Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness

Abstract

Bottlebrush polymers have great potential as vehicles to noncovalently sequester, stabilize, and deliver hydrophobic small molecule actives. To this end, we synthesized a poly(Nisopropylacrylamide-stat-N,N-dimethylacrylamide) bottlebrush copolymer using ring-opening metathesis polymerization and developed a facile method to control the thermoresponsive properties using postpolymerization modification. Six increasingly hydrophilic end-groups were installed, yielding cloud point temperature control over a range of 22−42 °C. Solubility enhancement of the antiseizure medication, phenytoin, increased significantly with the hydrophilicity of the end-group moiety. Notably, carboxylated bottlebrush copolymers solubilized formulations with higher drug loadings than linear copolymers because they exist as unimolecular nanoparticles with a synthetically defined density of polymer chains that are more stable in solution. This work provides the first investigation of bottlebrush polymers for hydrophobic noncovalent sequestration and solubilization of pharmaceuticals.

Tuning the Hydrophilic–Hydrophobic Balance of Molecular Polymer Bottlebrushes Enhances their Tumor Homing Properties

“…A copper‐catalysed azide‐alkyne cycloaddition (CuAAC) reaction was then used to “click” an ATTO 633‐ or Cy5‐alkyne fluorophore to the MPBs. [ 14d,h ] The extent of fluorophore labelling was in agreement with our targeted click ratio (≈1 dye molecule per MPB to not alter MPB surface properties) and confirmed qualitatively and quantitively via UV–vis spectroscopy (Figure S5, Supporting Information).…”

“…PEG‐based MPBs had previously shown to exhibit long‐circulating behavior in vivo. [ 14d,m,k ] For these studies, azido‐modified MPBs were fluorescently labelled with Cy5 (Figure S5‐1, Supporting Information) to enable in vivo tracking using the IVIS imaging system. For the tumor xenograft model, we used nude mice with subcutaneous A2780 ovarian cancer cells; tumors were allowed to reach 200–300 mm 3 (≈11 days post‐tumor challenge).…”

“…[ 20 ] This tendency has been noticeably detected in our previous studies looking at biodistribution of MPBs with different aspect ratios and sizes. [ 14d,21 ] However, the uptake of D60% MPB by spleen at 48 h was extremely high with 1327 ng MPBs per mg spleen compared to D20% (21.2 ng mg –1 ) and D40% (31.7 ng mg –1 ) (Table 3). One explanation for this result could be that D60% having a heightened aggregation above its T CP (35 ℃), which is lower than the body temperature for mice at 36.6 °C, 40 whereas the other three MPB will remain stable with a size of ≈40 nm.…”

“…In that context, polymeric NPs based on molecular polymer bottlebrushes (MPBs) offer a synthetic platform that allow for customizing physicochemical parameters independently, and owing their modular synthesis and functionalization, they have been attracting increased attention as future drug‐delivery carriers. [ 14 ] This branched macromolecule is produced from a single polymeric “backbone” densely grafted with numerous polymer “sidechains.” Because of the close proximity of sidechains, the backbone is forced out of its coiled conformation to prevent sidechain entanglement, leading to an extended backbone. As covalently linked constructs, they possess enhanced structural stability in vivo that enables their use as unimolecular carriers or as part of larger supramolecular assemblies.…”

“…This enhanced stability in combination with their high molecular weight grants supramolecular assemblies formed from MPBs greater stability compared to their linear counterparts. [ 14j ] Furthermore, the bottom‐up approach to synthesize MPBs (as with most polymeric NPs) renders them highly suitable for screening ideal NP physicochemical parameters for biomedical applications, since they can be fabricated to have single properties modified without changing others. [ 15 ]…”