Solvent Adaptive Dynamic Metal‐Organic Soft Hybrid for Imaging and Biological Delivery

A solvent responsive dynamic nanoscale metal‐organic framework (NMOF) [Zn( 1 a )(H₂O)₂] has been devised based on the self‐assembly of Zn^II and asymmetric bola‐amphiphilic oligo‐(p‐phenyleneethynylene) (OPE) dicarboxylate linker 1 a having dodecyl and triethyleneglycolmonomethylether (TEG, polar) side chains. In THF solvent, NMOF showed nanovesicular morphology ( NMOF‐1 ) with surface decorated dodecyl chains. In water and methanol, NMOF exhibited inverse‐nanovesicle ( NMOF‐2 ) and nanoscroll ( NMOF‐3 ) morphology, respectively, with surface projected TEG chains. The pre‐formed NMOFs also unveiled reversible solvent responsive transformation of different morphologies. The flexible NMOF showed cyan emission and no cytotoxicity, allowing live cell imaging. Cisplatin (14.4 wt %) and doxorubicin (4.1 wt %) were encapsulated in NMOF‐1 by non‐covalent interactions and, in vitro and in vivo drug release was studied. The drug loaded NMOFs exhibited micromolar cytotoxicity.     

Hypoxia‐Targeted siRNA Delivery

Altered vasculature and the resultant chaotic tumor blood flow lead to the appearance in fast‐growing tumors of regions with gradients of oxygen tension and acute hypoxia (less than 1.4 % oxygen). 1 Due to its roles in tumorigenesis and resistance to therapy, hypoxia represents a problem in cancer therapy. 1 , 2 Insufficient delivery of therapeutic agents to the hypoxic regions in solid tumors is recognized as one of the causes of resistance to therapy. 1 , 3 This led to the development of hypoxia imaging agents, 4 and the use of hypoxia‐activated anticancer prodrugs. 2a Here we show the first example of the hypoxia‐induced siRNA uptake and silencing using a nanocarrier consisting of polyethyleneglycol 2000, azobenzene, polyethyleneimine (PEI)(1.8 kDa), and 1,2‐dioleyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE) units (the nanocarrier is referred to as PAPD), where azobenzene imparts hypoxia sensitivity and specificity. 4a We report hypoxia‐activated green fluorescent protein (GFP) silencing in vitro and its downregulation in GFP‐expressing tumors after intravenous administration. The proposed nanoformulation represents a novel tumor‐environment‐responsive modality for cancer targeting and siRNA delivery.     

A Semiconducting Polymer Nano‐prodrug for Hypoxia‐Activated Photodynamic Cancer Therapy

Photodynamic therapy (PDT) holds great promise for cancer therapy; however, its efficacy is often compromised by tumor hypoxia. Herein, we report the synthesis of a semiconducting polymer nanoprodrug (SPNpd) that not only efficiently generates singlet oxygen (¹O₂) under NIR photoirradiation but also specifically activates its chemotherapeutic action in hypoxic tumor microenvironment. SPNpd is self‐assembled from a amphiphilic polymer brush, which comprises a light‐responsive photodynamic backbone grafted with poly(ethylene glycol) and conjugated with a chemodrug through hypoxia‐cleavable linkers. The well‐defined and compact nanostructure of SPNpd (30 nm) enables accumulation in the tumor of living mice. Owing to these features, SPNpd exerts synergistic photodynamic and chemo‐therapy, and effectively inhibits tumor growth in a xenograft tumor mouse model. This study represents the first hypoxia‐activatable phototherapeutic polymeric prodrug system with a high potential for cancer therapy.     

Tuning the low critical solution temperature of polymer brushes grafted on single‐walled carbon nanotubes and temperature dependent loading and release properties

A nondestructive method was developed for grafting and retrieving polymer brushes from single‐walled carbon nanotubes (SWCNT)s based on mussel‐inspired chemistry. Thermo‐responsive polymer brushes were grafted on SWCNTs by coating the tubes with polydopamine as a reactive underlayer and sequential surface‐initiated atom transfer radical polymerization of oligo(ethylene glycol) methacrylate (OEGMA, M_n = 475) and 2‐(2'‐methoxyethoxy)ethyl methacrylate (MEO2MA). Copolymer brushes were retrieved from the SWCNTs using 1 M NaOH to destroy the crosslinked polydopamine coating, and after that, the pristine properties of the SWCNTs were preserved. The low critical solution temperature (LCST) and molecular weight of the copolymer were measured using a nephelometer and gel permeation chromatograph, respectively. The loading and release behavior of Rhodamine 6G on responsive polymer‐grafted SWCNTs demonstrates that the copolymer brushes confer the SWCNTs an LCST dependence. This method can accurately confirm the molecular weights and polydispersity of stimuli‐responsive polymers grafted on any other nanoparticles and predict their controlled release behavior. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1807–1814     

