Pilot-scale production of expansile nanoparticles: Practical methods for clinical scale-up

被引:24
作者
Colby, Aaron H. [1 ,2 ]
Liu, Rong [3 ]
Doyle, Robert P. [4 ]
Merting, Alyssa [5 ]
Zhang, Heng [6 ]
Savage, Natasha [5 ]
Ngoc-Quynh Chu [3 ]
Hollister, Beth A. [7 ]
McCulloch, William [8 ]
Burdette, Joanna E. [9 ]
Pearce, Cedric J. [10 ]
Liu, Kebin [5 ]
Oberlies, Nicholas H. [11 ]
Colson, Yolonda L. [3 ]
Grinstaff, Mark W. [1 ,2 ,6 ]
机构
[1] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA
[2] Ion Pharmaceut LLC, Brookline, MA USA
[3] Massachusetts Gen Hosp, Boston, MA 02114 USA
[4] PCI Synth, Newburyport, MA USA
[5] Augusta Univ, Augusta, GA USA
[6] Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA
[7] HighRock Consulting, Oxford, NC USA
[8] Alba BioPharm Advisors Inc, Raleigh, NC USA
[9] Univ Illinois, Coll Pharm, Chicago, IL USA
[10] Mycosynthetix Inc, Hillsborough, NC USA
[11] Univ N Carolina, Dept Chem & Biochem, Greensboro, NC USA
关键词
Pilot-scale production; Expansile nanoparticle; Microfluidizer; Scale-up; Clinical translation; TUMOR-LOCALIZATION; IMPROVE SURVIVAL; EFFICACY; MODEL;
D O I
10.1016/j.jconrel.2021.07.012
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
One of the foremost challenges in translating nanoparticle technologies to the clinic is the requirement to produce materials on a large-scale. Scaling nanoparticle production methods is often non-trivial, and the success of these endeavors is frequently governed by whether or not an intermediate level of production, i.e., "pilot-scale" production, can be achieved. Pilot-scale production at the one-liter scale serves as a proof-of-concept that largescale production will be possible. Here, we describe the pilot-scale production of the expansile nanoparticle (eNP) technology including verification of activity and efficacy following scaleup. We describe the challenges of sonication-based emulsification procedures and how these were overcome by use of a Microfluidizer technology. We also describe the problem-solving process that led to pre-polymerization of the nanoparticle polymer-a fundamental change from the lab-scale and previously published methods. Furthermore, we demonstrate good control over particle diameter, polydispersity and drug loading and the ability to sterilize the particles via filtration using this method. To facilitate long-term storage of these larger quantities of particles, we investigated six lyoprotectants and determined that sucrose is the most compatible with the current system. Lastly, we demonstrate that these changes to the manufacturing method do not adversely affect the swelling functionality of the particles, their highly specific localization to tumors, their non-toxicity in vivo or their efficacy in treating established intraperitoneal mesothelioma xenografts.
引用
收藏
页码:144 / 154
页数:11
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