Abstract
Despite the apparent advantages for long-term treatment and local therapies against intestinal diseases, the oral delivery of nucleic acids has been challenging due to unfavorable physiological conditions for their stability. In this study, a novel nanodelivery system of PEG-PCL nanoparticles with encapsulated nucleic acids–mannosylated PEI (Man-PEI) complexes was developed for intestinal delivery. We complexed model nucleic acids with Man-PEI at the optimal N/P ratio of 20:1 for in vitro and in vivo analyses. Cells were transfected in vitro and analyzed for gene expression, receptor-mediated uptake, and PEG-PCL nanoparticles’ toxicity. We also evaluated the nucleic acid’s stability in the nanocarrier during formulation, and under simulated gastrointestinal environments or the presence of nucleases. Finally, we assessed the biodistribution for the PEG-PCL nanoparticles with encapsulated complexes and their ability to transfect intestinal cells in vivo. Nucleic acids complexed with Man-PEI were protected from degradation against nucleases. In comparison to the parent compound PEI, Man-PEI transfected the cells with an overall higher potency. Competition assay indicated receptor-mediated endocytosis promoted by mannose receptors. The PEG-PCL nanoparticles with Man-PEI/plasmid complexes indicated minimal cytotoxicity. The nanocarrier successfully protected the complexes in a simulated gastric fluid environment and released them in a simulated intestinal fluid environment, promoted by the presence of lipases. The oral administration of the PEG-PCL nanoparticles with encapsulated Man-PEI/plasmid complexes transfected intestinal cells with the plasmid in vivo, while presenting a time-dependent progression through the intestines. Conclusively, our carrier system can deliver genetic material to the GI tract and actively target mannose receptor overexpressing cells.
Highlights
Oral delivery of active pharmaceutical ingredients has been the predominately preferred route of administration due to its simplicity and capacity to induce topical and systemic administration while promoting patient compliance [1]
As mannosylated PEI (Man-PEI) was previously studied for other routes of administration with advantageous and promising results [26,27,28], here we present a new application for the successful oral delivery of nucleic acids with the polymer
We evaluated the complexation of Man-PEI with a model nucleic acid, the pGL-3 luciferase-expressing plasmid, using gel retardation assay at different nitrogen to phosphate (N/P) ratios
Summary
Oral delivery of active pharmaceutical ingredients has been the predominately preferred route of administration due to its simplicity and capacity to induce topical and systemic administration while promoting patient compliance [1]. Among the different types of diseases, gastrointestinal diseases present a unique target for oral drug delivery, as it can achieve a direct and topical drug presence in the intestinal tissues without the need for or the side effects associated with systemic absorption or circulation. Inflammatory Bowel Diseases (IBD), such as Crohn’s disease and colitis, as well as intestinal and colorectal cancers (CRC), are prominent examples of gastrointestinal diseases. IBD is frequently observed in western countries and it is estimated that approximately 1.3% of adults are diagnosed with either Crohn’s or ulcerative colitis in the US alone [2].
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