In addition to formation of injectable materials by guest-host mediated self- assembly, these unique interactions have significant applications in drug delivery strategies. The most widely used materials in this field have been the CD macrocycles, as they have been used in many pharmacological drug formulations including Sporanox©, Yaz©, and Abilify© among others.89 CDs form inclusion complexes with
various drugs, which improves the drug bioavailabilty by increasing drug solubility and protecting them from degradation, which has been reviewed extensively elsewhere.13,89,90 Guest-host interactions have also been used recently to develop materials as drug delivery systems, providing novel biofunctionality through non-covalent conjugation of bioactive pendant groups, as well as the development of bulk materials to provide the controlled release of growth factors, genetic material, and small molecule therapeutics.
While improving the physiochemical properties of drugs has prevailed in the translational application of guest-host complexes, more advanced nanoparticle systems
are also being developed. These systems leverage the formation of guest-host complexes as a conjugation strategy to provide stealth or targeting, or to allow nanoparticles to carry hydrophobic payloads (Figure 3.4A). Work from the Davis group provides an excellent example of exploiting guest-host complexes in delivery systems that have translated to clinical trials.91 They developed CD functionalized polymer
backbones that form polyplexes with siRNA payloads, with surfaces that may be decorated with Ad coupled macromolecules such as PEG or transferrin.92-94 This type of
conjugation allows for rapid and modular modification of particle systems with a variety of ligands. Similar non-covalent conjugation strategies have been employed using other guest-host pairs such as CB[6] with polyamines to provide targeted delivery of nanocapsules.95,96 In addition to strategies for noncovalent surface modification,
macrocycles have been incorporated into nanoparticles to act as molecular “docking” sites that can facilitate drug loading (Figure 3.4B). This carrier functionality has been
exploited using amphiphilic CD nanocapsules to entrap tamoxifen, ionic βCD
nanoparticles as doxorubicin carriers, and CB[6] particles to carry paclitaxel.96-98 Furthermore, macrocycle interactions have provided an avenue for direct, noncovalent conjugation of biofunctional groups to drug molecules (Figure 3.4C). As examples, βCD functionalized with lactoferrin and saccharide ligands has been used to complex and target drugs to lactoferrin and mannose receptors, respectively.99,100
In addition to nanoparticle strategies, guest-host systems have been leveraged in bulk hydrogels to provide controlled release of therapeutic payloads. Many groups have employed guest-host assembly to drive the formation of hydrogels that can provide sustained release of biomolecule payloads such as proteins and growth factors (Figure 3.4D). These systems provide diffusive release kinetics that may be tuned through network properties such as porosity, mesh size, and degradation, which may in part be mediated by dynamic supramolecular interactions. For example, Liu et al used
polyrotaxane assembly between αCD and tri-block copolymers to form gels that display tunable sustained release of dextran molecules as a model for release.101 Furthermore,
the Scherman group developed systems based on CB[8] assembly that provide tunable release of bioactive proteins over sustained periods in vitro, as previously discussed.85
Finally, work from the Hennink group as well as our own have shown tunable protein release from βCD-based hydrogels, where crosslink density was used to control release for up to 60 days.65,102 These applications have recently been extended in vivo, where
the guest-host hydrogel was used as an injectable material for diffusive local delivery of multiple biomolecules (interleukin-10 and anti-transforming growth factor β) to treat chronic kidney injury.103 Similarly, hydrogels composed of αCD pseudopolyrotaxanes
with PEO terminated block copolymers have been used as an injectable reservoir for delivery of erythropoietin (EPO) in a rodent model of MI. The therapy resulted in a tendency toward increased vascular density as well as a significant decline in apoptosis and increase in myocardial function (fractional shortening) as compared to saline, hydrogel alone, and soluble EPO injection. These examples demonstrate the multifaceted use of such material systems as an easily prepared injectable material to generate diffusively controlled drug delivery reservoirs in vivo.
A last mechanism by which guest-host interactions can control release of molecules is through inclusion effects of therapeutics with macrocycles anchored to a polymer backbone (Figure 3.4E). Several groups have investigated covalently crosslinked hydrogels containing CD pendant groups to provide sustained release of small molecules.104-109 In one example, the von Recum group developed polyurethane
gels containing CD as device coatings for the controlled release of numerous antibiotics.110 Work from our own group has also explored CD retentive effects for
controlled release of small molecules including doxorubicin, doxycycline, and peptides containing tryptophan residues, from guest-host assembled networks, leveraging these
interactions to provide materials that are simultaneously injectable and exhibit sustained release properties.109 These systems provide tunable small molecule release through the
engineering of host content, as well as the guest affinity for the host included in the network.
Figure 3.4. Guest-host interactions in drug delivery systems. Guest-host chemistry
may be used for direct, non-covalent modification of drug molecules with targeting ligands (A), to provide non-covalent modification of nanoparticle drug carriers with targeting or stealth ligands (B), and to impart molecular carrier functionality to nanoparticles (C). Furthermore, in hydrogel systems, guest-host chemistry may be used to tune crosslinks in hydrogels for the diffusive release of biomacromolecular therapeutics (D) or to promote retention of small molecule therapeutics within the hydrogel (E).