2 research outputs found
PEGylated Cationic Polylactides for Hybrid Biosynthetic Gene Delivery
Genetic vaccination is predicated
on the underlying principle that
diseases can be prevented by the controlled introduction of genetic
material encoding antigenic proteins from pathogenic organisms to
elicit the formation of protective immune responses. Driving this
process is the choice of carrier that is responsible for navigating
the obstacles associated with gene delivery. In this work, we expand
upon a novel class of hybrid biosynthetic gene delivery vectors that
are composed of a biomaterial outer coating and a bacterial (<i>Escherichia coli</i>) inner core. Specifically, a series of
newly developed biodegradable cationic polylactides (CPLAs) and their
PEGylated variants were selected to investigate the role of low polydispersity
index (PDI), charge density, and PEGylation upon hybrid vector assembly
and gene delivery efficacy. Upon assembly, hybrid vectors mediated
increased gene delivery beyond that of the individual bacterial vector
in isolation, including assays with increasing medium protein content
to highlight shielding properties afforded by the PEG-functionalized
CPLA component. Furthermore, after extensive characterization of surface
deposition of the polymer, results prompted a new model for describing
hybrid vector assembly that includes cellular coating and penetration
of the CPLA component. In summary, these results provide new options
and insight toward the assembly and application of next-generation
hybrid biosynthetic gene delivery vectors
Structure–Function Assessment of Mannosylated Poly(β-amino esters) upon Targeted Antigen Presenting Cell Gene Delivery
Antigen
presenting cell (APC) gene delivery is a promising avenue
for modulating immunological outcomes toward a desired state. Recently,
our group developed a delivery methodology to elicit targeted and
elevated levels of APC-mediated gene delivery. During these initial
studies, we observed APC-specific structure–function relationships
with the vectors used during gene delivery that differ from current
non-APC cell lines, thus, emphasizing a need to re-evaluate vector-associated
parameters in the context of APC gene transfer. Thus, we describe
the synthesis and characterization of a second-generation mannosylated
polyÂ(β-amino ester) library stratified by molecular weight.
To better understand the APC-specific structure–function relationships
governing polymeric gene delivery, the library was systematically
characterized by (1) polymer molecular weight, (2) relative mannose
content, (3) polyplex biophysical properties, and (4) gene delivery
efficacy. In this library, polymers with the lowest molecular weight
and highest relative mannose content possessed gene delivery transfection
efficiencies as good as or better than commercial controls. Among
this group, the most effective polymers formed the smallest polymer-plasmid
DNA complexes (∼300 nm) with moderate charge densities (<10
mV). This convergence in polymer structure and polyplex biophysical
properties suggests a unique mode of action and provides a framework
within which future APC-targeting polymers can be designed