Self-Catalyzed Degradable Cationic Polymer for Release of DNA

Abstract

The controlled release of siRNA or DNA complexes from cationic polymers is an important parameter design in polymer-based delivery carriers. In this work, we use the self-catalyzed degradable poly(2-dimethylaminoethyl acrylate) (PDMAEA) to strongly bind, protect, and then release oligo DNA (a mimic for siRNA) without the need for a cellular or external trigger. This self-catalyzed hydrolysis process of PDMAEA forms poly(acrylic acid) and N,N'-dimethylamino ethyl ethanol, both of which have little or no toxicity to cells, and offers the advantage of little or no toxicity to off-target cells and tissues. We found that PDMAEA makes an ideal component of a delivery carrier by protecting the oligo DNA for a sufficiently long period of time to transfect most cells (80% transfection after 4 h) and then has the capacity to release the DNA inside the cells after ~10 h. The PDMAEA formed large nanoparticle complexes with oligo DNA of ~400 nm that protected the oligo DNA from DNase in serum. The nanoparticle complexes showed no toxicity for all molecular weights at a nitrogen/phosphorus (N/P) ratio of 10. Only the higher molecular weight polymers at very high N/P ratios of 200 showed significant levels of cytotoxicity. These attributes make PDMAEA a promising candidate as a component in the design of a gene delivery carrier without the concern about accumulated toxicity of nanoparticles in the human body after multiadministration, an issue that has become increasingly more important.

An influenza virus-inspired polymer system for the timed release of siRNA

“…Single electron transfer-living radical polymerization (SET-LRP) 34 32,33 , and thus was used as the first block in this work. PDMAEA 65 was extended with blocks containing units of ImPAA, BA and/or dimethylacrylamide (DMA) comonomers as shown in Fig.…”

“…The complication arises in that many tissues and organs are not remotely accessible, and environmentally triggered stimuli can vary between cell lines and even within the same tissue or organ. Furthermore, after degradation, the polymers should form biologically benign particles avoiding toxic buildup in the tissues 32,33 .…”

Functionalized large pore mesoporous silica nanoparticles for gene delivery featuring controlled release and co-delivery

“…Previously, we have reported the use of poly-l-lysine (PLL) functionalised large pore mesoporous silica nanoparticles (LPMSN-P) as gene carriers. 15 PLL-functionalized nanoparticles had a strong binding towards nucleic acid molecules and delivered oligo DNA-Cy3 (a model 60 for siRNA) efficiently to HeLa cells. However, the low release of siRNA from the complex limited the effectiveness of this system.…”

“…23,24,25 In this work, we used PDMAEA covalently attached to the surface of large pore mesoporous silica nanoparticles (PDMAEA-LPMSN) to act as a dual delivery system. The surface bound PDMAEA can bind and release 15 siRNA 'on-demand'. Chloroquine was loaded in the nanopores of LPMSN as a model drug which helps endosome escape.…”

“…The reaction was maintained at 70 ºC for 24 hours. The product was 15 washed with toluene and methanol and followed by surfactant removal. The surfactant removal was conducted by using an extraction process in acidic-methanol for 24 hours and the process was repeated three times.…”