Concurrent Block Copolymer Polymersome Stabilization and Bilayer Permeabilization by Stimuli‐Regulated “Traceless” Crosslinking

Abstract

The fabrication of block copolymer (BCP) vesicles (polymersomes) exhibiting synchronized covalent crosslinking and bilayer permeabilization remains a considerable challenge as crosslinking typically leads to compromised membrane permeability. Herein it is demonstrated how to solve this dilemma by employing a stimuli-triggered crosslinking strategy with amphiphilic BCPs containing photolabile carbamate-caged primary amines. Upon self-assembling into polymersomes, light-triggered self-immolative decaging reactions release primary amine moieties and extensive amidation reactions then occur due to suppressed amine pKa within hydrophobic milieu. This leads to serendipitous vesicle crosslinking and the process is associated with bilayer hydrophobicity-to-hydrophilicity transition and membrane permeabilization.

Acid-Disintegratable Polymersomes of pH-Responsive Amphiphilic Diblock Copolymers for Intracellular Drug Delivery

“…48,53,68−70 Aiming to facilitate the formation of other morphologies (e.g., polymersomes) and regulate the drug-loading and releasing efficiency, we attempted to introduce additional hydrogen-bonding interaction in the pendant chains via the incorporation of carbamate linkages instead of conventional ester/carbonate bonds, which has been confirmed to be effective on the fabrication of photoresponsive polymersomes in our recent work. 23 We surmised that the additional hydrogen bonding interaction, together with the hydrophobic association originated from pH-responsive cyclic benzylidene moieties, could cooperatively facilitate the formation of vesicular assemblies. To this end, TTAMA monomer (2) composed of an acidic-responsive cyclic benzylidene moiety and a carbamate linkage was synthesized via the condensation of hydroxyl-containing cyclic benzylidene acetal precursor (1) and 2-isocyanatoethyl methacrylate in the presence of DBTL catalyst (Scheme 2).…”

2-Nitrobenzyl Borate Based Photolabile Linker for Breakable Polymer Vesicles

“…[3][4][5] Figure 2 B showed the time-dependent changes of the normalized intensity at 305 nm ( I 305 ) of NP-B-PEG aqueous solution upon irradiation at different light intensity. As shown in Figure 2 B, for 400 mW cm −2 irradiation, the I 305 value showed a saturating behavior from 1.00 to 1.96 within 12 s of irradiation time.…”

“…When irradiated with UV light, 2-nitrobenzyl borate ester would be photolyzed via a intramolecular rearrangement to release 2-nitrosobenzaldehyde as it occurs in other 2-nitrobenzyl functional systems. [3][4][5] Simultaneously, the hydrophobic borate tail was transformed into the more electron-defi cient borate acid with a hydrophilic hydroxyl group ( OH). Therefore, the remaining 2-pyridinylmethyl borate became much more fragile to the attack of water molecules and underwent fast hydrolysis, resulting in the disintegration of polymer self-assemblies in aqueous solution.…”

“…[ 4 ] Therefore, the 2-nitrobenzyl derivatives with functional groups (e.g., phosphate, carboxylates, hydroxyl, and amines) are particularly attractive in various fi elds, such as photocaged biological compounds and photoswitchable polymer materials. [ 5 ] Borate esters, as the name implies, are the esters of boric acid and alcohols (or phenols). The general procedure for the preparation of borate esters involves an azeotropic distillation of boric acid and alcohols in toluene medium or transesterifi cation with a lower boiling borate ester.…”

Photoresponsive nanoparticles for drug delivery

“…The resulting destabilization of the PMCL core caused the release of 61% of encapsulated protein after 5 min of UV irradiation (365 nm, 200 mW/cm 2 ). Recently, two anticancer drugs, hydrophilic doxorubicin (DOX·HCl) and hydrophobic camptothecin, have been encapsulated in photoresponsive polymersomes and could be released upon UV light irradiation due to an increase in membrane permeability or degradation of the bilayer membrane [115, 116]. …”