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(555c) pH Responsive Polycationic Nanoparticles for siRNA Delivery in Inflammatory Bowel Diseases

Authors: 
Shodeinde, A. B., The University of Texas at Austin
Wagner, A., The University of Texas at Austin
Peppas, N. A., University of Texas at Austin

Title:   pH responsive polycationic
nanoparticles for siRNA delivery in Inflammatory Bowel Diseases

Authors: 
Aaliyah B.
Shodeinde1,2, Angela M. Wagner1,2, Noor Al-Sayyad3
and Nicholas A. Peppas1,2,4,5,6

McKetta Department of Chemical Engineering, The University of
Texas at Austin, Austin, TX, USA 

2 Institute for Biomaterials, Drug Delivery, and
Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA

3 Department of Physics, The
University of Texas at Austin, Austin, Texas, USA

4 Department of Biomedical Engineering, The University of
Texas at Austin, Austin, Texas, USA

5 Department of Pediatrics, and Department of Surgery and
Perioperative Care, Dell Medical School, The University of Texas at Austin,
Austin, TX, USA

Division of Molecular Pharmaceutics and Drug Delivery, College
of Pharmacy, The University of Texas at Austin, Austin, TX, USA

The
RNA interference (RNAi) mechanism has become an increasingly desirable approach
to elicit gene knockdown. Specifically, small interfering RNAs (siRNA) have
been successfully incorporated within the native RNAi machinery to induce the
degradation of undesirable mRNA in multiple pathogeneses. Due to the ease of
enzymatic degradation of siRNA in addition to their propensity for renal
clearance upon systemic administration, it is essential to develop novel
carriers to ensure the delivery of the payload to the desired site of action.
We report a novel method for the synthesis of a methacrylate based polycationic
nanoparticle system in aqueous media. These nanoparticles have been shown to exhibit
lower pKa values than previous cationic nanoparticle formulations, preventing
premature swelling upon interaction with the intestinal mucosa. Furthermore, greater
localization of the siRNA payload within the nanoparticle core has been
observed which ensures siRNA protection pending cellular internalization.

The physical properties of the resulting
nanoparticles were characterized using dynamic light scattering, zeta
potential, titration, pyrene fluorescence, and red blood cell hemolysis to deduce
the influence of polymer composition on surface charge, pKa, swelling ratio, hydrophile-hydrophobe
phase transition, and erythrocyte membrane disruption capability. In vitro biocompatibility
was assessed with relevant cell lines using MTS cell proliferation and LDH
membrane integrity assays. The delivery capacity of the nanoparticles was
analyzed using multiple agents for loading and release studies.