Hydrogels have found promising applications in drug delivery due to their biocompatibility, high drug loading capability, and tunable release profiles. However, hydrogel-based carriers are primarily employed for delivering hydrophilic payloads while hydrophobic drugs cannot be efficiently delivered due to the lack of hydrophobic domains within conventional hydrogel matrices. Herein, we report that thermo- and photo-responsive hydrogels could be constructed from amphiphilic triblock copolymers, poly(N-isopropylacrylamide)-b-poly(4-acryloylmorpholine)-b-poly(2-((((2-nitrobenzyl)oxy)carbonyl) amino)ethyl methacrylate) (PNIPAM-b-PNAM-b-PNBOC), and the resulting hydrogels could be further engineered a new carrier for both hydrophilic gemcitabine (GCT) and hydrophobic doxorubicin (DOX). PNIPAM-b-PNAM-b-PNBOC triblock copolymers were first self-assembled into micelles with hydrophobic photosensitive PNBOC cores, hydrophilic PNAM inner shells, and thermoresponsive PNIPAM coronas below the lower critical solution temperature (LCST), while hydrogels of physically cross-linked micellar nanoparticles were achieved at elevated polymer concentrations and high temperatures above the critical gelation temperature (CGT). Rheological experiments revealed that the CGT was highly dependent on polymer compositions and concentrations, that is, a longer hydrophobic PNBOC block or a higher polymer concentration led to a decreased CGT. However, the CGT prior to UV irradiation (CGT0) could be drastically elevated after UV irradiation (CGTUV) as a result of UV irradiation-induced concurrently cross-linking and hydrophobic-to-hydrophilic transition within PNBOC cores. As such, gel-to-sol transition could be accomplished by either temperature decrease or exposure to UV irradiation at a fixed temperature lower than the CGTUV. Note that both GCT and DOX could be simultaneously encapsulated into the hydrogels due to the coexistence of extramicellar aqueous phase and hydrophobic micellar cores. Intriguingly, the subsequent co-release of GCT and DOX could be regulated by taking advantage of either temperature or UV irradiation-mediated gel-to-sol transitions.Download high-res image (318KB)Download full-size image

The development of stimuli-responsive magnetic resonance imaging (MRI) contrast agents that can selectively enhance imaging contrasts at pathological sites is of potential use in clinical diagnosis. Herein, a T2-type MRI contrast agent with synergistically photoregulated enhanced MRI contrast and drug release was achieved by coassembly of superparamagnetic iron oxide nanoparticles (SPIONs) and doxorubicin (DOX) with amphiphilic block copolymer assemblies. Photosensitive amphiphilic diblock copolymers, poly(ethylene oxide)-b-poly(2-((((2-nitrobenzyl)oxy)carbonyl)amino)ethyl methacrylate) (PEO-b-PNBOC), were synthesized through reversible addition–fragmentation chain transfer (RAFT) polymerizations. The resulting block copolymers were coassembled with hydrophobic oleic acid (OA)-stabilized SPIONs and DOX via an oil-in-water (O/W) emulsion and a subsequent solvent evaporation procedure, resulting in the formation of DOX/SPION coloaded hybrid nanovectors. The as-assembled hybrid nanovectors exhibited retarded DOX release and weak T2 relaxivity (r2) prior to UV-irradiation. However, upon UV-irradiation, the hybrid nanovectors underwent cross-linking and a hydrophobic-to-hydrophilic transition within the cores, thereby selectively triggering DOX release and elevating T2 relaxivities. In vitro DOX release results revealed approximately 85% of DOX was released within 10 h under 20 min UV-irradiation, and this was in sharp contrast with less than 5% of DOX release without UV-irradiation. The selective DOX release under UV-irradiation showed significantly increased cytotoxicity toward HepG2 cells. Meanwhile, the r2 of UV-irradiated nanovectors exhibited 4.5- and 1.9-fold increases as compared to cetyltrimethylammonium bromide (CTAB)-stabilized monodispersed SPIONs and nonirradiated hybrid nanovectors. Moreover, there was a linear correlation between the r2 changes and cumulative DOX release extents, enabling instantaneously visualizing the DOX release by the MRI technique. Further, we demonstrated that the cellular internalization efficiency of the coloaded hybrid nanovectors increased by 2.7-fold in the presence of an external magnet. The magnetically guided cellular uptake, triggered release profile, and enhanced MRI contrast characteristics may presage potential applications as a new generation of theranostic platform.

Polymer chain architectures play a crucial role in the physical properties of polymers and this unique phenomenon has been recognized as the topological effects. As one of the most representative architectures, macrocyclic polymers characterized by the endless topology have received extensive attention due to their distinct physical properties as compared to the linear counterparts. To understand these differences and unravel the underlying mechanisms, there is a long pursuit to efficiently fabricate macrocyclic polymers. To date, both ring-closing and ring-expansion strategies have been developed, which drastically elevates the accessibility of macrocyclic polymers. The improved availability of macrocyclic polymers enables the further investigation of the biomedical applications and the preliminary results suggest that macrocyclic polymers outperform their linear analogs in terms of improving gene delivery efficiency, elevating blood circulation time, and enhancing colloidal stability of nanoparticles.

The construction of intelligent vesicular nanocarriers and nanoreactors has received increasing interests due to their potential in mimicking natural counterparts such as cells and organelles. Herein, we report thermoresponsive and photoreactive vesicles could be fabricated from amphiphilic block copolymers (BCPs), poly(N-isopropylacrylamide)-b-poly(2-((((2-nitrobenzyl)oxy)carbonyl)amino)ethyl acrylate) (PNIPAM-b-PNBOCA), which were synthesized via consecutive reversible addition–fragmentation chain transfer (RAFT) polymerizations. The resulting BCPs self-assembled into vesicles when temperatures were lower than the lower critical solution temperature (LCST) of PNIPAM blocks (defined as LCST0). However, the resulting vesicles irreversibly formed collapsed vesicles upon temperature rise (T > LCST0), and a further temperature increase (T > Tagg,0) led to the formation of irregular aggregates of collapsed vesicles. On the other hand, upon UV irradiation, the initially hydrophobic PNBOCA bilayers underwent aminolysis-induced cross-linking and hydrophobic-to-hydrophilic transition, resulting in elevated LCST (defined as LCSTuv). Although the thermo-induced collapse of PNIPAM coronas (T > LCSTuv) and the formation of aggregates of cross-linked vesicles (T > Tagg,uv) were observed, the initially vesicular morphology could be restored when cooling to lower than LCSTuv, as opposed to irreversible morphological transition without UV irradiation. The vesicular assemblies were engineered as nanocarriers for both hydrophilic (doxorubicin hydrochloride, DOX) and hydrophobic (Nile red, NR) payloads. The corelease profiles could be delicately regulated by both temperature variations and UV irradiation. Interestingly, DOX release could be also regulated by thermo-induced vesicle collapse without recourse to UV irradiation or by near-infrared (NIR) irradiation-induced vesicle collapse in the presence of photothermal agents coloaded within vesicular interiors as a result of the relatively low glass transition temperature of PNBOCA blocks. Moreover, nanoreactors were constructed by loading glucose oxidase (GOx) into the aqueous interiors of the vesicles, allowing for activating fluorogenic reactions by UV irradiation and temperature change.