Design and proof of reversible micelle‐to‐vesicle multistimuli‐responsive morphological regulations

Multistimuli‐responsive precise morphological control over self‐assembled polymers is of great importance for applications in nanoscience as drug delivery system. A novel pH, photoresponsive, and cyclodextrin‐responsive block copolymer were developed to investigate the reversible morphological transition from micelles to vesicles. The azobenzene‐containing block copolymer poly(ethylene oxide)‐b‐poly(2‐(diethylamino)ethyl methacrylate‐co‐6‐(4‐phenylazo phenoxy)hexyl methacrylate) [PEO‐b‐P(DEAEMA‐co‐PPHMA)] was synthesized by atom transfer radical polymerization. This system can self‐assemble into vesicles in aqueous solution at pH 8. On adjusting the solution pH to 3, there was a transition from vesicles to micelles. The same behavior, that is, transition from vesicles to micelles was also realizable on addition of β‐cyclodextrin (β‐CD) to the PEO‐b‐P(DEAEMA‐co‐PPHMA) solution at pH 8. Furthermore, after β‐CD was added, alternating irradiation of the solution with UV and visible light can also induce the reversible micelle‐to‐vesicle transition because of the photoinduced trans‐to‐cis isomerization of azobenzene units. The multistimuli‐responsive precise morphological changes were studied by laser light scattering, transmission electron microscopy, and UV–vis spectra. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

A Phototheranostic Strategy to Continuously Deliver Singlet Oxygen in the Dark and Hypoxic Tumor Microenvironment

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT‐induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell‐killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE@PEG‐Py NPs) prepared by using a 2‐pyridone‐based diblock polymer (PEG‐Py) to encapsulate a semiconducting, heavy‐atom‐free pyrrolopyrrolidone‐tetraphenylethylene (DPPTPE) with high singlet‐oxygen‐generation ability both in dichloromethane and water. The PEG‐Py can trap the ¹O₂ generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release ¹O₂ in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence‐imaging‐guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.     

Restoration of Ribozyme Tertiary Contact and Function by Using a Molecular Glue for RNA

Some RNA classes require folding into the proper higher‐order structures to exert their functions. Hammerhead ribozyme (HHR) requires a folding conformation stabilized by tertiary interaction for full activity. A rationally engineered HHR was developed that was inactive, but could be activated by a synthetic RNA‐binding ligand, naphthyridine carbamate tetramer with Z‐stilbene linker (Z‐NCTS). Binding of Z‐NCTS could induce the formation of an active folding structure and thereby restore ribozyme activity, where Z‐NCTS acts as a molecular glue to bring two isolated RNA loops into contact with each other. Next, we designed a Z‐NCTS‐responsive genetic switch using the HHR sequence inserted into the 3′ untranslated region as a cis‐acting element. We demonstrated that the rationally designed ribozyme switch enabled regulation of gene expression by Z‐NCTS and was functional in mammalian cells.     

Multi‐Stimuli‐Responsive Polymeric Prodrug for Enhanced Cancer Treatment

Accomplishing efficient delivery of a nanomedicine to the tumor site will encounter two contradictions as follows: 1) a contradiction between prolonged circulation time and endocytosis by cancer cells; 2) a dilemma between the stability of nanomedicine during blood circulation and intracellular drug release. While developing a nanomedicine which can solve the above two contradictions simultaneously is still a challenge, here, a multi‐stimuli‐responsive polymeric prodrug (PLys‐co‐(PLys‐DA)‐co‐(PLys‐SS‐PTX))‐b‐PLGLAG‐mPEG (P‐PEP‐SS‐PTX‐DA) is synthesized which is multi‐sensitive to overexpressed matrix metalloproteinase‐2 (MMP‐2), low pH, and high concentration of glutathione in tumors. The P‐PEP‐SS‐PTX‐DA can be dePEGylated and reversed from negative at normal physiological pH to positive charge at tumor extracellular microenvironment; in this way, it can solve the contradiction between prolonged circulation time and endocytosis by cancer cells. Owing to the high reductive conditions in cancer cells, P‐PEP‐SS‐PTX‐DA is ruptured to release paclitaxel (PTX) intracellular efficiently; therefore, it can resolve the dilemma between the stability of nanomedicine during blood circulation and intracellular drug release. These indicate that the multi‐stimuli‐responsive polymeric prodrug has potential application prospects in drug delivery and cancer therapy.     

