Polydopamine nanoplatform with near infrared light and pH dual stimuli-responsive for chemo-photothermal cancer therapy.

Photothermal agent accompanying with thermally responsive materials, displays well controlled drug release property, which is well-received as an outstanding design strategy for simultaneous photothermal/chemotherapy in cancer. Cyanine dye, as the prestigious photothermal agent has shown great potential due to its preeminent near-infrared absorbance and excellent thermal conversion efficiency. However, their inherent defect such as inferior photothermal stability, high leakage risk and poor therapy efficacy limit their further application in cancer therapy. Hence, a facile and universal strategy to make up these deficiencies is developed. Chemotherapeutic drug DOX and cyanine dye were loaded into polydopamine (PDA) nanoparticles. The PDA encapsulation dramatically improved the photothermal stability of cyanine dye. Attributed by the PDA structure feature, the thermo-sensitive small molecule glyamine (Gla) is introduced into the PDA surface to lessen leakage. The Gla can form a dense encapsulation layer on the dopamine surface through hydrogen bond. This newly fabricated Cyanine/DOX@PDA-Gla nanopaltform is characterized with NIR light/pH dual-responsive property, high NIR photothermal conversion performance and fluorescence guided chemo-photothermal therapy.

One step assembly of ginsenoside Rb1-based nanovehicles with fast cellular transport in photothermal-chemical combined cancer therapy.

Nowadays, the research of photothermal-chemical co-therapy provides new ideas for the treatment of cancer. However, the harsh photothermal temperature hinders the clinical development of photothermal therapy. To ensure low-temperature photothermal-chemical combined therapy, a safe and feasible drug delivery system is highly desirable. Herein, through one step co-precipitation method, ginsenoside Rb1-based nanovehicles composed of the hydrophobic drug doxorubicin, the photochemical reagent Cypate and the heat shock protein inhibitor gambogic acid was prepared, resulting from the amphiphilicity and membrane permeability of Rb1. Encouragingly, this platform exhibited excellent biocompatibility and rapid cellular uptake, both of which led to significant and irreversible death of breast cancer cells under the trigger of short-term near-infrared light.

Construction of biocompatible bovine serum albumin nanoparticles composed of nano graphene oxide and AIEgen for dual-mode phototherapy bacteriostatic and bacterial tracking.

BACKGROUND: Efficient and highly controllable antibacterial effect, as well as good biocompatibility are required for antibacterial materials to overcome multi-drug resistance in bacteria. Herein, nano graphene oxide (NGO)-based near-infrared (NIR) photothermal antibacterial materials was schemed to complex with biocompatible bovine serum albumin (BSA) and aggregation-induced emission fluorogen (AIEgen) with daylight-stimulated ROS-producing property for dual-mode phototherapy in the treatment of antibiotic resistance bacteria. RESULTS: Upon co-irradiation of daylight and NIR laser, NGO-BSA-AIE nanoparticles (NPs) showed superiorly antibacterial effect (more than 99%) both against amoxicillin (AMO)-resistant Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by comparison with sing-model phototherapy. Meanwhile, the NGO-BSA-AIE NPs displayed prominent stability and excellently controllable biocompatibility. More importantly, under daylight irradiation, the AIEgen not only produced plentiful ROS for killing bacteria, but also presented fluorescence image for tracking bacteria. CONCLUSIONS: Hence, the designed system provided tempting strategy of employing light as impetus for tracking bacterial distribution and photothermal/photodynamic synergistic treatment of antibiotic resistance antibacterial.

An Acid-Triggered Degradable and Fluorescent Nanoscale Drug Delivery System with Enhanced Cytotoxicity to Cancer Cells.

To reduce side-effects of anticancer drugs, development of nanocarriers with precise biological functions is a critical requirement. In this study, the multifunctional nanoparticles combining imaging and therapy for tumor-targeted delivery of hydrophobic anticancer drugs were prepared via self-assembly of amphiphilic copolymers obtained using RAFT polymerization, specifically, acid-labile ortho ester and galactose. First, boron-dipyrromethene dye-conjugated chain transfer agent provides fluorescent imaging capability for diagnostic application. Second, nanoparticles were stable under physiological conditions but degraded in acidic tumor microenvironment, leading to enhanced anticancer efficacy. Third, the application of biocompatible glycopolymers efficiently increased the target-to-background ratio through carbohydrate-protein interactions. Data from cell viability, cellular internalization, flow cytometry, biodistribution and anticancer efficacy tests showed that the drug-loaded nanoparticles were capable of inhibiting cancer cell proliferation with significantly enhanced capacity. Our newly developed multifunctional nanoparticles may thus facilitate the development of effective drug delivery systems for application in diagnosis and therapy of cancer.

