Tailorable Degradation of pH-Responsive All-Polyether Micelles: Unveiling the Role of Monomer Structure and Hydrophilic–Hydrophobic Balance

Abstract

Polymeric micelles have been widely used as ideal drug-delivery vehicles with unique advantages. However, fine tuning of the degradation rates of micelles over a wide time frame remains challenging. Herein, we designed and synthesized a novel pH-responsive, hydrophobic epoxide monomer, tetrahydrofuranyl glycidyl ether (TFGE), carrying an acetal group as a cleavable linkage. The hydrolysis kinetics of TFGE was carefully evaluated with representative functional epoxide monomers, such as 1-ethoxyethyl glycidyl ether and tetrahydropyranyl glycidyl ether, via in situ 1H NMR spectroscopy and quantum mechanical calculations. Interestingly, the hydrolysis kinetics and the associated energy barrier were closely related not only to the cyclic/acyclic structure of the monomers but also to their hydrophobicity. Subsequently, a series of amphiphilic block copolymers (mPEG-b-PTFGE) were synthesized via anionic ring-opening polymerization and the self-assembled polymeric micelles were evaluated with respect to critical micelle concentration, encapsulation efficiency, drug release, and cell viability. Most notably, the release kinetics of the model compound from polymeric micelles exhibited a different trend, confirming the critical role of hydrophobicity in governing the pH-responsive hydrolysis of the polymeric micelles. This study provides new insights applicable to the design of functional monomers for tailoring the release profiles of polymeric micelles for smart drug delivery.

Synthesis of functional and architectural polyethers via the anionic ring-opening polymerization of epoxide monomers using a phosphazene base catalyst

“…2, t-Bu-P 4 has been utilized for the AROP of glycidyl ethers bearing various side chains to produce side-chain-functionalized polyethers with desirable end groups, narrow dispersities, and predicted molecular weights. Among them, OH-protected glycidyl ethers, such as 1-ethoxy ethyl glycidyl ether (M6) [16,21,25], benzyl glycidyl ether (M7) [16], tert-butyl glycidyl ether (M8) [16,21], tetrahydrofuranyl glycidyl ether (M9) [26], and tetrahydropyranyl glycidyl ether (M10) [27], are particularly interesting because their deprotection reaction yields linear polyglycidols. However, the chain transfer reaction has been found to occur in the t-Bu-P 4 -catalyzed AROP of M6 [16,21].…”

“…Indeed, by taking advantage of the well-controlled nature of t-Bu-P 4 -catalyzed AROP, several groups, including ours, have successfully created polyetherbased or polyether-containing functional materials. Examples include thermoresponsive materials [39], solid electrolytes for lithium batteries [40], organic memory devices [24], antifouling materials [41], and polymeric micelles [26,27,42,43].…”

“…3 Synthesis of functional polyethers via t-Bu-P 4 -catalyzed AROP: a LCST-type thermoresponsive polyethers; b polyether-based ABA-type triblock copolymer for application as a solid electrolyte for Li+ batteries forming favorable Li + conducting channels. Notably, Kim's group developed polyether-based BCP materials for potential application as drug nanocarriers [26,27] and antifouling coatings [4], synthesized via the t-Bu-P 4 -catalyzed AROP of functional glycidyl ethers using PEO as the macroinitiator. Ree's group also reported the successful synthesis of functional polyether-based BCPs for applications in organic memory devices through a sequential AROP of M6 and M14, followed by a series of side-chain functionalizations to install electroactive side chains [46].…”

Acetal‐Based Functional Epoxide Monomers: Polymerizations and Applications

“…Organic superbase based on phosphazene can also provide an alternative means of synthesizing polyethers. [ 27,41,42 ] Due to the significant size and charge separation of the countercation, they can effectively act as bases rather than nucleophiles, thereby preventing other side reactions. However, the relatively lower basicity of the phosphazene family compared to metal hydroxides makes them useful in only limited cases such as polymerization using epoxide as a monomer.…”

“…After the successful introduction of the EEGE monomer, various types of acetal‐based monomers have been employed in the synthesis of polyethers, including 1,2‐isopropylidene glyceryl glycidyl ether (IGG), [ 23 ] catechol acetonide glycidyl ether (CAGE), [ 24 ] 1‐(glycidyloxy)ethyl ethylene glycol ether (GEGE), [ 25 ] tetrahydropyranyl glycidyl ether (TPGE), [ 26 ] tetrahydrofuranyl glycidyl ether (TFGE), [ 26,27 ] and cyclohexyloxy ethyl glycidyl ether (CHGE) [ 28 ] ( Figure 1 ). These monomers not only utilized as protecting groups for hydroxyl groups under AROP conditions but also used as pH‐responsive moieties in biomedical applications, further expanding their utility in the use of functionalized polyethers.…”