Stabilizing Entropically Driven Self-Assembly of Self-Immolative Polyurethanes in Water: A Strategy for Tunable Encapsulation Stability and Controlled Cargo Release

Stimuli-responsive amphiphilic polymer assemblies are of great interest in the area of targeted drug delivery applications as they can sequester guest molecules in one set of conditions and release them under another. Hence, developing a strategy of molar mass controlled synthesis, in-depth understanding of the thermodynamics of the self-assembly process, stabilization, and triggered guest release in a controlled fashion would be highly anticipated in the field of drug delivery applications. As polymer molar mass has a significant impact on the self-assembly process or material property of polymers, we focused on a methodology of controlled molar mass polyurethane synthesis using recycled plastic waste and synthesized a series of self-immolative amphiphilic polyurethanes of varying molar masses and polydispersity indexes. All of the polymers were equipped with periodically grafted triethyleneglycol monomethyl ether as a pendant, a redox-responsive disulfide bond, a tertiary amine, and an aromatic moiety on the backbone. In aqueous milieu, these polymers are found to form entropically driven nanoassemblies (ΔS > 0), which were further stabilized by supramolecular cross-linking via the synergistic effect of π–π stacking (aromatic moiety), H-bonding (urethane functionality), and hydrophobic interactions, which eventually amplifies the guest encapsulation stability. A guest release profile in the presence of a redox environment shows ∼65% release in a controlled fashion. Furthermore, the tertiary amine on the polymer backbone leads to the formation of positively charged nanoassemblies at the tumor-relevant pH (pH ∼ 6.5–6.8), which could potentially enhance the cellular uptake of nanocarriers in tumor cells. Thus, a strategy for molar mass controlled polyurethane synthesis, understanding the effect of polymer molar mass on thermodynamics of self-assembly, establishing a stable micellar nanostructure endowed with environment-specific surface charge modulation, and controlled guest release, we believe, will significantly contribute to the development of robust chemotherapeutics.