Imidazole‐Mediated Dual Location Disassembly of Acid‐Degradable Intracellular Drug Delivery Block Copolymer Nanoassemblies

Abstract

Acid‐degradable (or acid‐cleavable) polymeric nanoassemblies have witnessed significant progress in anti‐cancer drug delivery. However, conventional nanoassemblies designed with acid‐cleavable linkages at a single location have several challenges, such as, sluggish degradation, undesired aggregation of degraded products, and difficulty in controlled and on‐demand drug release. Herein, a strategy that enables the synthesis of acid‐cleavable nanoassemblies labeled with acetaldehyde acetal groups in both hydrophobic cores and at core/corona interfaces, exhibiting synergistic response to acidic pH at dual locations and thus inducing rapid drug release is reported. The systematic analyses suggest that the acid‐catalyzed degradation and disassembly are further enhanced by decreasing copolymer concentration (i.e., increasing proton/acetal mole ratio). Moreover, incorporation of acid‐ionizable imidazole pendants in the hydrophobic cores improve the encapsulation of doxorubicin, the anticancer drug, through π‐π interactions and enhance the acid‐catalyzed hydrolysis of acetal linkages situated in the dual locations. Furthermore, the presence of the imidazole pendants induce the occurrence of core‐crosslinking that compensates the kinetics of acetal hydrolysis and drug release. These results, combined with in vitro cell toxicity and cellular uptake, suggest the versatility of the dual location acid‐degradation strategy in the design and development of effective intracellular drug delivery nanocarriers.

Multidimensional Control of Repeating Unit/Sequence/Topology for One-Step Synthesis of Block Polymers from Monomer Mixtures

“…After CHO was completely consumed and EPO conversion reached 7.2%, we added another 7.5 equiv of CHO to the reaction mixture, causing PA/EPO ROCOP to temporarily cease and PA/CHO ROCOP to commence. Perfect chemoselectivity was observed by 1 H NMR analysis of aliquots taken at regular intervals throughout the process (entry 2 in Table 2 and Figure 3). Extended reaction time initially caused the resonance signals of PA (proton 2′ at 8.0 and 7.9 ppm) and CHO (proton 3′ at 3.1 ppm) to decrease gradually.…”

“…The properties of block polymers can be adjusted by varying their monomer sequence. Consequently, this endows block polymers with the ability to provide a platform for the production of a wide range of advanced materials, with applications in drug delivery, , data storage, microelectronics, , and nanolithography . Regarding the synthesis of block polymer, self-switchable polymerization is the most promising method because it applies mixture of monomers and uses a single catalyst that spontaneously connects different catalytic cycles to produce block sequence, − thereby overcoming the disadvantages of conventional procedures, e.g., sequential monomer addition approach and coupling of premade blocks. , …”

Synthesis of multiple stimuli-responsive degradable block copolymers via facile carbonyl imidazole-induced postpolymerization modification

“…CIMA was synthesized according to our previous publication with minor modifications. 78 HEMA (6.0 g, 46.1 mmol) was added dropwise to a clear solution containing CDI (9.9 g, 61.3 mmol) and anhydrous DCM (120 mL) over 20 min. The reaction mixture was stirred vigorously for 18 h at room temperature, and then washed with distilled water three times.…”

Shell-Sheddable/Core-Degradable ABA Triblock Copolymer Nanoassemblies: Synthesis via RAFT and Concurrent ATRP/RAFT Polymerization and Drug Delivery Application

“…The asprepared polymer solutions were purified as reported elsewhere. 67 A similar procedure was used except with P1 (0.17 g, 25.2 μmol), HMssEt (0.75 g, 2.14 mmol), [Cu(II)TPMA-Br]Br Studies of Aqueous Micellization. The critical micellar concentration (CMC) of P2 copolymers was determined with the NR probe as described elsewhere.…”

“…Polymerization was stopped by cooling the reaction mixture in an ice bath and exposing it to air. The as-prepared polymer solutions were purified as reported elsewhere …”