Iridium(III) Anthraquinone Complexes as Two‐Photon Phosphorescence Probes for Mitochondria Imaging and Tracking under Hypoxia

In the present study, four mitochondria‐specific and two‐photon phosphorescence iridium(III) complexes, Ir1 – Ir4 , were developed for mitochondria imaging in hypoxic tumor cells. The iridium(III) complex has two anthraquinone groups that are hypoxia‐sensitive moieties. The phosphorescence of the iridium(III) complex was quenched by the functions of the intramolecular quinone unit, and it was restored through two‐electron bioreduction under hypoxia. When the probes were reduced by reductase to hydroquinone derivative products under hypoxia, a significant enhancement in phosphorescence intensity was observed under one‐ (λ=405 nm) and two‐photon (λ=720 nm) excitation, with a two‐photon absorption cross section of 76–153 GM at λ=720 nm. More importantly, these probes possessed excellent specificity for mitochondria, which allowed imaging and tracking of the mitochondrial morphological changes in a hypoxic environment over a long period of time. Moreover, the probes can visualize hypoxic mitochondria in 3D multicellular spheroids and living zebrafish through two‐photon phosphorescence imaging.     

Glucose‐Responsive Sequential Generation of Hydrogen Peroxide and Nitric Oxide for Synergistic Cancer Starving‐Like/Gas Therapy

Glucose is a key energy supplier and nutrient for tumor growth. Herein, inspired by the glucose oxidase (GOx)‐assisted conversion of glucose into gluconic acid and toxic H₂O₂, a novel treatment paradigm of starving‐like therapy is developed for significant tumor‐killing effects, more effective than conventional starving therapy by only cutting off the energy supply. Furthermore, the generated acidic H₂O₂ can oxidize l ‐Arginine (l ‐Arg) into NO for enhanced gas therapy. By using hollow mesoporous organosilica nanoparticle (HMON) as a biocompatible/biodegradable nanocarrier for the co‐delivery of GOx and l ‐Arg, a novel glucose‐responsive nanomedicine (l ‐Arg‐HMON‐GOx) has been for the first time constructed for synergistic cancer starving‐like/gas therapy without the need of external excitation, which yields a remarkable H₂O₂–NO cooperative anticancer effect with minimal adverse effect.     

Dual‐Targeting Nanovesicles for In Situ Intracellular Imaging of and Discrimination between Wild‐type and Mutant p53

p53 is a tumor‐suppressor protein related to the cell cycle and programmed cell apoptosis. Herein, dual‐targeting nanovesicles are designed for in situ imaging of intracellular wild‐type p53 (WTp53) and mutant p53 (MUp53). Nanovesicle‐encapsulated plasmonic gold nanoparticles (AuNPs) were functionalized with consensus DNA duplexes, and a fluorescein isothiocyanate (FITC)‐marked anti‐MUp53 antibody was conjugated to the nanovesicle surface. After entering the cytoplasm, the released AuNPs aggregated through recognition of WTp53 and the double‐stranded DNA. The color changes of AuNPs were observed using dark‐field microscopy, which showed the intracellular WTp53 distribution. The MUp53 location was detected though the immunological recognition between FITC‐labeled anti‐MUp53 and MUp53. Thus, a one‐step incubation method for the in situ imaging of intracellular WTp53 and MUp53 was obtained; this was used to monitor the p53 level under a drug treatment.     

Facile Generation of Tumor‐pH‐Labile Linkage‐Bridged Block Copolymers for Chemotherapeutic Delivery

Successful bench‐to‐bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor‐pH‐labile linkage‐bridged copolymers of clinically validated poly(d,l ‐lactide) and poly(ethylene glycol) (PEG‐Dlink_m‐PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG‐Dlink_m‐PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1 % in comparison to 47.8 % of the non‐responsive control. Furthermore, PEG‐Dlink_m‐PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG‐b‐PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.     

Manipulating Band Structure through Reconstruction of Binary Metal Sulfide for High‐Performance Thermoelectrics in Solution‐Synthesized Nanostructured Bi13S18I2

Reconstructing canonical binary compounds by inserting a third agent can significantly modify their electronic and phonon structures. Therefore, it has inspired the semiconductor communities in various fields. Introducing this paradigm will potentially revolutionize thermoelectrics as well. Using a solution synthesis, Bi₂S₃ was rebuilt by adding disordered Bi and weakly bonded I. These new structural motifs and the altered crystal symmetry induce prominent changes in electrical and thermal transport, resulting in a great enhancement of the figure of merit. The as‐obtained nanostructured Bi₁₃S₁₈I₂ is the first non‐toxic, cost‐efficient, and solution‐processable n‐type material with z T=1.0.     

