•PEG-PLA-PEG copolymer micelles with double disulfide linkage were synthesized.•DOX loaded in the micelles can be released rapidly under triggering of GSH.•The micelles exhibited higher ability of drug release than PLA-PEG-PLA micelles.•The drug-loading micelles have great potential for cancer therapy.Redox-responsive linkages dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their niche. In the present work, triblock copolymer PEG-PLA-PEG synthesized and characterized by 1H -NMR and SEC can self-assemble into redox-responsive micelles in aqueous media with nanosized 33 nm and 47 nm. And the copolymers PEG2000-PLA3000-PEG2000 and PEG2000-PLA5000-PEG2000 present lower CMC with 0.034 and 0.022 mg/mL, and higher DLC of 4.28% and 5.14% respectively, compared with that of diblock copolymer. Moreover, drug release from the micelles can be triggered and significantly accelerated in reductive environment. The low cytotoxicity of redox-responsive micelles was confirmed by MTT assay against NIH 3 T3 cells. All of these results demonstrated that these polymeric micelles self-assembled from double-disulfide tethered block copolymers are promising carriers for the redox-responsive intracellular delivery of hydrophobic anticancer drugs.

NaYF4:Yb,Er upconversion nanoparticles (UCNPs) capped with long-chain carboxylic acid were synthesized and then conjugated with chitosan (CS) in the aid of N-hydroxysuccinimide. The resultant nanocompound was integrated with doxorubicin (DOX) and Roussin’s black salt (RBS), a photosensitive nitric oxide (NO) donor to produce stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres as nanocarriers for controllable drug delivery. On the one hand, the encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible photons to trigger NO release. On the other hand, the entrapped DOX can be released at lowered pH from the swollen nanospheres caused by stretched oleoyl-CS chains under acidic conditions. The UCNPs(DOX)@CS-RBS nanospheres exhibit great therapeutic efficacy, which is attributable to the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study highlights the controllable release of NO and DOX from the same nanocarriers and the synergistic therapeutic effect on tumors, which could give new insights into improving cancer nanotherapeutics.Statement of SignificanceIn this paper, core-shell structured UCNPs(DOX)@CS-RBS nanospheres have been designed and synthesized via a step-by-step procedure. The stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres act as nanocarriers for controllable drug delivery towards cancer therapy. The encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible light to trigger NO release. Meanwhile, the entrapped DOX can be released from the swollen nanospheres caused by stretched oleoyl-CS chains at lowered pH typical of intracellular environment. Synergistic cancer therapy will be achieved through the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study provides new drug nanocarriers with high antitumor efficacy for synergistic cancer therapy.Download high-res image (132KB)Download full-size image

An acid-cleavable linker based on a dimethylketal moiety was synthesized and used to connect a nucleotide with a fluorophore to produce a 3′-OH unblocked nucleotide analogue as an excellent reversible terminator for DNA sequencing by synthesis.

A cleavable azo linker was synthesized and reacted with 5-(6)-carboxytetramethyl rhodamine succinimidyl ester, followed by further reactions with di(N-succinimidyl) carbonate and 5-(3-amino-1-propynyl)-2′-deoxyuridine 5′-triphosphate [dUTP(AP3)] to obtain the terminal product dUTP-azo linker-TAMRA as a potential reversible terminator for DNA sequencing by synthesis with no need for 3′-OH blocking.

Multi-block copolymers, which are composed of two or more covalent interconnected polymeric segments of different types, offer unparalleled opportunities for designing new nanostructured materials with enhanced functionality and properties. Using double disulfide linkages coupling with complementary double H-bonding sequences, we demonstrated a new synthetic approach to multi-block copolymers that produces alternating architectures. It offers a new synthetic strategy for synthesizing multi-block copolymers which not only applies to PLA and PEG blocks for multi-block copolymers, but also to other kinds of polymers especially for those hard to be linked by a traditional method. In this study, we synthesized an amphiphilic multi-block copolymer [PLA-PEG]t containing redox-responsive disulfide linkages. Their structures were confirmed by 1H NMR and GPC. These amphiphilic multi-block copolymers can self-assemble into spherical micelles in aqueous media. Compared with di-block copolymers reported in our previous work, multi-block copolymer micelles have a higher drug loading content (DLC), higher stability and more compact spherical structure, whilst maintaining excellent redox-responsive properties and are able to release drugs triggered by intracellular GSH. Fluorescence microscopy measurements and MTT assay demonstrated that the micelle exhibited faster drug release and higher cellular proliferation inhibition due to intracellular GSH responsiveness. These results suggested that the micelles would provide a favorable platform to construct drug delivery systems for cancer therapy.

