Dextran–Peptide Hybrid for Efficient Gene Delivery

Abstract

Gene therapy has drawn significant interest in the past two decades since it provides a promising strategy to treat both genetic disorders and acquired diseases. However, the transfer of gene therapy to clinical applications is troubled with many difficulties, since many current systems are of toxicity, low transfection efficiency and low biodegradability. To address these challenges, we developed a dextran-peptide hybrid system as a safe and efficient vector for gene therapy and investigated the structure-function-cytotoxicity relationship of this dextran-peptide hybrid system. Dextrans (Dex10, Dex20, and Dex70) with different molecular weights (10, 20 and 70 kDa) were conjugated with a cationic peptide, R5H5, at various degrees of substitution. Gene expression and cytotoxicity mediated by this delivery system were evaluated against SKOV-3 human ovarian carcinoma cells and compared to 25 kDa branched poly(ethylenimine) (PEI). The results showed that Dex10-R5H5 and Dex20-R5H5 hybrids derived from low molecular weight dextrans induced higher gene expression and lower cytotoxicity than Dex70-R5H5 hybrid from higher molecular weight dextran. The best performance on gene expression was achieved by Dex10-R5H5 at 40% substitution of R5H5, which induced greater gene expression than PEI at a low N/P ratio of 5. Dex10-R5H5/DNA complexes at 40% substitution of R5H5 also showed much higher cell viability (93%) than PEI/DNA (66%) at the same N/P ratio. These results indicate that the Dex-R5H5 hybrid with the low molecular weight of dextran and the high degree of substitution of R5H5 is a very promising material for safe and efficient gene therapy.

Synthesis and functionalization of dextran-based single-chain nanoparticles in aqueous media

“…22 Using highly polar solvents such as water and under controlled pH, thiols can be used as Michael donors in additions which proceed with high yields and selectivity in mild and clean conditions. [23][24][25] SCPNs resembling disordered proteins were recently prepared by Pomposo et al through classic Michael addition between polymeric precursors The degree of substitution of DXT-MA (DS, MA groups per repeating unit) was around 52%, which is high enough to allow for both intrachain collapse and further functionalization of DXT-SCPN and low enough to maintain water dispersibility. As an example of functionalization, we incorporated carboxylic groups into DXT-SCPN by reaction with mercaptopropionic acid (MPA).…”

Targeting the C-type Lectins-Mediated Host-Pathogen Interactions with Dextran

“…Skewing the T helper responses could be a mechanism that allowed dextran derivatives to decrease tissue remodelling in the BCG infection model (159, 166) (Figure 4). Dextran has been recently used as a backbone for the nucleic acids delivery conjugate and our analysis could help in the development of this field (199). We also note that dextran could be of use in the glycosilation of adenoviruses used for gene transfer (200), possibly improving the biocompatibility and providing predictable uptake by certain cell types and receptors.…”

Amino Acid–Substituted Dextran‐Based Non‐Viral Vectors for Gene Delivery

“…The compaction of DNA decreased about 25% for arginine versus lysine peptides with the same charge . The role of histidine for the condensation of DNA as well as the control of the endosomal release owing to its high buffering capacity, could be shown by several authors (ref) using, for example, histidine containing peptide grafted dextran . In addition, the position of the amino group seemed to be of great interest for the resulting properties, which has been shown for the different performance of amphiphilics with alanine and β‐alanine head groups .…”