MnOx Nanospikes as Nanoadjuvants and Immunogenic Cell Death Drugs with Enhanced Antitumor Immunity and Antimetastatic Effect

Despite the widespread applications of manganese oxide nanomaterials (MONs) in biomedicine, the intrinsic immunogenicity of MONs is still unclear. MnO_x nanospikes (NSs) as tumor microenvironment (TME)‐responsive nanoadjuvants and immunogenic cell death (ICD) drugs are proposed for cancer nanovaccine‐based immunotherapy. MnO_x NSs with large mesoporous structures show ultrahigh loading efficiencies for ovalbumin and tumor cell fragment. The combination of ICD via chemodynamic therapy and ferroptosis inductions, as well as antigen stimulations, presents a better synergistic immunopotentiation action. Furthermore, the obtained nanovaccines achieve TME‐responsive magnetic resonance/photoacoustic dual‐mode imaging contrasts, while effectively inhibiting primary/distal tumor growth and tumor metastasis.     

Synthesis and characterization of stimuli‐responsive porous/hollow nanoparticles by self‐assembly of chitosan‐based graft copolymers and application in drug release

In this research, stimuli‐responsive porous/hollow nanoparticles were prepared by the self‐assembly method. First, chitosan‐graft‐poly(N‐isopropylacrylamide) (CS‐g‐PNIPAAm) copolymers were synthesized through polymerization of N‐isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) solution using ceric ammounium nitrate as the initiator. Then, the CS‐g‐PNIPAAm copolymers were dissolved in the acetic acid aqueous solution and heated to 40 °C to induce their self‐assembly. After CS‐g‐PNIPAAm assembled to form micelles, a cross‐linking agent was used to reinforce the structure to form nanoparticles. The molecular weight of grafted PNIPAAm on CS chains was changed to investigate its effect on the structure, morphology, thermo‐, and pH‐responsive properties of the nanoparticles. TEM images showed that a porous or hollow structure in the interior of nanoparticles was developed, depending on the medium temperature. The synthesized nanoparticles carried positive charges on the surface and exhibited stimuli‐responsive properties, and their mean diameter thus could be manipulated by changing the pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in vitro release experiment. These porous/hollow particles with environmentally sensitive properties are expected to be used in hydrophilic drug delivery system. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2377–2387, 2010     

Current Rectification in Temperature‐Responsive Single Nanopores

Herein we demonstrate a fully abiotic smart single‐nanopore device that rectifies ionic current in response to the temperature. The temperature‐responsive nanopore ionic rectifier can be switched between a rectifying state below 34 °C and a non‐rectifying state above 38 °C actuated by the phase transition of the poly(N‐isopropylacrylamide) [PNIPAM] brushes. On the rectifying state, the rectifying efficiency can be enhanced by the dehydration of the attached PNIPAM brushes below the LCST. When the PNIPAM brushes have sufficiently collapsed, the nanopore switches to the non‐rectifying state. The concept of the temperature‐responsive current rectification in chemically‐modified nanopores paves a new way for controlling the preferential direction of the ion transport in nanofluidics by modulating the temperature, which has the potential to build novel nanomachines with smart fluidic communication functions for future lab‐on‐chip devices.     

Marrying mussel inspired chemistry with SET‐LRP: A novel strategy for surface functionalization of carbon nanotubes

Surface functionalization of carbon nanotubes (CNTs) with a thermo responsive polymer was achieved via combination of mussel inspired chemistry and surface initiated single electron transfer living radical polymerization (SET‐LRP). In this procedure, CNTs were first coated with polydopamine (PDA) through self polymerization under a rather mild condition. And then PDA functionalized CNTs bearing with amino and hydroxyl groups were further reacted with bromo isobutyryl bromide. Finally, a thermo responsive polymer poly(N‐isopropylacrylamide) (PNIPAM) was introduced on the CNTs via SET‐LRP. The successful surface modification of CNT‐PDA‐PNIPAM was evidenced by a series of characterization techniques. The resulting CNT‐PDA‐PNIPAM showed significant enhancement of dispersibility in both aqueous and organic solvents. More importantly, these CNT‐polymer nanocomposites showed obvious thermo responsive behavior due to the surface coating CNTs with PNIPAM. As compared with previous methods, this method is not required oxidation of CNTs to introduce funcitonal groups for immobilization of the polymerization initiators. More importantly, this method could also be utilized for fabricating many other polymer nanocomposites because of the strong and universal adhesive of PDA to various materials. It is therefore, the novel strategy via marrying mussel inspired chemistry with SET‐LRP should be a simple, general and effective method for surface functionalization. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1872–1879     

