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

Abstract

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.

Bioderived Lipoic Acid-Based Dynamic Covalent Nanonetworks of Poly(disulfide)s: Enhanced Encapsulation Stability and Cancer Cell-Selective Delivery of Drugs

“…The heat change associated with the disassembly of the nanoaggregates is documented in the ITC experiment, and from the data, enthalpy of micellization and other thermodynamic parameters associated with the self-assembly process are calculated using the equations reported in the literature. , In the ITC dilution experiment of GS solution at 25 °C, an exothermic heat flow was observed, which eventually saturated beyond a certain concentration (considered CAC), as there was no more disassembly of micelles. The exothermic heat change (Δ H = −0.2 kcal/mol) in disassembly makes the process enthalpically favorable, and on the contrary, self-assembly becomes an enthalpically disfavored process (Δ H = 0.2 kcal/mol) (Figure a), which is previously found for other systems as well. , The entropy associated with the self-assembly (Δ S = 16.8 cal/mol/K) was found to be positive, which indicates that the assembly is enthalpically disfavored but entropically favorable, therefore making the overall self-assembly a spontaneous process with a free energy (Δ G ) value of −5.2 kcal/mol (Figure b). The entropy-driven process can be attributed to the release of ester-bound water molecules to the bulk during the self-assembly process.…”

“…The exothermic heat change (ΔH = −0.2 kcal/mol) in disassembly makes the process enthalpically favorable, and on the contrary, self-assembly becomes an enthalpically disfavored process (ΔH = 0.2 kcal/mol) (Figure 2a), which is previously found for other systems as well. 81,82 The entropy associated with the self-assembly (ΔS = 16.8 cal/ mol/K) was found to be positive, which indicates that the assembly is enthalpically disfavored but entropically favorable, therefore making the overall self-assembly a spontaneous process with a free energy (ΔG) value of −5.2 kcal/mol (Figure 2b). The entropy-driven process can be attributed to the release of ester-bound water molecules to the bulk during the self-assembly process.…”

Tumor acidity-induced surface charge modulation in covalent nanonetworks for activated cellular uptake: targeted delivery of anticancer drugs and selective cancer cell death

“…2a) showed an exothermic heat flow during disassembly (Δ H = −0.138 kcal mol −1 ) in the dilution process, thus suggesting that the self-assembly here is an enthalpically disfavoured process (Δ H = 0.138 kcal mol −1 ), which corroborates with other reports in the literature. 78–80 The free energy (Δ G ) and entropy of micellization (Δ S ) were estimated using the following equations (eqn (1) and (2)), in which CAC, R and T represent the critical aggregation concentration, universal gas constant and experimental temperature, respectively.Δ G = RT ln CACΔ G = Δ H − T Δ S …”

Degradable Polymer-Based Nanoassemblies for Precise Targeting and Drug Delivery to Breast Cancer Cells without Affecting Normal Healthy Cells

“…There are various types of dual pH- and GSH-responsive polymeric nanoaggregates reported in the literature, − but we are interested in polyurethane-based nanoassemblies due to (i) the ease of synthesis, (ii) formation of stable nanocarriers due to the H-bonding nature of the backbone, and (iii) excellent biocompatibility and biodegradability. − In this article, we designed and synthesized an amphiphilic polyurethane endowed with a redox-responsive self-immolative linker on the backbone and hydrophilic pendant tetraethyleneglycol monomethyl ether, which was periodically grafted on the backbone by a tertiary amine group. Since self-immolative polymers are recognized as an emerging class of polymers due to their excellent degradability, − we believe the introduction of a self-immolative linker on the polyurethane backbone would make a new class of degradable polyurethanes for a wide range of applications, including drug delivery. A few interesting features of this design are listed as follows: (i) The polymer is biocompatible, and the self-immolative linker-based backbone is completely degradable.…”