Block versus Random Amphiphilic Glycopolymer Nanopaticles as Glucose-Responsive Vehicles.

To explore the effect of polymer structure on their self-assembled aggregates and their unique characteristics, this study was devoted to developing a series of amphiphilic block and random phenylboronic acid-based glycopolymers by RAFT polymerization. The amphiphilic glycopolymers were successfully self-assembled into spherically shaped nanoparticles with narrow size distribution in aqueous solution. For block and random copolymers with similar monomer compositions, block copolymer nanoparticles exhibited a more regular transmittance change with the increasing glucose level, while a more evident variation of size and quicker decreasing tendency in I/I0 behavior in different glucose media were observed for random copolymer nanoparticles. Cell viability of all the polymer nanoparticles investigated by MTT assay was higher than 80%, indicating that both block and random copolymers had good cytocompatibility. Insulin could be encapsulated into both nanoparticles, and insulin release rate for random glycopolymer was slightly quicker than that for the block ones. We speculate that different chain conformations between block and random glycopolymers play an important role in self-assembled nanoaggregates and underlying glucose-sensitive behavior.

[Effects of Tansvaginal Aspiration of Hydrosalpinx Combined Auricular Point Sticking on IVF-ET Outcomes].

OBJECTIVE: To explore effective pretreated methods for hydrosalpinx before frozen embryo transfer (FET). METHODS: A randomized controlled study was performed on 229 FET cycles of hydrosalpinx patients. They were assigned to two groups by random digit table, Group A (94 cases), Group B (89 cases), and Group C (46 cases). Patients in Group A received transvaginal aspiration of hydrosalpinx combined with auricular point sticking. Those in Group B received transvaginal aspiration of hydrosalpinx group. Those in Group C received no transvaginal aspiration of hydrosalpinx. Pregnancy outcomes of FET, endometrial and subendometrial blood flow distribution on the embryo transfer day were compared among the three groups. RESULTS: There was no statistical difference in the endometrial thickness on FET day, the number of transfer embryos, the number of transferred good quality embryos among the three groups (P > 0.05). The clinical pregnancy rate and the embryo implantation rate were significantly higher in Group A than in Group C (P < 0.05), and the clinical pregnancy rate was significantly higher in Group A than in Group B (P < 0.05). The early abortion rate and the transfer cycle cancel rate were significantly lower in Group A than in Group C (P < 0.05). Type A endometrial and subendometrial blood flow distribution was dominant in Group A, which was significantly higher in Group A than the rest two groups (P < 0.05). Type A distribution rate was also significantly higher in Group B than in Group C (P < 0.05). CONCLUSION: Transvaginal aspiration of hydrosalpinx combined with auricular point sticking before FET could improve the endometrial receptivity and improve outcomes of IVF.

Construction of traceable cucurbit[7]uril-based virus-mimicking quaternary complexes with aggregation-induced emission for efficient gene transfection.

Construction of an efficient cationic gene delivery system with low cytotoxicity, high transfection efficacy, as well as gene tracking function remains a major challenge in gene therapy. Fabrication of simple and reversible nanocomplexes based on host-guest interaction provides an opportunity to construct stimuli-responsive intelligent supramolecular systems. Inspired by the hierarchical structure of viruses, a novel virus-mimicking PG/CB/TPE/DNA gene delivery system is developed via a multistep noncovalent self-assembly process between pDNA and the preformed PG/CB/TPE complexes based on the host-guest interaction between cucurbit[7]uril (CB[7]) and the protonated diamine group in the poly(glycidyl methacrylate)s derivative (PG), as well as the electrostatic interaction between para-carboxyl functionalized tetraphenylethylene (TPE) and cationic PG. The developed efficient multifunctional gene delivery system exhibits stimuli responsive characteristics and aggregation-induced emission phenomena, thereby enabling gene delivery pH responsiveness and traceability. Moreover, the introduction of TPE and CB[7] endows the self-assembled PG/CB/TPE/DNA complexes with virus-mimicking architecture and properties such as low cytotoxicity, high stability, excellent endosomal escape, and efficient transfection, which are expected to be used as a promising gene delivery system.

