(Macro)molecular self-assembly for hydrogel drug delivery

Abstract

Hydrogels prepared via self-assembly offer scalable and tunable platforms for drug delivery applications. Molecular-scale self-assembly leverages an interplay of attractive and repulsive forces; drugs and other active molecules can be incorporated into such materials by partitioning in hydrophobic domains, affinity-mediated binding, or covalent integration. Peptides have been widely used as building blocks for self-assembly due to facile synthesis, ease of modification with bioactive molecules, and precise molecular-scale control over material properties through tunable interactions. Additional opportunities are manifest in stimuli-responsive self-assembly for more precise drug action. Hydrogels can likewise be fabricated from macromolecular self-assembly, with both synthetic polymers and biopolymers used to prepare materials with controlled mechanical properties and tunable drug release. These include clinical approaches for solubilization and delivery of hydrophobic drugs. To further enhance mechanical properties of hydrogels prepared through self-assembly, recent work has integrated self-assembly motifs with polymeric networks. For example, double-network hydrogels capture the beneficial properties of both self-assembled and covalent networks. The expanding ability to fabricate complex and precise materials, coupled with an improved understanding of biology, will lead to new classes of hydrogels specifically tailored for drug delivery applications.

Keywords: Biomaterials; Block copolymers; Molecular engineering; Peptide self-assembly; Supramolecular chemistry.

Figure 1:

(A) Non-polar motifs can be coupled to peptides to (B) drive self-assembly through hydrophobic association. (C) Directional non-covalent interactions between adjacent molecules, such as the formation of β-sheet hydrogen bonding networks, drives the formation of high-aspect ratio nanostructures. (D) Peptides can form ordered arrangements of hydrogen bonds (in red), most often resembling β-sheet secondary structures, by positioning adjacent proton donors and acceptors on their amide backbone. (E) Hydrogen bond networks drive axial organization are are a common driving force for the formation of high-aspect ratio nanostructures.

Figure 2:

(A) Peptides can be modified with hydrophobic aromatic groups both as terminal prosthetic groups and through the inclusion of aromatic amino acids like phenylalanine. (B) This design enables directional π-π stacking, (C) leading to axial organization and nanofibril formation.

Figure 3:

(A) Self-assembling peptides typically contain hydrophilic domains comprised of charged amino acids, leading to electrostatic repulsion which may disfavor self-assembly under physiological conditions. (B) These repulsive forces can be overcome to drive self-assembly and/or stabilize assembled nanostructures by changing pH or adding ions, like calcium, to screen and/or bridge charged groups.

Figure 4:

Bioactivity can be incorporated into self-assembled hydrogels by (A) the addition of cell-signaling peptides on the exterior of nanostructures or (B) the inclusion of binding sequences for bioactive proteins.

Figure 5:

Self-assembled nanostructures are able to sequester drugs through (A) encapsulation due to hydrophobic partitioning or (B) covalent conjugation to the peptide sequence.

Figure 6:

(A) Self-assembling peptides can be designed as substrates for cell-secreted enzymes such as kinases, (B) which enables these enzymes to be cues for disassembly and drug release from peptide-based carriers. This figure illustrates concepts from reference .

Figure 7:

(A) Self-assembling peptides can be mixed with biopolymers and biopolymer-binding growth factors. (B) Self-assembly of these components creates protein-loaded nanofibrous hydrogels. (C) These peptides contain a substrate for MMP-2, with this protease promoting hydrogel degradation and growth factor release. This figure illustrates concepts from reference .

Figure 8:

(A) Example of thermoresponsive ABA block copolymer gelators which feature two hydrophilic PEG blocks flanking a midblock prepared from a polymer which transitions to hydrophobic according to a temperature stimulus. Shown are the structures of PEG-PPO-PEG and PEG-PLLA-PEG copolymers. These polymers transition from a soluble sol state to a hydrogel state characterized by packed micelle structures. (B) Example of thermoresponsive BAB block copolymer gelators which feature a PEG midblock flanked by two blocks prepared from a polymer which transitions to hydrophobic according to a temperature stimulus. Shown are the structures of PLGA-PEG-PLGA and PCL-PEG-PCL copolymers. These copolymers transition from a soluble sol state to a hydrogel state characterized by self-associating aggregates of the ‘A’ blocks which are bridged by soluble PEG chains.

Figure 9:

The mechanical properties of self-assembling hydrogels can be improved through conjugation to a covalent polymer network. These hybrid-hydrogel networks and be made through (A) direct conjugation of peptides to the polymer network or (B) growing peptides from functional groups on the polymer backbone. Panel A is based on concepts from reference and Panel B is based on concepts from reference .

Figure 10:

Hydrogel networks with coupled covalent and non-covalent interactions have exceptional mechanical properties, including stretchability and fracture toughness. Figure based on concepts from reference .