•Copolymer PEG-SS-DMTK-PLA with both double disulfide and DMTK was synthesized.•The micelles are responsive with both glutathione and reactive oxygen species.•The dual responsive micelles led to much faster drug release in several cancer cells.The need for smart materials in the area of biotechnology has accelerated the development of stimuli-responsive copolymer micelles. Here, we reported a novel dual-stimuli-responsive block copolymer PEG-DMTK-SS-PLA with both dimethyl thioketal (DMTK) and disulfide linkage incorporated into the backbone, capable of triggering fast drug release properties upon both oxidative (H2O2) and reductive (GSH) environment. The CMC values of these copolymer micelles ranging from 0.051 to 0.087 mg mL−1, the average diameters are from 34 nm to 55 nm and 65 nm to 198 nm for blank and DOX-loaded micelles respectively. MTT assay conducted in NIH 3T3 cells showed the low cytotoxicity of these micelles even when the concentration reached up to 500 μg/mL. Considering tumor microenvironment’s diverse in kinds of tumor cells, fluorescence microscopy, flow cytometry and MTT activity analysis were conducted in several cancer cells (e.g., cervix, lung, gastric, and colon cancer cells), and further confirmed that the dual responsive PEG-DMTK-SS-PLA micelles were degraded much faster than that of non-responsive PEG-PLA and single responsive PEG-SS-PLA and PEG-DMTK-PLA micelles. These results indicate that the dual-responsive micelles are promising for efficient anticancer drug delivery.

A folic acid (FA) conjugated chitosan oligosaccharide (CSO) polylactic acid (PLA) copolymer FA-CSO-PLA with double disulphide linkage in the backbone directed by H-bonding association duplex was synthesized, and its self-assembled micelles were evaluated as smart targeted drug delivery carriers. Both of the intermediates and the terminal copolymers were characterized by 1H-NMR and gel permeation chromatography (GPC). The critical micelle concentration (CMC) value is 0.045 mg mL−1 which suggests the micelles are highly stable in dilute solution. TEM and DLS further confirmed the successful formation of micelles with an average size of 61 and 100 nm, PDI of 0.209 and 0.230 for blank and DOX loaded micelles, respectively. The micelles were destructed under a reductive environment, leading to encapsulated drug release. Moreover, fluorescence microscopy demonstrated that the micelles exhibited both a passive and active targeting ability in HeLA cells due to an EPR effect and folate-mediated endocytosis. These results suggested the micelles would provide a favourable platform for constructing excellent drug delivery systems for cancer therapy.

Inorganic mesoporous materials have been attracting increasing attention during the past decade. In the present work, photoluminescent Ag2S nanospheres with mesoporous structures were prepared by assembling Ag2S nanoparticles with opposite charges in aqueous phase. Without structure-directing templates, mesoporous Ag2S with well-ordered face-centered cubic superlattice structures and high specific surface area was obtained. The mesoporous Ag2S nanospheres had the same crystal phase as their precursors Ag2S nanoparticles. Different from their near-infrared emitting precursors, the mesoporous Ag2S nanospheres exhibited cyan emission under ultraviolet excitation. The large number of sulfur-related defects existing in the mesostructures is most likely responsible for the photoluminescence. This work provides new insights into fabricating photoluminescent mesostructured materials via scale-up strategy.

•Water-dispersible AgInS2 QDs with bright near-infrared emission were synthesized.•Multidentate polymer was utilized as a compact capping ligand for the AgInS2 QDs.•The AgInS2 QDs possess good photostability and can be well used for in vivo imaging.A new strategy for fabricating water-dispersible AgInS2 quantum dots (QDs) with bright near-infrared (NIR) emission is demonstrated. A type of multidentate polymer (MDP) was synthesized and utilized as a compact capping ligand for the AgInS2 QDs. Using silver nitrate, indium acetate and sulfur–hydrazine hydrate complex as the precursors, MDP-capping AgInS2 QDs were synthesized in aqueous solution at room temperature. Characterization indicates that the MDP-capping AgInS2 QDs are highly photoluminescent in NIR window and possess good photostability. Also, the QDs are stable in different media and have low cytotoxicity. Nude mice photoluminescence imaging shows that the MDP-capping AgInS2 QDs can be well applied to in vivo imaging. These readily prepared NIR fluorescent nanocrystals have huge potential for biomedical applications.

