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Degradation kinetics of high molecular weight poly(L-lactide) microspheres and release mechanism of lipid:DNA complexes

Authors

  • Mayank M. Patel,

    Corresponding author
    1. Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Box C238, 4200 E. Ninth Ave., Denver, Colorado 80262
    • Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Box C238, 4200 E. Ninth Ave., Denver, Colorado 80262. Telephone: (303)-315-0359; Fax: (303)-315-6281
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  • Michelle G. Zeles,

    1. Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado 80309
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  • Mark C. Manning,

    1. Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Box C238, 4200 E. Ninth Ave., Denver, Colorado 80262
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  • Theodore W. Randolph,

    1. Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado 80309
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  • Thomas J. Anchordoquy

    1. Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Box C238, 4200 E. Ninth Ave., Denver, Colorado 80262
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Abstract

Plasmid DNA encoding the green lantern protein was ion-paired with 1,2-dioleoyl, 3-trimethylammonium propane (DOTAP) at a (+/−) charge ratio of (1:1) to form a hydrophobic ion-pair (HIP) complex using the Bligh and Dyer method, and transferred into methylene chloride. Precipitation with a compressed antisolvent (PCA) was then employed to encapsulate plasmid DNA into poly(L-lactide) (PLLA) microspheres. The hydrophobicity of DOTAP:DNA complexes allowed consistently high encapsulation efficiencies (>70%) to be achieved. Release of the DOTAP:DNA complex from PLLA microspheres exhibited minimal burst and a short (ca. 1 week) lag phase, followed by sustained release over a 20 week period. Release kinetics were consistent with a simple Fickian diffusion model. No correlation was identified between release rate of soluble poly(L-lactide) species (≤10 lactate units) from PLLA and the DNA release kinetics. Only ∼12% of the polymer was degraded into soluble poly(L-lactide) over the time frame where ∼90% of the plasmid load had been released. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2573–2584, 2004

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