Distinct Morphological Transitions of Photoreactive and Thermoresponsive Vesicles for Controlled Release and Nanoreactors

Abstract

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 selfassembled into vesicles when temperatures were lower than the lower critical solution temperature (LCST) of PNIPAM blocks (defined as LCST 0 ). However, the resulting vesicles irreversibly formed collapsed vesicles upon temperature rise (T > LCST 0 ), and a further temperature increase (T > T agg,0 ) led to the formation of irregular aggregates of collapsed vesicles. On the other hand, upon UV irradiation, the initially hydrophobic PNBOCA bilayers underwent aminolysisinduced cross-linking and hydrophobic-to-hydrophilic transition, resulting in elevated LCST (defined as LCST uv ). Although the thermo-induced collapse of PNIPAM coronas (T > LCST uv ) and the formation of aggregates of cross-linked vesicles (T > T agg,uv ) were observed, the initially vesicular morphology could be restored when cooling to lower than LCST uv , 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 (GO x ) into the aqueous interiors of the vesicles, allowing for activating fluorogenic reactions by UV irradiation and temperature change.

Regulating vesicle bilayer permeability and selectivity via stimuli-triggered polymersome-to-PICsome transition

“…1). 2-Nitrobenzyl ester photo-caged carboxyl monomer (NCMA) and disulfide-caged carboxyl monomer (DCMA) generate carboxyl moieties upon actuation of UV irradiation and reductive milieu, respectively [26][27][28] . For the second series, pH-responsive DPA and DEA monomers containing both carbamate linkage and tertiary amine moieties were synthesized ( Supplementary Fig.…”

“…2). We intentionally integrate carbamate linkage into both tertiary amine-containing comonomers and caged carboxyl comonomers to strengthen intra-and inter-chain HB interactions within vesicle bilayers [26][27][28]52 , which provide a pre-organized milieu for cooperative noncovalent interactions with directional orientation and high local concentration. Upon triggered cleavage and generation of carboxyl moieties within bilayers, proton transfer from carboxyl to tertiary amine in situ generates ionized carboxyl and protonated amine moieties.…”

“…These approaches typically involve tedious procedures and need to introduce external additives, leading to unsatisfactory permselectivity and loss of structural integrity in certain cases. We previously proposed the concept of "traceless crosslinking" and achieved concurrent vesicle crosslinking and membrane permeabilization [26][27][28] . However, the nature of irreversible bilayer chemical crosslinking restricts their in vivo applications considering biodegradation and clearance issues; in addition, it still remains a challenge to achieve molecular size-selective release and permselectivity regulation features.…”

Recent Progress in Micro/Nanoreactors toward the Creation of Artificial Organelles

“…On a different approach, polymersomes with switchable permeability under UV light have also been employed as enzymatic nanoreactors . Yao et al encapsulated the GOx enzyme within polymersomes consisting of poly( N ‐isopropylacrylamide)‐ b ‐poly(2((((2‐nitrobenzyl)oxy)‐carbonyl)amino)ethyl acrylate) (PNIPAM‐ b ‐PNBOCA).…”

UV‐triggered CO2‐responsive behavior of nanofibers and their controlled drug release properties

“…Investigations have shown that the morphology of the carriers plays an essential role in influencing their release behavior. Therefore, drug carriers prepared from stimuli-responsive polymers that can be (self-)assembled in varying morphologies have been explored, such as vesicles, 15,17 micelles, [18][19][20] nanogels, [21][22][23] nanofibers, 6,[24][25][26] and so forth, each with certain advantages and disadvantages. Among them, "smart" nanofibers as drug carriers have attracted great interest due to their unique features.…”