Developing smart nanocarriers for drug delivery system is advantageous for many kinds of successful biomedicinal therapy. In this study, we designed an amphiphilic block copolymers containing pH-responsive tetrahydropyran (THP) and tetrahydrofuran (THF) linkage. Their structures were confirmed by 1H NMR and gel permeation chromatography (GPC). The release rate of encapsulated drugs depends upon the pH value and pH sensitive linkage in the backbone of copolymers. For PLA–THP–PEG micelles the cumulative release amount of doxorubicin (DOX) was 62% at pH 5.0, which is about four times higher than that at pH 7.4. Under the same conditions the release rate for PLA–THF–PEG micelles is a little faster than that of the PLA–THP–PEG micelles. Cellular uptake study demonstrates that DOX-loaded micelles can easily enter the cells and produce the desired pharmacological action and minimizing the side effect of free DOX. These findings indicate that THP and THF linked diblock copolymer micelles is a promising candidate for drug carrier.

Instructed by association units that allow reversible and unsymmetrical disulfide bond formation, hydrophilic (PEG) and hydrophobic (PLA) polymer chains are efficiently coupled into amphiphilic diblock copolymers. The desymmetrization of otherwise symmetrical reversible disulfide bond formation is achieved with amide association units that integrate both directional H-bonding and reversible disulfide bond formation, which ensure the connection of different polymer blocks while minimizing self-coupling. The resultant amphiphilic block copolymers self-assemble into long-lasting spherical micelles that are responsive to free thiols.

Cyclofenil analogs (2a–2f) and their fluorine-containing derivatives (3a–3f) were synthesized and evaluated as candidate ligands for positron emission tomography (PET) imaging of estrogen receptors. Most of them show relatively high binding affinities comparable with estradiol (E2). (4-Fluoroethoxyphenyl)-(4-hydroxyphenyl) methylenecyclopentane (3a) showed both the highest binding affinity for ERs (88.6 for ERβ, 13.8 for ERα) and highest β/α ratio (β/α for 6.4-fold). The radioactive compound [18F]3a was prepared via displacement of the corresponding mesylate precursor 4 with [18F]fluoride (18F: β+; 96.7%, T1/2 = 109.8 min). The biodistribution studies in immature female SD rats demonstrated that the uptake in the uterus and ovaries were 1.358 ± 0.089% ID/g, 1.439 ± 0.214% ID/g, respectively, both of the ratios of uterus/blood and ovaries/blood was less than 2:1. Micro-PET imaging of immature female SD rats has also been reported.Graphical abstractStructural studies on the ERs have suggested there is ample unoccupied space within the ligand binding pocket. Since our previous study focused on the effect of developing Tc-99m cyclofenil complexes for potential SPECT imaging agents. In the study reported here, a series of fluorinated cyclofenil analogs were designed and evaluated for a estrogen receptor imaging agent. These preliminary results suggested that the FEt-cyclofenil (3a) analogs might be potential PET imaging agents.Highlights► SAR relating ERα/ERβ binding affinities was established. ► The radioactive compound [18F]3a was prepared in good purity. ► The biodistribution demonstrated relatively high uptake in target tissues.

A cleavable azo linker was synthesized and reacted with 5-(6)-carboxytetramethyl rhodamine succinimidyl ester, followed by further reactions with di(N-succinimidyl) carbonate and 5-(3-amino-1-propynyl)-2′-deoxyuridine 5′-triphosphate [dUTP(AP3)] to obtain the terminal product dUTP-azo linker-TAMRA as a potential reversible terminator for DNA sequencing by synthesis with no need for 3′-OH blocking.

An acid-cleavable linker based on a dimethylketal moiety was synthesized and used to connect a nucleotide with a fluorophore to produce a 3′-OH unblocked nucleotide analogue as an excellent reversible terminator for DNA sequencing by synthesis.