Reactive Oxygen Species Self-Sufficient Multifunctional Nanoplatform for Synergistic Chemo-Photodynamic Therapy with Red/Near-Infrared Dual-Imaging.

Developing multifunctional nanoplatforms that combine controlled drug release, therapy, and real-time monitoring of intracellular distribution of therapeutic agents can provide a solution for practical precision cancer therapy. Herein, a daylight activatable and red to near-infrared (NIR) dual-imaging guided multifunctional anticancer nanoplatform based on diselenium-conjugated and aggregation-induced emission fluorogen (AIEgen)-cross-linked oligoethylenimine polymer loaded with cisplatin (Pt) and biscyclometalated iridium(III) (Ir(III)) complex (Pt&Ir@P NPs) is reported. Upon short-time daylight irradiation, the nanoplatform generates reactive oxygen species (ROS), which help them to escape from endo/lysosomes via enhanced lysosomal membrane permeability. Meanwhile, the chemotherapeutic drug cisplatin and the photosensitizer (PS) Ir(III) complex are released via breaking the ROS-labile diselenium bond. The released PS, together with AIEgen, respond to the continuous long-time daylight irradiation and produce more ROS, inducing photodynamic therapy (PDT) and damaging the nucleus. Along with PDT, selenium liberates cisplatin and exerts chemotherapy in the presence of endogenous spermine. In addition, the red/NIR emitting Ir(III) complex and the engineered AIEgen act as dual-imaging agents for real-time monitoring the distribution of PS and polymer. This daylight responsive multifunctional nanoplatform for efficient anticancer therapy and imaging could provide an intriguing strategy for developing theranostic antitumor platforms.

A cyanine-based polymeric nanoplatform with microenvironment-driven cascaded responsiveness for imaging-guided chemo-photothermal combination anticancer therapy.

Finding out how to overcome multistage biological barriers for nanocarriers in cancer therapy to obtain highly precise drug delivery is still a challenge. Herein, we prepared a multistage and cascaded switchable polymeric nanovehicle, self-assembled from polyethylene glycol grafted amphiphilic copolymer containing hydrophobic poly(ortho ester) and hydrophilic ethylenediamine-modified poly(glycidyl methacrylate) (PEG-g-p(GEDA-co-DMDEA)) for imaging-guided chemo-photothermal combination anticancer therapy. Notably, a novel ATRP initiator containing cyanine dye was designed and attached to the polymer, providing the nanovehicle with NIR-light induced photothermal and fluorescent properties. The PEG shell displayed tumor-microenvironment-induced detachment, resulting in the surface charge change of the nanovehicle from neutral to positive and thus enhancing cellular uptake. Subsequently, the hydrophobic pDMDEA hydrolyzed into a hydrophilic segment in the acidic lysosome, leading to sufficient drug release. Finally, with the aid of the photothermal property, the therapeutic drug DOX successfully escaped from the lysosome to exert chemotherapy. This well-defined polymeric nanoplatform promoted the development of designing novel theranostic polymeric nanovehicles for precise cancer therapy.

Multipronged design of theranostic nanovehicles with endogenous and exogenous stimuli-responsiveness for precise cancer therapy.

Near-infrared (NIR) light-induced photothermal agent-based stimuli-responsive materials have attracted great interest from researchers. However, the highly smart release with precise control by NIR light is not yet well established because of the lack or inadequacy of intelligent release systems, such as premature release of drug and/or photothermal agent. Herein, we put forward a novel and convenient strategy to synthesize cyanine dye-functionalized polymeric materials, where cyanine dye was schemed to attach to polymeric materials by copolymerization, endowing the polymeric materials with NIR light-responsive photothermal property and fluorescent nature for real-time imaging of endocytosis and intracellular trafficking of nanovehicles. Meanwhile, the chemotherapy drug DOX was introduced into the cyanine-containing polymeric materials via formation of dynamic covalent hydrazone bond to circumvent the blood circulation barrier. The nanovehicles displayed fine pH/NIR light-controlled drug release and excellent tumor intracellular drug transposition, which were ulteriorly combined with photo-triggered hyperthermia for enhanced antitumor effect. Therefore, this multipronged design of theranostic nanovehicles with endogenous and exogenous stimuli-responsiveness provides a novel strategy to attain highly smart drug delivery for precise cancer therapy.

