Abstract
Polyethylenimine (PEI) is considered to be a promising non-viral gene delivery vector. To solve the toxicity versus efficacy and tumor-targeting challenges of PEI used as gene delivery vector, we constructed a novel non-viral vector DR5-TAT-modified Pluronic-PEI (Pluronic-PEI-DR5-TAT), which was based on the attachment of low-molecular-weight polyethylenimine (LMW-PEI) to the amphiphilic polymer Pluronic to prepare Pluronic-modified LMW-PEI (Pluronic-PEI). This was then conjugated to a multifunctional peptide containing a cell-penetrating peptide (TAT) and a synthetic peptide that would bind to DR5—a receptor that is overexpressed in cancer cells. The vector showed controlled degradation, favorable DNA condensation and protection performance. The Pluronic-PEI-DR5-TAT/DNA complexes at an N/P ratio of 15:1 were spherical nanoparticles of 122 ± 11.6 nm and a zeta potential of about 22 ± 2.8 mV. In vitro biological characterization results indicated that Pluronic-PEI-DR5-TAT/DNA complexes had a higher specificity for the DR5 receptor and were taken up more efficiently by tumor cells than normal cells, compared to complexes formed with PEI 25 kDa or Pluronic-PEI. Thus, the novel complexes showed much lower cytotoxicity to normal cells and higher gene transfection efficiency in tumor cells than that exhibited by PEI 25 kDa and Pluronic-PEI. In summary, our novel, degradable non-viral tumor-targeting vector is a promising candidate for use in gene therapy.
Highlights
In recent years, gene therapy has been considered to be the most promising strategy for the treatment of unresectable cancer
There is a critical need to develop a novel gene delivery system that can fulfill the special requirements for successful gene delivery, such as high transfection efficiency and low cytotoxicity as well as high level of targeting specificity to cancer cells
The results showed that the constructed novel gene delivery system has high non-viral transfection efficiency, high tumor cells, and tissuespecific targeting as well as good security and stability
Summary
Gene therapy has been considered to be the most promising strategy for the treatment of unresectable cancer. The vital technology for the success of gene therapy is gene delivery, which is greatly limited by the lack of a safe and efficient delivery system [1, 2]. There is a critical need to develop a novel gene delivery system that can fulfill the special requirements for successful gene delivery, such as high transfection efficiency and low cytotoxicity as well as high level of targeting specificity to cancer cells. Wu et al Nanoscale Research Letters (2016) 11:122 the stability of PEI/DNA complexes is improved as hydrophilicity increases, but this reduces the ability to penetrate cellular membranes. To overcome these limitations, considerable attempts have been made to modify PEI. Degradable PEIs have been formed by cross-linking with PEG/Pluronic chains that contain biodegradable moieties, and targeted vectors have been developed by combining PEI with ligands for cell- or tissue-specific targeting [15,16,17,18,19,20]
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