Abstract
Bottlebrush copolymers are a versatile class of macromolecular architectures with broad applications in the fields of drug delivery, self-assembly, and polymer networks. Here, the modular nature of graft-through ring-opening metathesis polymerization (ROMP) is exploited to synthesize “ABC” triblock bottlebrush copolymers (TBCs) from polylactic acid (PLA), polyethylene glycol (PEG), and poly(N-isopropylacrylamide) (PNIPAM) macromonomers. Due to the hydrophobicity of their PLA domains, these TBCs self-assemble in aqueous media at room temperature to yield uniform ∼100 nm micelles that can encapsulate a wide range of therapeutic agents. Heating these micellar solutions above the lower critical solution temperature (LCST) of PNIPAM (∼32 °C) induces the rapid formation of multi-compartment hydrogels with PLA and PNIPAM domains acting as physical crosslinks. Following the synthesis and characterization of these materials in vitro, TBC micelles loaded with various biologically active small molecules were investigated as injectable hydrogels for sustained drug release in vivo. Specifically, intratumoral administration of TBCs containing paclitaxel and resiquimod—the latter a potent Toll-like receptor (TLR) 7/8 agonist—into mice bearing subcutaneous CT26 tumors resulted in a significantly enhanced therapeutic index compared to the administration of these two drugs alone. This effect is attributed to the TBC hydrogel maintaining a high local drug concentration, thus reducing systemic immune activation and local inflammation. Collectively, this work represents, to our knowledge, the first example of thermally-responsive TBCs designed for multi-compartment hydrogel formation, establishing these materials as versatile scaffolds for self-assembly and drug delivery.
Highlights
To study the impact of block size and sequence on the properties of triblock bottlebrush copolymers (TBCs), a series of related copolymers was synthesized for comparison to ABC: “CBA” was prepared via sequential Ring-opening metathesis polymerization (ROMP) of the same MMs in the same ratios as ABC but in the reverse order; “ABC-stat” was synthesized by mixing the three MMs with G3 providing a statistical copolymer with the same overall composition as ABC; lastly, a diblock bottlebrush copolymer “AB” lacking a PNIPAM block was synthesized as a non-thermoresponsive analogue of ABC
Our results demonstrate that TBC-based hydrogels enable delivery of a combination of a chemotherapeutic (PTX) and a TLR7/8 agonist (R848), promoting tumor-controlling immunologic effects while reducing dose-limiting systemic and local toxicities associated with such therapies
We developed an effective protocol for the synthesis of modular TBCs
Summary
Efficiency and tolerance toward a wide range of functional groups; this approach has been used to generate bottlebrush-based polymer architectures with unique self-assembly, imaging, and drug delivery capabilities.[14,15,16,17] Despite these advances, and given the well-established utility of triblock copolymers in self-assembly and biomedicine,[18,19,20,21] there are limited examples of triblock bottlebrush copolymers (TBCs).[22,23,24] For instance, Bates and coworkers prepared two-component “ABA” TBCs from polystyrene and polyethylene glycol (PEG) MMs and demonstrated their utility as Li-ion conductors.[22]. These results align with a pharmaceutical industry-wide shi toward immunomodulator formulations that retain the drug at the site of injection, enhancing therapeutic index.[72,73,74] In addition to induction of higher unwanted systemic in ammatory cytokines, intratumoral injections of free R848 + PTX resulted in delayed cures with persistent in ammation at the injection site, which are likely caused by burst exposure to PTX with subsequent massive antigen release occurring a er a majority of the R848 immunomodulator has diffused away from the site of injection, promoting tolerance.[56,79] it has been previously demonstrated that improper timing of immune activation and antigen release can signi cantly dampen antitumor immune responses.[80] We observed higher systemic levels of the anti-in ammatory cytokine IL-10 for longer periods in mice given the free drug combination (Fig. S19b†), which could partially explain delayed clearing of the tumors.[81]. Our results demonstrate that TBC-based hydrogels enable delivery of a combination of a chemotherapeutic (PTX) and a TLR7/8 agonist (R848), promoting tumor-controlling immunologic effects while reducing dose-limiting systemic and local toxicities associated with such therapies
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