine: An Integrative Approach to Combat Cancers
Herbal Medicine: Back to the Future
Thrombosis in Cancer: A Medical Professional's Guide to Cancer Associated Thrombosis
Article Metrics
42
2