2 research outputs found
Parallel Synthesis and Quantitative Structure–Activity Relationship (QSAR) Modeling of Aminoglycoside-Derived Lipopolymers for Transgene Expression
We
describe the parallel synthesis of lipopolymers generated by
conjugating alkanoyl chlorides to polymers derived from aminoglycoside
antibiotic monomers as novel vehicles for transgene delivery and expression
in mammalian cells. Parallel screening of lipopolymers led to the
identification of six leads that demonstrated higher transgene expression
efficacies in several cancer cells, when compared to the parental
polymers as well as 25 kDa polyÂ(ethylene imine), a current standard
for polymer-mediated transgene expression. Quantitiative structure–activity
relationship (QSAR)-based cheminformatics modeling was employed in
order to investigate the role of lipopolymer physicochemical properties
(molecular descriptors) on transgene expression efficacy. The predictive
ability of the QSAR model, investgated using lipopolymers not employed
for training the model, demonstrated excellent agreement with experimentally
observed transgene expression. Our findings indicate that lipid substitution
on aminoglycoside-derived polymers results in high levels of transgene
expression compared to unsubstituted polymers. Taken together, these
materials show significant promise in nonviral transgene delivery
with several applications in biotechnology and medicine
Aminoglycoside Antibiotic-Derived Anion-Exchange Microbeads for Plasmid DNA Binding and in Situ DNA Capture
Plasmid DNA (pDNA) therapeutics are
being investigated for gene therapy and DNA vaccines against diseases
including cancer, cystic fibrosis and AIDS. In addition, several applications
in modern biotechnology require pDNA for transient protein production.
Here, we describe the synthesis, characterization, and evaluation
of microbeads (“Amikabeads”) derived from the aminoglycoside
antibiotic amikacin for pDNA binding and in situ DNA capture from
mammalian cells. The parental aminoglycoside-derived microbeads (Amikabeads-P)
acted as anion-exchange materials, and demonstrated high capacities
for binding pDNA. Binding of pDNA was significantly enhanced following
quaternization of the amines on the microbeads (Amikabeads-Q). Amikabeads
were further employed for the disruption and extraction of DNA from
mammalian cells, indicating their utility for in situ DNA capture.
Our results indicate that Amikabeads are a novel material, with multiple
reactive groups for further conjugation, and can have several applications
in plasmid DNA biotechnology