Herein, we report the photoinitiated polymerizationinduced self-assembly (photo-PISA) of spherical micelles consisting of proapoptotic peptide-polymer amphiphiles. The one-pot synthetic approach yielded micellar nanoparticles at high concentrations and at scale (150 mg mL À1) with tunable peptide loadings up to 48 wt. %. The size of the micellar nanoparticles was tuned by varying the lengths of hydrophobic and hydrophilic building blocks. Critically, the peptide-functionalized nanoparticles imbued the proapoptotic "KLA" peptides (amino acid sequence: KLAKLAKKLAKLAK) with two key properties otherwise not inherent to the sequence: 1) proteolytic resistance compared to the oligopeptide alone; 2) significantly enhanced cell uptake by multivalent display of KLA peptide brushes. The result was demonstrated improved apoptosis efficiency in HeLa cells. These results highlight the potential of photo-PISA in the large-scale synthesis of functional, proteolytically resistant peptide-polymer conjugates for intracellular delivery.
Over
the past decade, the field of polymer–oligonucleotide
nanomaterials has flourished because of the development of synthetic
techniques, particularly living polymerization technologies, which
provide access to polymers with well-defined architectures, precise
molecular weights, and terminal or side-chain functionalities. Various
“living” polymerization methods have empowered chemists
with the ability to prepare functional polymer–oligonucleotide
conjugates yielding a library of architectures, including linear diblock,
comb, star, hyperbranched star, and gel morphologies. Since oligonucleotides
are hydrophilic and synthetic polymers can be tailored with hydrophobicity,
these amphiphilic polymer–oligonucleotide conjugates are capable
of self-assembling into nanostructures with different shapes, leading
to many high-value-added biomedical applications, such as drug delivery
systems, gene regulation, and 3D-bioprinting. This review aims to
highlight the main living polymerization approaches to polymer–oligonucleotide
conjugates, including ring-opening metathesis polymerization, atom
transfer radical polymerization (ATRP), reversible addition–fragmentation
transfer polymerization (RAFT), and ring-opening polymerization of
cyclic esters and N-carboxyanhydride. The self-assembly
properties and resulting applications of polymer–DNA hybrid
materials are highlighted as well.
Harnessing metal‐free photoinduced reversible‐deactivation radical polymerization (photo‐RDRP) in organic and aqueous phases, we report a synthetic approach to enzyme‐responsive and pro‐apoptotic peptide brush polymers. Thermolysin‐responsive peptide‐based polymeric amphiphiles assembled into spherical micellar nanoparticles that undergo a morphology transition to worm‐like micelles upon enzyme‐triggered cleavage of coronal peptide sidechains. Moreover, pro‐apoptotic polypeptide brushes show enhanced cell uptake over individual peptide chains of the same sequence, resulting in a significant increase in cytotoxicity to cancer cells. Critically, increased grafting density of pro‐apoptotic peptides on brush polymers correlates with increased uptake efficiency and concurrently, cytotoxicity. The mild synthetic conditions afforded by photo‐RDRP, make it possible to access well‐defined peptide‐based polymer bioconjugate structures with tunable bioactivity.
Peptide-brush polymers
(PBPs), wherein every side-chain of the
polymers is peptidic, represent a new class of proteomimetic with
unusually high proteolytic resistance while maintaining bioactivity.
Here, we sought to determine the origin of this behavior and to assess
its generality via a combined theory and experimental approach. A
series of PBPs with various polymer backbone structures were prepared
and examined for their proteolytic stability and bioactivity. We discovered
that an increase in the hydrophobicity of the polymer backbones is
predictive of an elevation in proteolytic stability of the side-chain
peptides. Computer simulations, together with small-angle X-ray scattering
(SAXS) analysis, revealed globular morphologies for these polymers,
in which pendant peptides condense around hydrophobic synthetic polymer
backbones driven by the hydrophobic effect. As the hydrophobicity
of the polymer backbones increases, the extent of solvent exposure
of peptide cleavage sites decreases, reducing their accessibility
to proteolytic enzymes. This study provides insight into the important
factors driving PBP aqueous-phase structures to behave as globular,
synthetic polymer-based proteomimetics.
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