Construction of an Antibacterial Membrane Based on Dopamine and Polyethylenimine Cross-Linked Graphene Oxide.

Bacterial infections have been considered to be one of the greatest threats to human health. In this study, a covalently cross-linked GO membrane was fabricated through vacuum-assisted filtration self-assembly after being consequentially functionalized with dopamine (GO-PDA) and branched polyethylenimine (GO-PDA-PEI). The characteristics of GO, GO-PDA, and GO-PDA-PEI membranes were confirmed by X-ray diffraction, Fourier transform infrared measurements, scanning electron microscopy images, static water contact angle measurements, etc. The GO-PDA-PEI membrane showed extraordinary stability, compared with GO and GO-PDA, confirmed by ultrasonication treatment. Notably, the GO-PDA-PEI membrane exhibited excellent antibacterial efficiency for both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli (more than 99%) upon irradiation by a 795 nm near-infrared (NIR) laser. Interestingly, the GO-PDA-PEI membrane can be recycled, that is, the photothermal effect, as well as the antibacterial activity of the GO-PDA-PEI membrane, remained the same after 5-time recycling. Hence, the proposed system has great potential for future design of recyclable, highly stable, superior bacteriostatic membrane materials.

A theranostic saponin nano-assembly based on FRET of an aggregation-induced emission photosensitizer and photon up-conversion nanoparticles.

A photodynamic aggregation-induced emissive (AIE) fluorophore, characterized by near-infrared (NIR) emission, was created based on a fluorescence resonance energy transfer (FRET) donor of appreciable NIR up-conversion nanoparticles (UCNPs) and acceptor of immense fluorescence emissive AIEgen. Hence, the entrapment of the FRET couple into an amphiphilic saponin-based nanoscaled self-assembly demonstrated appealing theranostic functions in producing immense fluorescence emission and cytotoxic reactive oxygen species (ROS).

Hyaluronic acid/PEGylated amphiphilic nanoparticles for pursuit of selective intracellular doxorubicin release.

Polyethylene glycol (PEG)-lyted cationic amphiphilic copolymers were employed as complexing agents with biocompatible anionic hyaluronic acid (HA) for the controlled release of doxorubicin (DOX). The overexpressed receptors to HA in a variety of cancerous cells enable preferential endocytosis of the HA-functionalized nanoparticles. Moreover, introduction of HA is supposed to diminish the unfavorable non-specific reactions in the biological milieu. Particularly, the drastic positive charge was validated post-endocytosis as a consequence of our strategic molecular design for the promotion of positive charges of cationic components. This deshielding effect of the anionic hyaluronic acid by endogenous hyaluronidase in endosomes and demotion of PEG at the endosome acid microenvironment consequently results in the structural rearrangement and favorable reaction of the resulting positive-charged structure with the intracellular species and structures, ultimately giving rise to liberation of the doxorubicin for the subsequent molecular pharmaceutic consequences. Simultaneously, the system containing quaternary ammonium salt and hydrophobic n-octyl acrylate (OA) possesses considerable antibacterial ability to alleviate anti-cancer drugs resistance. This delivery system is intended to overcome the intratumor bacteria-induced tumor resistance.

A multifunctional polymeric gene delivery system for circumventing biological barriers.

