Smart nanocarriers are of particular interest as nanoscale vehicles of imaging and therapeutic agents in the field of theranostics. Herein, we report dually pH/reduction-responsive terpolymeric vesicles with monodispersive size distribution, which are constructed by assembling acetal- and disulfide-functionalized star terpolymer with near-infrared cyanine dye and anticancer drug. The vesicular nanostructure exhibits multiple theranostic features including on-demand drug releases responding to pH/reduction stimuli, enhanced photothermal conversion efficiency of cyanine dye, and efficient drug translocation from lysosomes to cytoplasma, as well as preferable cellular uptakes and biodistribution. These multiple theranostic features result in ultrahigh-contrast fluorescence imaging and thermo-chemotherapy-synergized tumor ablation. The dually stimuli-responsive vesicles represent a versatile theranostic approach for enhanced cancer imaging and therapy.

Facile construction of novel functional dendritic copolymers by combination of self-condensing vinyl polymerization, sequence-controlled copolymerization and RAFT process was presented. RAFT copolymerization of a disulfide-linked polymerizable RAFT agent and equimolar feed ratio of styrenic and maleimidic macromonomers afforded multicleavable A m B n dendritic comblike copolymers with alternating PEG (A) and PCL (B) grafts, and a subsequent chain extension polymerization of styrene, tert-butyl acrylate, methyl methacrylate, and N-isopropylacrylamide gave A m B n C o dendritic toothbrushlike copolymers. (PEG) m (PCL) n copolymers obtained were of adjustable molecular weight, relatively low polydispersity (PDI = 1.10−1.32), variable CTA functionality ( f CTA = 4.3−7.5), and similar segment numbers of PEG and PCL grafts, evident from 1 H NMR and GPC-MALLS analyses. Their branched architecture was confirmed by (a) reduction-triggered degradation, (b) decreased intrinsic viscosities and Mark−Houwink−Sakurada exponent than their "linear" analogue, and (c) lowered glass transition and melting temperatures and broadened melting range as compared with normal A m B n comblike copolymer. In vitro drug release results revealed that the drug release kinetics of the disulfide-linked A m B n copolymer aggregates was significantly affected by macromolecular architecture, end group and reductive stimulus. These stimuli-responsive and biodegradable dendritic copolymer aggregates had a great potential as controlled delivery vehicles.

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Novel 5-arm PEG(PCL) 2 (PNIPAM) 2 (S1) and PEG(PCL) 2 (PAA) 2 (S3) star terpolymers were synthesized, and their aggregates formed by a single star or mixed stars were efficiently used for loading and release of doxorubicin upon dual and triple stimuli. The star terpolymers had two disulfide moieties and poly(ethylene glycol) (PEG, A), poly(3-caprolactone) (PCL, B), poly(N-isopropylacrylamide) (PNIPAM, C 1 ), poly(tert-butyl acrylate) (PtBA, C 2 ), and poly(acrylic acid) (PAA, C 3 ) segments. Terminal diazide functionalized PEG (PEG-(N 3 ) 2 ) and alkyne-mid-functionalized PCL-b-PNIPAM and PCL-b-PtBA diblock copolymers were subjected to an azide-alkyne cycloaddition reaction to generate AB 2 C 2 (C ¼ C 1 and C 2 ) stars followed by selective hydrolysis to obtain a PEG(PCL) 2 (PAA) 2 star. Polymeric micelles were prepared by self-assembly of a single star in aqueous solution, and coaggregates were obtained by coassembly of S1 and S3 mixtures. Various polymeric aggregates had great potential as controlled delivery vehicles due to their reasonable drug loading efficiency and stimuli-adjustable drug release properties. As compared with dually sensitive micelles formed from a single star, triply stimuli-responsive coaggregates may be more promising as controlled delivery vehicles since the drug release properties can be potentially adjusted by various external stimuli and composition of star mixtures.

A novel disulfide-and acetal-linked graft copolymer (SACG) comprising acetal-bridged poly-(3-caprolactone)-b-poly(ethylene glycol) and PEG pendent chains and relatively short polymethacrylate backbone (DP z 24) was synthesized and self-assembled for in vitro encapsulation and release of an anticancer drug, doxorubicin (DOX). Three-step reactions involving (i) RAFT copolymerization of 2hydroxyethyl methacrylate and poly(ethylene glycol) methyl ether methacrylate, (ii) ring-opening polymerization to generate PCL chains, and (iii) hydroxyl-vinyloxy adductive reaction to introduce acidcleavable PEG segments were used to achieve the target copolymer. Meanwhile, well-defined normal (CP) and disulfide-linked (SCP) poly(PEG-co-PCL) comb-like copolymers and acid-cleavable poly(PEGco-PCL)-graft-MVPEG copolymer (ACG) were synthesized and acted as analogues of SACG upon external stimuli. The macromolecular architecture significantly affected the melting and crystallization behaviors and aggregation properties of copolymers, and the difference in topology and location of cleavable linkages resulted in distinctly different stimuli-triggered drug release behaviors. Owing to the dissociation and reaggregation of cleaved copolymer aggregates, stimuli-cleavable aggregates in response to external stimuli (pH 5.0, 10 mM DTT) could exhibit faster release kinetics than CP aggregates, and the maximum increment of cumulative release from various aggregates for 72 h was liable to decrease in the order SACG > ACG > SCP > CP. The cumulative release from SACG aggregates could be adjusted in the widest range via addition of different stimuli, revealing the great potential of dually cleavable copolymer aggregates in smart drug delivery systems.