Tunable Properties of Poly-DL-Lactide-Monomethoxypolyethylene Glycol Porous Microparticles for Sustained Release of Polyethylenimine-DNA Polyplexes
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Direct pulmonary delivery is a promising step in developing effective gene therapies for respiratory disease. Gene therapies can be used to treat the root cause of diseases, rather than just the symptoms. However, developing effective therapies that do not cause toxicity and that successfully reach the target site at therapeutic levels is challenging. We have developed a polymer-DNA complex utilizing polyethylene imine (PEI) and DNA, which was then encapsulated into poly(lactic acid)-co-monomethoxy poly(ethylene glycol) (PLA-mPEG) microparticles via double emulsion, solvent evaporation. Then, the resultant particle size, porosity, and encapsulation efficiency were measured as a function of altering preparation parameters. Microsphere formation was confirmed from scanning electron micrographs and the aerodynamic particle diameter was measured using an aerodynamic particle sizer. Several formulations produced particles with aerodynamic diameters in the 0–5 μm range despite having larger particle diameters which is indicative of porous particles. Furthermore, these aerodynamic diameters correspond to high deposition within the airways when inhaled and the measured DNA content indicated high encapsulation efficiency. Thus, this formulation provides promise for developing inhalable gene therapies.
KEY WORDSPLA PEG polyplexes microspheres
The authors would like to acknowledge Terra M. Kruger for help with the NMR spectra, and Prof. Kristan S. Worthington for assistance with the polymerization reaction. The SEM images were obtained using an SEM instrument in the Central Microscopy Research Facilities at The University of Iowa.
A.K.S acknowledges support from the NIH P30 CA086862 grant and the Lyle and Sharon Bighley Chair of Pharmaceutical Sciences. T.L.T. acknowledges support from the Department of Education GAANN Fellowship program. B.E.G. acknowledges funding support from the Alfred P. Sloan Foundation, the University of Iowa Graduate College, and the National GEM Consortium. V. G. J. R. acknowledges support from the Jacques S. Yeager, Sr. endowment.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 31.Klassen CD, Watkins JBI. Casarett & Doull’s essentials of toxicology. 2nd ed: McGraw-Hill Education / Medical; 2015. 528 pGoogle Scholar
- 32.Kamada Ltd. International study evaluating the safety and efficacy of inhaled, human, alpha-1 antitrypsin (AAT) in alpha-1 antitrypsin deficient patients with emphysema. 2014.Google Scholar
- 35.Abramoff MD, Magalhaes PJ, Ram SJ. Image processing with ImageJ. Biophoton Int. 2004;11(7):36–42.Google Scholar
- 36.Singh NA, Mandal AKA, Khan ZA. Fabrication of PLA-PEG nanoparticles as delivery systems for improved stability and controlled release of catechin. J Nanomater. 2017;2017:1–9.Google Scholar
- 45.Zhu KJ, Lin XZ, Yang SL. Preparation, characterization, and properties of polylactide (Pla) poly(ethylene glycol) (peg) copolymers - a potential-drug carrier. J Appl Polym Sci. 1990;39(1):1–9.Google Scholar
- 47.Kricheldorf HR, Sumbel MV, Kreiser-Saunders I. Polylactones. 20. Polymerization of iε-caprolactone with tributyltin derivatives: a mechanistic study. Macromolecules. 1991;24(8):1944–9.Google Scholar
- 48.Kricheldorf HR, Kreiser-Saunders I, Stricker A. Polylactones 48. SnOct2-initiated polymerizations of lactide: a mechanistic study. Macromolecules. 2000;33(3):702–9.Google Scholar
- 49.Beletsi A, Leontiadis L, Klepetsanis P, Ithakissios DS, Avgoustakis K. Effect of preparative variables on the properties of poly(dl-lactide-co-glycolide)-methoxypoly(ethyleneglycol) copolymers related to their application in controlled drug delivery. Int J Pharm. 1999;182(2):187–97.PubMedGoogle Scholar
- 51.Alibolandi M, Sadeghi F, Sazmand SH, Shahrokhi SM, Seifi M, Hadizadeh F. Synthesis and self-assembly of biodegradable polyethylene glycol-poly (lactic acid) diblock copolymers as polymersomes for preparation of sustained release system of doxorubicin. Int J Pharm Investig. 2015;5(3):134–41.PubMedPubMedCentralGoogle Scholar
- 52.Luo WJ, Li SM, Bei JZ, Wang SG. Synthesis and characterization of poly(L-lactide)- poly(ethylene glycol) multiblock copolymers. J Appl Polym Sci. 2002;84(9):1729–36.Google Scholar
- 62.Biddiscombe MF, Usmani OS. Inhaler characteristics in asthma. EU Respir Pulm Dis. 2017;3:32–7.Google Scholar
- 63.Huang YY, Chung TW, Tzeng TW. Drug release from PLA/PEG microparticulates. Int J Pharm. 1997;156(1):9–15.Google Scholar