Aiming to circumvent the pre-defined obstacles in the journey of gene transportation, we attempt to compile a number of functional components into a tandem tri-copolymeric material. Herein, a ß-cyclodextrin-functionalized poly(glycerol methacrylate) (PG) segment and a quaternary amine-functionalized poly[(2-acryloyl)-ethyl-(p-boronic acid pinacol ester benzyl)diethylammonium bromide] (BP) segment are attached to complex DNA to formulate a nanoscaled delivery system based on electrostatic interactions. The formulated polyplex is strengthened by a hydrophobic poly[2-(5,5-dimethyl-1,3-dioxan-2-yloxy)ethyl acrylate] (PDM) segment, affording improved complex stability. To retrieve the polyplex from entrapment by acidic and digestive endo/lysosomes, light-stimulated ROS-producing 4,4'-(1,2-diphenylethene-1,2-diyl)bis(1,4-phenylene)diboronic acid (TPE) is installed in the cavities of cyclodextrin. Upon light irradiation, TPE is triggered to produce abundant ROS, not only committing disruption of the endo/lysosome membrane for polyplex escape from the entrapment but also inducing the transformation of the positively charged BP to become negatively charged. This charge conversion behavior, together with the transformation of PDM to be hydrophilic and responsive to an acidic endosome pH gradient (pH 5.0) is envisioned to induce the dissociation of the electrostatically-assembled polyplex, thereby facilitating the release of the DNA payload for the subsequent transcription machinery. This strategically-tailored and easily synthesized tandem tri-copolymer exhibits excellent gene expression activity and provides a facile response to endogenous and exogenous stimuli for active gene expression.

Construction of Bovine Serum Albumin/AIE-Based Quaternary Complexes for Efficient Gene Transfection.

High transfection efficiency and superior cell imaging are required for cationic polymers-based gene delivery system to afford high therapeutic effect but its high toxicity and unstable cell imaging are easily ignored. In this study, cationic amino poly(glycerol methacrylate) derivative (PGMA-EDA) is used to incorporate bovine serum albumin (BSA) and aggregation-induced emission (AIE) molecular (tetraphenylethylene derivatives, TPE) as an efficient carrier for gene transfection and intracellular imaging. The obtained polymer/pDNA-TPE/BSA (PDTB) quaternary nanoparticles (NPs) not only exhibit efficient gene transfection but also show excellent biocompatibility. After inclusion of TPE/BSA (TB) NPs, BSA promoted dissociation of the complexes upon being protonated and the lipophilic TPE-reduced endosomal membrane stability, which enhanced endosomal escape of pDNA payload, finally resulting in an excellent gene transfection. On the other hand, less positive surface charge of PDTB NPs than that of the binary PD complexes, as well as the addition of biocompatible BSA, both factors contribute to the improved cell viability. Moreover, the AIE feature of TPE compared to aggregation-caused quenching character of conventional fluorophores enables the complex with stably tracking the delivery of pDNA into cancer cells. Therefore, the newly developed PDTB complexes may be a promising candidate vector for traceable, safe, and effective gene delivery.

Targeted Next Generation Sequencing Revealed a Novel Homozygous Loss-of-Function Mutation in ILDR1 Gene Causes Autosomal Recessive Nonsyndromic Sensorineural Hearing Loss in a Chinese Family.

Hereditary hearing impairment is one of the major and common birth defects in Chinese population. Non-syndromic sensorineural hearing loss (NSHL) is the most common types of hereditary hearing impairment. Genotypically and phenotypically NSHL is extremely heterogenous and follow either autosomal dominant or autosomal recessive or X-linked mode of inheritance. Presently, 127 genes have been identified to be associated with both syndromic and (NSHL). Here, we studied a Chinese family with moderate and profound hearing impairment. The proband is a 30-year old Chinese man. The proband was born with normal hearing and at the age of 5-years, the proband was first noticed with hearing impairment. Gradually and progressively the proband was presented with loss of hearing in his both right and left ears at the age of 30 years. The clinical symptoms, age of onset or progression to loss of hearing was similar in both the proband and his younger brother. The proband's parents are phenotypically normal and non-consanguineous. Clinical diagnosis of the proband and his younger brother has been done by classical pure tone audiogram (PTA). Computed Tomography (CT) found no abnormality in bilateral external ear, middle ear and inner ear. Targeted next generation sequencing was performed with a panel of 127 genes reported to be associated with hereditary hearing impairment. A novel homozygous single nucleotide deletion (c.427delT) in exon 4 of ILDR1 gene has been identified in proband and in his younger brother. Sanger sequencing confirmed that proband's father and mother are carrying this mutation in a heterozygous manner. This mutation has not been identified in 100 normal healthy control individuals. This mutation (c.427delT) causes frameshift (p.Tyr143Ilefs∗19) which leads to the formation of a truncated ILDR1 protein of 162 amino acids instead of the wild type ILDR1 protein of 546 amino acids. ILDR1 associated hereditary hearing impairment is very rare and this is the first report of identifying a loss-of-function mutation in ILDR1 gene associated with hereditary hearing impairment in Chinese population. Our present study also emphasized the significance of rapid, accurate and cost-effective screening for the patient with hereditary hearing impairment by targeted next generation sequencing.

