Disulfide-Containing Brushed Polyethylenimine Derivative Synthesized by Click Chemistry for Nonviral Gene Delivery

Abstract

Polyaspartamide-based disulfide-containing brushed polyethylenimine derivatives P(Asp-Az)X-SS-PEIs were synthesized via click chemistry and evaluated as nonviral gene delivery carrier. First, azide-functional poly(aspartic acid) derivatives with various azide-group densities and monoalkyne-terminated PEI with disulfide linkages were synthesized. Then, click reaction between the azide-functional poly(aspartic acid) derivative as main chain and the monoalkyne-terminated PEI as branched chain resulted in high-molecular-weight disulfide-containing brushed PEI derivative. The structure of obtained polymers was confirmed by (1)H NMR and FTIR. It was shown that the disulfide-containing P(Asp-Az)X-SS-PEIs were able to bind plasmid DNA and condense DNA into small positive nanoparticles. The reduction-sensitivity of the P(Asp-Az)X-SS-PEI/DNA polyplexes was confirmed by gel retardation assay and dynamic light scattering (DLS) in the presence of DTT. In vitro experiments revealed that the reducible P(Asp-Az)X-SS-PEI not only had much lower cytotoxicity, but also posed high transfection activity (both in the presence and absence of serum) as compared to the control nondegradable 25 kDa PEI. This study indicates that a reducibly degradable brushed polymer P(Asp-Az)X-SS-PEI composed of low-molecular-weight (LMW) PEI via a disulfide-containing linkage can be a promising gene delivery carrier.

Facile synthesis of thermosensitive functional polyaspartamide derivatives by click chemistry

“…1 H NMR spectra of P(Asp‐Az) X ‐HPA polymers (Fig. ) were determined with different solvents according to our previous work . It can be seen from Figure (A–C) that no peak around 5.3 ppm is observed, which indicates no unreacted succinimide rings existed in all obtained P(Asp‐Az) X ‐HPAs.…”

“…Although the PEGylation phe‐ g ‐PHPAs were synthesized as drug delivery for paclitaxel (PTX), grafting efficiency of aromatic rings to poly‐(5‐hydroxypentyl‐ N ‐α/β asparagines) (PHPA) was <50% . Because of the high selectivity and high fidelity, “click” chemistry has rapidly become a very popular method for polymer synthesis and modification . In this study, two examples of thermoresponsive polyaspartamide derivatives containing pendant aromatic structures and thermo/pH‐responsive polyaspartamide derivatives containing pendant imidazole rings were designed and synthesized successfully with very high reaction efficiency by click chemistry as depicted in Scheme .…”

A review of the developments of characteristics of PEI derivatives for gene delivery applications

“…It was shown that a higher degree of thiolation resulted in smaller nanoparticles (Figure ) . Another important approach for thiolating PEI involves employing various kinds of crosslinkers containing disulfide linkages; this is the most common strategy for providing bioreducibility to polymers …”

A family of cationic polyamides for in vitro and in vivo gene transfection

“…In addition to aminobutanol and disulfide linkage, other hit functionalities used for the design of potent polymeric gene delivery vectors largely encompass oligoamine, low-molecular weight BPEI and imidazole group [12]. For example, bioreducible BPEIs obtained by disulfide-crosslinking of low-molecular weight BPEI were found to be highly potent for in vitro gene delivery followed by low cytotoxicity [13,14]. Bioreducible poly(amido amine)s with imidazole side chain displayed superior transfection activity to 25 kDa BPEI [15,16].…”