pH‐Tunable Endosomolytic Oligomers for Enhanced Nucleic Acid Delivery

Abstract

Oligomeric sulfonamides (OSAs) are explored as a tool for the effective endosomal release of polyplexes or delivery of nucleic acid. The OSAs tested in this study show varying proton‐buffering regions and pH‐dependent solubility transitions within the endosomal pH range, and are influenced by the pKa value and hydrophobicity of a given sulfonamide group. In addition, OSA presents negligible toxicity. The oligomers are added to the nucleic acid solution for polyplex formation with positively charged polymeric nucleic acid carriers. The resulting nanoscale, positively charged, and OSA‐incorporated poly(L‐lysine) (PLL)/DNA complexes (OSA‐polyplexes) show a 4–55‐fold increase in in vitro gene expression compared to PLL/DNA (control), depending upon the cell line and the nature of the used OSA. In cellular uptake and intracellular trafficking studies using pH‐sensitive or pH‐insensitive dye‐labeled DNAs, there is no significant difference in the amount of DNA uptake using OSA polyplexes and PLL/DNA. However, OSA–polyplexes induce a broader intracellular distribution of the DNA than PLL/DNA complexes do. These results, coupled with the enhanced DNA transfection using OSA–polyplexes, indicate a mechanism by which OSA induces endosomal release of polyplexes and/or nucleic acids. The findings suggest that OSA could enhance polymer‐based nucleic acid delivery. Furthermore, such materials offer significant potential for effective cytosolic delivery of chemical, biological, and diagnostic therapeutics.

All-trans-retinoic acid (ATRA)-grafted polymeric gene carriers for nuclear translocation and cell growth control

“…The particle sizes and surface charges of PRA/pDNA and PEI/ pDNA complexes prepared at various N/P ratios (e.g., [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] were measured as shown in Fig. 5(b) and (c).…”

“…These specific interactions improve the transfection efficiency of delivered transgenes at the cells of interest due both to cell targetability and facilitated cellular internalization. After the polyplexes are internalized, the endolysosomal escape of polyplexes or transgenes is crucial for the prevention of transgene degradation from lysosomal enzymes and can be conducted by polymeric materials evidencing proton buffering or pH-modulated conformational changes (e.g., polyethyleneimines (PEIs) [8], polyhistidines [9], poly(2-alkylacrylic acid) [10], and oligomeric sulfonamides [11]). In addition, for the facilitated nuclear import of polyplexes or transgenes released into the cytoplasm, nuclear localization signals (NLSs) have been assessed, because NLS can dilate nuclear pores and transport pharmaceutical cargos via the classical nuclear import pathway.…”

Tunable pH- and CO2-Responsive Sulfonamide-Containing Polymers by RAFT Polymerization

“…NMR spectra and monomer conversions were obtained using a Varian INOVA 300 MHz NMR spectrometer in DMSO-d 6 . Polymer molecular weights and molecular weight distributions (M w /M n ) were determined by size exclusion chromatography (SEC) using 95:5 (v:v) DMF:CH 3 COOH 20 mM LiBr as the eluent at a flow rate of 1.0 mL/min in combination with two Agilent PolarGel-M columns heated to 50°C and connected in series with a Wyatt Optilab DSP interferometric refractometer and Wyatt DAWN Scheme 1. pH-Dependent Solubility of pMSAs 11 sulfa drug (40.0 mmol) was dissolved in 160 mL of a 1:1 (v:v) mixture of acetone and 0.5 N aqueous NaOH and stirred while cooling in an ice bath. Methacryloyl chloride (4.10 mL, 42.0 mmol) was then added dropwise over 30 min followed by removing the ice bath and stirring the reaction at room temperature for an additional 60 min.…”

pH‐responsive poly(2‐ethylacrylic acid‐co‐alkyl methacrylate) copolymers as biomembrane switches

“…17 Figure 4 shows the copolymers' hemolytic activity data at three different pH values (5.8, 6.6, or 7.4) and three different concentrations (10,20, 50 lg/mL). The copolymer [poly(EAA-co-BMA)-1] is most hemolytic at pH 5.8, whereas the copolymer presented limited hemolytic activity at neutral pH and the lowest hemolytic at pH 7.4 at all concentrations tested.…”

“…[7][8][9] Another approach of the use of carboxylic acid-containing polyanions such as poly(2-alkylacrylic acid) and methacrylic acid copolymers demonstrate pHinduced coil-to-globule transitions. 10,11 These polymers contain a critical balance of acidic carboxyl groups and hydrophobic alkyl or aromatic groups. The carboxylate ion of these polymers become protonated at endosomal pH values, and the polymer undergo a change from a hydrophilic, biologically inert state to a hydrophobic and endosomal membrane-destabilizing one.…”