6 research outputs found
Elastin-Like Peptide Amphiphiles Form Nanofibers with Tunable Length
Peptide amphiphiles (PAs) self-assemble nanostructures
with potential
applications in drug delivery and tissue engineering. Some PAs share
environmentally responsive behavior with their peptide components.
Here we report a new type of PAs biologically inspired from human
tropoelastin. Above a lower critical solution temperature (LCST),
elastin-like polypeptides (ELPs) undergo a reversible inverse phase
transition. Similar to other PAs, elastin-like PAs (ELPAs) assemble
micelles with fiber-like nanostructures. Similar to ELPs, ELPAs have
inverse phase transition behavior. Here we demonstrate control over
the ELPAs fiber length and cellular uptake. In addition, we observed
that both peptide assembly and nanofiber phase separation are accompanied
by a distinctive secondary structure attributed primarily to a type-1
β turn. We also demonstrate increased solubility of hydrophobic
paclitaxel (PAX) in the presence of ELPAs. Due to their biodegradability,
biocompatibility, and environmental responsiveness, elastin-inspired
biopolymers are an emerging platform for drug and cell delivery; furthermore,
the discovery of ELPAs may provide a new and useful approach to engineer
these materials into stimuli-responsive gels and drug carriers
Multimeric Disintegrin Protein Polymer Fusions That Target Tumor Vasculature
Recombinant protein therapeutics
have increased in number and frequency
since the introduction of human insulin, 25 years ago. Presently,
proteins and peptides are commonly used in the clinic. However, the
incorporation of peptides into clinically approved nanomedicines has
been limited. Reasons for this include the challenges of decorating
pharmaceutical-grade nanoparticles with proteins by a process that
is robust, scalable, and cost-effective. As an alternative to covalent
bioconjugation between a protein and nanoparticle, we report that
biologically active proteins may themselves mediate the formation
of small multimers through steric stabilization by large protein polymers.
Unlike multistep purification and bioconjugation, this approach is
completed during biosynthesis. As proof-of-principle, the disintegrin
protein called vicrostatin (VCN) was fused to an elastin-like polypeptide
(A192). A significant fraction of fusion proteins self-assembled into
multimers with a hydrodynamic radius of 15.9 nm. The A192-VCN fusion
proteins compete specifically for cell-surface integrins on human
umbilical vein endothelial cells (HUVECs) and two breast cancer cell
lines, MDA-MB-231 and MDA-MB-435. Confocal microscopy revealed that,
unlike linear RGD-containing protein polymers, the disintegrin fusion
protein undergoes rapid cellular internalization. To explore their
potential clinical applications, fusion proteins were characterized
using small animal positron emission tomography (microPET). Passive
tumor accumulation was observed for control protein polymers; however,
the tumor accumulation of A192-VCN was saturable, which is consistent
with integrin-mediated binding. The fusion of a protein polymer and
disintegrin results in a higher intratumoral contrast compared to
free VCN or A192 alone. Given the diversity of disintegrin proteins
with specificity for various cell-surface integrins, disintegrin fusions
are a new source of biomaterials with potential diagnostic and therapeutic
applications