Stabilization of a hyaluronate-associated gene delivery system using calcium ions

Abstract

A “DPH” ternary complex consisting of plasmid DNA (pDNA), intracellularly degradable polyethyleneimine, and hyaluronic acid (HA) is a promising non-viral gene carrier with low toxicity and good gene transfection efficiency. HA plays a key role in providing an optimal balance between DNA protection and release, but it causes aggregation due to the entanglement of HA chains of neighbouring DPH particles. Here we report that the addition of an optimal level of Ca2+ successfully prevents particle aggregation and maintains a relatively small size. The Ca-stabilized DPH is comparable to DPH in cytotoxicity and gene transfection efficiency. MW monitoring and conductometric titration suggest that such size stabilization effect is partly mediated by the complexation between HA and Ca2+, which enables intra- and intermolecular interactions of HAs.

Chemistry specificity of DNA–polycation complex salt response: a simulation study of DNA, polylysine and polyethyleneimine

“…12 Furthermore, Ca 2+ ions are known to promote transfection, possibly by regulating the size or aggregation of the complexes, or by aiding in the release of the genetic material from the complex. [13][14][15] Indeed, we recently demonstrated the sensitivity of poly-L-lysine-DNA complexes to Ca 2+ ions and provided an atomistically detailed description of the dissociation mechanism via molecular simulations. 16 Therefore, the response of polycation-DNA complexes to small ions is a significant topic with direct implications to the design of efficient gene carriers.…”

Redox Sensitive Nanoparticles with Disulfide Bond Linked Sheddable Shell for Intracellular Drug Delivery

“…Most redoxsensitive NPs contain disulfide bond (-S-S-) linked PEG shell, which can be cleaved rapidly in reductive environment analog to tumor intracellular environment, while relatively stable in blood circulation ( Figure 2) [26,27,31]. The most often used disulfide bond containing agents are cystamine [32][33][34], dithiodipropionic acid [35], bis(2-methacryloyloxyethyl) disulfide [36], dimethyl 3,3-dithiobispropionimidate (DTBP) [37], 3,3'-dithiobis(sulfosuccin imidyl propionate) (DTSSP) [38], dithiobis (succinimidylpropionate) (DSP) [39], 2-(pyridyldithio)-ethylamine (PDA) [40], cystamine bisacrylamide (CBA) [41], and N-Succinimidyl 3-(2-pyridyldithio) propionate (SPDP) [42]. Table 1 summarizes some representative NPs that bear disulfide bonds or other crosslinker with a sheddable shell for intracellular drug or gene delivery.…”

Linear Poly(ethylenimine-propylenimine) Random Copolymers for Gene Delivery: From Polymer Synthesis to Efficient Transfection with High Serum Tolerance

“…Polymer hydroxylation 40 or PEGylation 41 may be employed to decrease protein binding, but it can also lead to less efficient DNA packing and lowered transfection efficiencies. 42 Strengthening polymer−DNA interactions by incorporating additional stabilizing forces such as aromatic intercalation, 43 hydrogen bonds, 44 physical crosslinks, 45 and chemical cross-links 46 reduces the nonspecific binding of serum proteins and the resulting aggregation, yet these additional interactions may also hinder transfection. 42 The introduction of hydrophobic moieties helps shield the polyplexes from the adherence of anionic blood components and prevents dissociation by serum proteins.…”