Antitumor activity of docetaxel-loaded polymeric nanoparticles fabricated by Shirasu porous glass membrane-emulsification technique

International Journal of Nanomedicine Antitumor activity of docetaxel-loaded polymeric nanoparticles fabricated by Shirasu porous glass membrane-emulsification technique Yunni Yu 2 Songwei Tan 1 2 Shuang Zhao 2 Xiangting Zhuang 2 Qingle Song 2 Yuliang Wang 2 Qin Zhou 0 1 Zhiping Zhang 1 2 0 College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan , People's Republic of China 1 National Engineering Research Center for Nanomedicine 2 Tongji School of Pharmacy Docetaxel (DTX) has excellent efficiency against a wide spectrum of cancers. However, the current clinical formulation has limited its usage, as it causes some severe side effects. Various polymeric nanoparticles have thus been developed as alternative formulations of DTX, but they have been mostly fabricated on a laboratory scale. Previously, we synthesized a novel copolymer, poly(lactide)-d -α-tocopheryl polyethylene glycol 1000 succinate (PLATPGS), and found that it exhibited great potential in drug delivery with improved properties. In this study, we applied the Shirasu porous glass (SPG) membrane-emulsification technique to prepare the DTX-loaded PLA-TPGS nanoparticles on a pilot scale. The effect of several formulation variables on the DTX-loaded nanoparticle properties, including particle size, zeta potential, and drug-encapsulation efficiency, were investigated based on surfactant type and concentration in the aqueous phase, organic/aqueous phase volumetric ratio, membrane-pore size, transmembrane cycles, and operation pressure. The DTX-loaded nanoparticles were obtained with sizes of 306.8 ± 5.5 nm and 334.1 ± 2.7 nm (mean value ± standard deviation), and drugencapsulation efficiency of 81.8% ± 4.5% and 64.5% ± 2.7% for PLA-TPGS and poly(lacticco-glycolic acid) (PLGA) nanoparticles, respectively. In vivo pharmacokinetic study exhibited a significant advantage of PLA-TPGS nanoparticles over PLGA nanoparticles and Taxotere. Drug-loaded PLA-TPGS nanoparticles exhibited 1.78-, 6.34- and 3.35-fold higher values for area under the curve, half-life, and mean residence time, respectively, compared with those of PLGA nanoparticles, and 2.23-, 13.2-, 8.51-fold higher than those of Taxotere, respectively. In vivo real-time distribution of nanoparticles was measured on tumor-bearing mice by near-infrared fluorescence imaging, which demonstrated that the PLA-TPGS nanoparticles achieved much higher concentration and longer retention in tumors than PLGA nanoparticles after intravenous injection. This is consistent with the pharmacokinetic behavior of the nanoparticles. The tumorinhibitory effect of DTX-loaded nanoparticles was observed in vivo in an H22 tumor-bearing mice model via intravenous administration. This indicated that PLA-TPGS nanoparticles are a feasible drug-delivery formulation with a pilot fabrication technique and have superior pharmacokinetic and anticancer effects compared to the commercially available Taxotere. - *These authors contributed equally to this work system (DDS) that will reduce the side effects and improve its therapeutic efficiency. Nanotechnology is being widely applied, and the nanocarriers for drug can not only increase drug solubility but also accumulate in tumor tissue through the well-known enhanced-permeability-and-retention effect.5 As a result, the therapeutic effects can be greatly improved. 18 Many nanosized DTX formulations, such as liposomes, l-02 prodrugs, polymeric nanoparticles, and micelles, have been -Ju2 investigated and shown improved therapeutic efficiency.3,6–12 1no Among these, polymeric nanoparticles have been found to 027 offer better stability, high drug-loading efficiency (DLE), ..64 small particle size, and preferable in vivo pharmacokinet.579 ics/pharmacodynamics.13,14 Poly(lactic acid) (PLA) and y3b poly(lactide-co-glycolide) (PLGA) have been widely used in /om DDS because they are approved as good biodegradability and .ssc biocompatibility agents by the US Food and Drug Administrarep tion (FDA).15,16 However, the disadvantages of hydrophobicity ve and fast clearance after injection have limited their applica.doww l.yno tions in vivo.17 To overcome these drawbacks, we designed tt//sphw lsaueno aponlyoevtehlylbeinoedegglyracodlab1l0e00cospuoclcyimnaetre: (PPLLAA--dT-PαG-Sto)c.1o3pThPeGrySl : om rse has been widely investigated for its emulsifying, dispersing, fr p ded roF gelling, and solubilizing effects on poorly water-soluble loa drugs. It can also act as a P-glycoprotein inhibitor, and has now served as an excipient for overcoming multidrug resistance iicedden acenrddfrourgisn.cSreinacsienTgPthGeSohraals bbieoeanvaaiplapbroilviteydobfymthaenyFDanAticaasnaonm safe pharmaceutic adjuvant, many TPGS-based DDSs have faN been developed. The PLA-TPGS copolymer brings the loa special properties of TPGS, and the resultant PLA-TPGS rnuo nanoparticles have exhibited superiority over ordinarily used lJa PLGA nanoparticles, eg, long circulation time in vivo after itno (...truncated)