Near-infrared AIEgen-functionalized and diselenide-linked oligo-ethylenimine with self-sufficing ROS to exert spatiotemporal responsibility for promoted gene delivery.

Reversible stabilities are required for therapeutic (e.g. DNA) delivery systems to afford adequate stability in the journey to therapeutic targets but make the systems susceptible to structural disassembly and the liberation of their therapeutic payloads. For this purpose, we attempted to synthesize an oligo-ethyleneimine (OEI)-crosslinked polycation, characterized with self-sufficing reactive oxygen species (ROS) by virtue of a functional aggregation-induced emissive (AIE) component (with good near-infrared imaging functions) and an ROS-labile diselenide linkage. The strategic AIE component was capable of exerting facile ROS production upon convenient daylight irradiation (unprecedented ROS-producing efficiency of 80.14%), consequently helping to activate an endosomal escape functionality and the fragmentation of the OEI-crosslinked polycation into low molecular weight OEI products. Consequently, the engineered capabilities enabled the spatiotemporal control of the stabilities of the electrostatic-based DNA self-assembled formation so that it was adequately stable in the gene transportation journey to the targets but could reverse the stabilities to liberate pDNA to execute the subsequent biological processes, evidenced by the disassociation of the near-infrared emission of AIEgen and Cy5-pDNA. Therefore, our devised strategies provided tempting design implications for utilizing daylight as an impetus for the intracellular delivery of functional molecules, and thus could be developed further to find broad utilities in the transportation of a variety of biological substances in therapeutic applications.

Hierarchical design of a polymeric nanovehicle for efficient tumor regression and imaging.

Effective delivery of therapeutics to disease sites significantly contributes to drug efficacy, toxicity and clearance. Here we designed a hierarchical polymeric nanoparticle structure for anti-cancer chemotherapy delivery by utilizing state-of-the-art polymer chemistry and co-assembly techniques. This novel structural design combines the most desired merits for drug delivery in a single particle, including a long in vivo circulation time, inhibited non-specific cell uptake, enhanced tumor cell internalization, pH-controlled drug release and simultaneous imaging. This co-assembled nanoparticle showed exceptional stability in complex biological media. Benefiting from the synergistic effects of zwitterionic and multivalent galactose polymers, drug-loaded nanoparticles were selectively internalized by cancer cells rather than normal tissue cells. In addition, the pH-responsive core retained their cargo within their polymeric coating through hydrophobic interaction and released it under slightly acidic conditions. In vivo pharmacokinetic studies in mice showed minimal uptake of nanoparticles by the mononuclear phagocyte system and excellent blood circulation half-lives of 14.4 h. As a result, tumor growth was completely inhibited and no damage was observed for normal organ tissues. This newly developed drug nanovehicle has great potential in cancer therapy, and the hierarchical design principle should provide valuable information for the development of the next generation of drug delivery systems.

In situ cross-linked polysaccharide hydrogel as extracellular matrix mimics for antibiotics delivery.

Many synthetic hydrogels for drug delivery have been based on polyethylene glycol which is non-natural, non-biodegradable and only terminal-functionalizable. The polysaccharides dextran and chitosan not only are highly hydrophilic, biodegradable and pendant-functionalizable, but also more closely mimic the nature extracellular matrix glycosaminoglycans. Here, a biomimetic hydrogel based on chitosan and dextran was synthesized by the Michael addition reaction. The hydrogels have good swelling and cytocompatibility against NIH3T3. Moreover, vancomycin-loaded hydrogels were formed in situ, and could kill both Gram-positive bacteria and Gram-negative bacteria, indicating that the hydrogel as a wound dressing could provide protection against bacterial infection. Notably, the drug release was controlled via modifying the compositions. Therefore, the biomimetic polysaccharide hydrogels as a promising carrier have potential application for wound healing.