Stimuli‐Responsive Polypeptide‐Based Supramolecular Hydrogels Mediated by Ca2+ Ion Cross‐Linking

Hydrogels cross‐linked with metal ions (e.g., Ca²⁺) represent a promising class of bioinspired materials for a wide range of biomedical applications. Herein, we report a facile approach to obtain cross‐linked stimuli‐responsive supramolecular polypeptide hydrogels. The hydrogel is prepared by statistical/block copoly(L‐glutamate)s based copolymers cross‐linked with calcium ions. The incorporation of both oligo(ethylene glycol) (OEG) and glutamic acid residues in the polymer offers thermal‐responsive property and cooperative binding sites with Ca²⁺ ions simultaneously. We present a systematic study of the influence of calcium ions on the gelation behaviors of these copolymers. It is observed that the addition of calcium ions induces the formation of hydrogels. Increasing the concentration of Ca²⁺ ions can significantly enhance the gelation ability of the samples as indicated by increased storage modulus and decreased sol‐to‐gel transition temperature (T_sol‐gel). We further demonstrate that the influence of monomer distribution on the gelation behavior is trivial, which is possibly due to similar morphology of the self‐assemblies. The obtained hydrogels exhibit thermal‐responsive gelation behavior mediated by ion cross‐linking, which enables them to be ideal smart hydrogel system for many applications.     

Tuning the sugar‐response of boronic acid block copolymers

A detailed study of the pH‐ and sugar‐responsive behavior of poly(3‐acrylamidophenylboronic acid pinacol ester)‐b‐poly(N,N‐dimethylacrylamide) (PAPBAE‐b‐PDMA) block copolymers is presented. Reversible addition‐fragmentation chain transfer (RAFT) polymerization of the pinacol ester of 3‐acrylamidophenylboronic acid resulted in homopolymers with molecular weights between 12,000 and 37,000 g/mol. The resulting homopolymers were employed as macro‐chain transfer agents during the polymerization of N,N‐dimethylacrylamide (DMA). Successful chain extension and removal of the pinacol protecting groups to yield poly(3‐acrylamidophenylboronic acid)‐b‐PDMA (PAPBA‐b‐PDMA) with free boronic acid moieties resulted in pH‐ and sugar‐responsive block copolymers that were subsequently investigated for their behavior in aqueous solution. The PAPBA‐b‐PDMA block copolymers were capable of solution self‐assembly due to the PAPBA block being water‐insoluble below its pK_a. The resulting aggregates were demonstrated to solubilize and release model hydrophobic compounds, as demonstrated by fluorescence studies. Dissociation of the aggregates was induced by raising the pH above the pK_a of the boronic acid residues or by adding sugars capable of forming boronate esters. Aggregate size, dissociation kinetics, and the effect of various sugars were considered. The critical sugar concentration needed to induce aggregate dissociation was tuned by incorporation of hydrophilic DMA units within the PAPBA responsive segment to yield PDMA‐b‐poly(3‐acrylamidophenylboronic acid‐co‐DMA) block copolymers. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Layered microcapsules for daunorubicin loading and release as well as in vitro and in vivo studies

Anti‐cancer drug daunorubicin (DNR) was encapsulated in preformed multilayer microcapsules and was applied in tumor treatment by in vitro cell culture and in vivo animal experiments. The microcapsules were fabricated by an alternate deposition of oppositely charged polysaccharides, i.e. chitosan and alginate onto carboxymethyl cellulose (CMC) doped CaCO₃ colloidal particles in a sequential assembly procedure, followed by crosslinking of the capsule shells with glutaraldehyde (GA) and removal of the templates by disodium ethylenediaminetetraacetic acid (EDTA). The as‐prepared microcapsules showed strong ability to induce the positively charged DNR to deposit into the microcapsule interiors. Confocal microscopy and transmission electron microscopy observed homogeneous distribution of the drug within microcapsules. The loaded DNR could be released again, following a diffusion‐controlled model at the initial stage. In vitro experiments demonstrated that the encapsulated DNR can effectively induce the apoptosis of BEL‐7402 tumor cells, as evidenced by various microscopy techniques after acridine orange (AO), Hoechst 33342, and osmium tetraoxide staining. By seeding the BEL‐7402 hepatoma cells into BALB/c/nu mice, tumors were created for the animal experiments. The results showed that the encapsulated DNR had better efficacy than that of the free drug in terms of tumor inhibition in a 4 week in vivo culture period. Copyright © 2007 John Wiley & Sons, Ltd.