Journal
ACS OMEGA
Volume 4, Issue 4, Pages 6796-6807Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.8b02757
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Funding
- Politecnico di Milano
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The decoration of polyamidoamine (PAMAM) dendinhers with some functional moieties holds promises for improving the gene-delivery behavior of the resulting polyplexes. Herein, we reported the synthesis and the development of nonviral gene vectors built on an array of PAMAMs, spanning generation 2 (G2), G4, and G7, specifically tethered with multivalent neomycin (Neo) or guanidinoneomycin (GNeo). Following a thorough chemical characterization by means of NMR and MALDI analyses, the ability of PAMAM-(G)Neo conjugates to serve as transfectants was investigated. First, we demonstrated that every PAMAM, whether or not tethered with Neo (or GNeo), exhibited greater DNA packing ability than the gold standard transfectant 25 kDa bPEI. Measurements of the colloidal properties showed that PAMAMs, when mixed with plasmid DNA (pDNA) as a function of the nitrogen-to-phosphate ratio (N/P), allowed preparing complexes of approximate to 150-300 nm in diameter with a positive surface charge of approximate to+20-35 mV, strictly dependent on the PAMAM generation. The conjugation with Neo affected the DNA release behavior from PAMAM-based polyplexes and their ultimate transfection efficiency. When low generation PAMAM G2 was tethered with Neo, we obtained the most efficient transfectants, with remarkable antibacterial activity against Gram negative bacteria. It is worth noting that pDNA/PAMAM-(G)Neo nanoassemblies, which were tested at the optimal N/P, invariably showed better transfection efficiency than 25 kDa bPEI, along with low cytotoxicity in both HeLa and COS-7 cells. Altogether, these results underline the potential of such PAMAM-(G)Neo dendrimers as promising vehicles for efficient gene delivery into cells.
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