Flash nanocomplexation as a scalable production method for therapeutic pdna/lpei nanoparticles

Heng Wen Liu, Yizong Hu, Il Minn, Martin Gilbert Pomper, Hai Quan Mao

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Statement of Purpose: Plasmid DNA (pDNA) nanoparticles synthesized by linear polyethylenimine (lPEI) have shown to be effective gene delivery vehicles for therapeutic applications in animal models. However, a critical barrier to clinical translation lies with producing nanoparticles with optimized physicochemical properties in a scalable and reproducible manner. The method should be validated by reliable characterization standards, with a good level of quality control. We have developed a scalable and controllable manufacturing method for production of shelf-stable pDNA/lPEI nanoparticles. Specifically, we have turned a batch mode (pipet mixing) method into a continuous process using the flash nanocomplexation (FNC) method [1]. We have demonstrated excellent reproducibility for this FNC process under quality assurance and quality control standards at different production batch sizes. The sizes of the FNC pDNA/lPEI nanoparticles were tunable with a PDI lower than 0.2. In addition, the FNC nanoparticles could be reliably lyophilized. The lyophilized formulation preserved the composition, physicochemical properties, and bioactivity of the nanoparticles; and, to date, a stability for at least 9 months in-20°C has been achieved. Furthermore, systemically delivered FNC nanoparticles were well tolerated in mice and a large animal model, and biodistribution, determined by bioluminescence and QPCR respectively, showed the efficacy to deliver into many organs/tissues. In vitro and in vivo toxicity assessment of pDNA/lPEI nanoparticles were studied and demonstrated the safety in the translation. These results confirmed that FNC production could overcome many manufacturing limitations of pDNA/lPEI nanoparticles and open up new opportunities for clinical translation of DNA nanomedicine products.

Original languageEnglish (US)
Title of host publicationSociety for Biomaterials Annual Meeting and Exposition 2019
Subtitle of host publicationThe Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting
PublisherSociety for Biomaterials
Number of pages1
ISBN (Electronic)9781510883901
StatePublished - Jan 1 2019
Event42nd Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence - Seattle, United States
Duration: Apr 3 2019Apr 6 2019

Publication series

NameTransactions of the Annual Meeting of the Society for Biomaterials and the Annual International Biomaterials Symposium
Volume40
ISSN (Print)1526-7547

Conference

Conference42nd Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence
CountryUnited States
CitySeattle
Period4/3/194/6/19

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ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biotechnology
  • Biomaterials
  • Materials Chemistry

Cite this

Liu, H. W., Hu, Y., Minn, I., Pomper, M. G., & Mao, H. Q. (2019). Flash nanocomplexation as a scalable production method for therapeutic pdna/lpei nanoparticles. In Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting (Transactions of the Annual Meeting of the Society for Biomaterials and the Annual International Biomaterials Symposium; Vol. 40). Society for Biomaterials.