Ionic Covalent-Organic Framework Nanozyme as Effective Cascade Catalyst against Bacterial Wound Infection.

The increasing resistance risks of conventional antibiotic abuse and the formed biofilm on the surface of wounds have been demonstrated to be the main problems for bacteria-caused infections and unsuccessful wound healing. Treatment by reactive oxygen species, such as the commercial H2 O2 , is a feasible way to solve those problems, but limits in its lower efficiency. Herein, an ionic covalent-organic framework-based nanozyme (GFeF) with self-promoting antibacterial effect and good biocompatibility has been developed as glucose-triggered cascade catalyst against bacterial wound infection. Besides the efficient conversion of glucose to hydrogen peroxide, the produced gluconic acid by loading glucose oxidase can supply a compatible catalytic environment to substantially improve the peroxidase activity for generating more toxic hydroxyl radicals. Meanwhile, the adhesion between the positively charged GFeF and the bacterial membrane can greatly enhance the healing effects. This glucose-triggered cascade strategy can reduce the harmful side effects by indirectly producing H2 O2 , potentially used in the wound healing of diabetic patients.

π-Stacked Donor-Acceptor Dendrimers for Highly Efficient White Electroluminescence.

π-Stacked dendrimers consisting of cofacially aligned donors and acceptors are developed by introducing three dendritic teracridan donors with orthogonal configuration and three triazine acceptors in periphery of hexaphenylbenzene skeleton. The dendritic structure and orthogonal configuration of teracridan not only make their outer acridan segments approaching to acceptor in close distance, but also fix donor and acceptor in face-to-face alignment, leading to through-space charge transfer emission with thermally activated delayed fluorescence (TADF) effect. By regulating charge transfer strength via substituent effect of acceptor, emission color of the dendrimers can be tuned from blue to yellow/red region. Solution-processed two-color white organic light-emitting diodes (OLEDs) based on blue and yellow π-stacked donor-acceptor dendrimers exhibit the maximum external quantum efficiency of 20.6 % and maximum power efficiency of 58.9 lm W-1 , representing the state-of-the-art efficiency for all-TADF white OLEDs by solution process.

Through-Space Charge-Transfer Polynorbornenes with Fixed and Controllable Spatial Alignment of Donor and Acceptor for High-Efficiency Blue Thermally Activated Delayed Fluorescence.

Through-space charge transfer polynorbornenes with fixed and controllable spatial alignment of donor and acceptor in edge-to-face/face-to-face stacking patterns are developed for achieving high-efficiency blue thermally activated delayed fluorescence (TADF). The alignment is realized by using the cis, exo-configuration of norbornene to confine donor and acceptor in close proximity, and utilizing orthogonal and dendritic structures of donors to provide either perpendicular or parallel stacking motif relative to acceptors. Compared to edge-to-face counterparts, polynorbornenes with face-to-face aligned donor and acceptor exhibit much larger oscillator strength and higher photoluminescence quantum yield. The resulting polymers exhibit deep blue (422 nm) to sky blue (482 nm) emission and TADF effect with reverse intersystem crossing rates of 0.4-5.9×106  s-1 , giving the maximum external quantum efficiency of 18.8 % for non-doped blue organic light-emitting diodes by solution process.

A Paclitaxel Prodrug Activatable by Irradiation in a Hypoxic Microenvironment.

The innate hypoxic microenvironment of most solid tumors has a major influence on tumor growth, invasiveness, and distant metastasis. Here, a hypoxia-activated self-immolative prodrug of paclitaxel (PTX2 -Azo) was synthesized and encapsulated by a peptide copolymer decorated with the photosensitizer chlorin e6 (Ce6) to prepare light-boosted PTX nanoparticle (Ce6/PTX2 -Azo NP). In this nanoparticle, PTX2 -Azo prevents premature drug leakage and realizes specific release in hypoxic tumor microenvironment and the photosensitizer Ce6 not only efficiently generates singlet oxygen under light irradiation but also acts as a positive amplifier to promote the release of PTX. The combination of photodynamic therapy (PDT) and chemotherapy results in excellent antitumor efficacy, demonstrating the great potential for synergistic cancer therapy.

Developing Through-Space Charge Transfer Polymers as a General Approach to Realize Full-Color and White Emission with Thermally Activated Delayed Fluorescence.

Through-space charge transfer polymers (TSCT polymers) that contain a non-conjugated polystyrene backbone and spatially separated donor and acceptor units for solution-processed OLEDs with full-color and white emission is reported. By tuning the charge transfer strength between donor and acceptors with different electron-accepting ability, emission color spanning from deep blue to red can be achieved. By incorporating two kinds of donor/acceptor pairs in one polymer to create duplex through-space charge-transfer channels, blue and yellow emission can be simultaneously obtained to realize white electroluminescence from a single polymer. The TSCT polymers exhibit thermally activated delayed fluorescence effect with delayed-component lifetimes in range of 0.36-1.98 µs, and unexpected aggregation-induced emission (emission intensity enhancement of up to 117 from solution to aggregation state).

The Effect of Molecular Structure on Cytotoxicity and Antitumor Activity of PEGylated Nanomedicines.

Fundamental studies on the cellular uptake and drug release of PEGylated nanomedicines are beneficial to understand their fate in vivo and construct ideal nanoparticle formulations. In this work, the detailed metabolic process of PEGylated doxorubicin (Dox) nanomedicines were investigated via confocal laser scanning microscopy (CLSM), flow cytometry (FCM), cytotoxicity test, fluorescence imaging in vivo (FLIV) and liquid chromatography tandem mass spectrometry (LC-MS/MS). Among them, only LC-MS/MS could accurately determine the content of PEGylated Dox and Dox in vitro and in vivo. To the best of our knowledge, this was the first time the PEGylated Dox and released Dox were simultaneously quantified. The interplay of molecular structures, cellular uptake, drug release, and antitumor effect was well characterized. PEG with high molecular weight impeded the cellular uptake of nanoparticles, and the acid-labile hydrazone bond between Dox and PEG promoted Dox release significantly. Cellular uptake and drug release play decisive roles in cytotoxicity and antitumor effect, as evidenced by LC-MS/MS. We emphasized that LC-MS/MS would be a practicable method to quantify PEGylated drugs without complex tags, which could be more in-depth to understand the interaction between PEGylated nanomedicines and their antitumor efficacy.

Blue Thermally Activated Delayed Fluorescence Polymers with Nonconjugated Backbone and Through-Space Charge Transfer Effect.

We demonstrate novel molecular design for thermally activated delayed fluorescence (TADF) polymers based on a nonconjugated polyethylene backbone with through-space charge transfer effect between pendant electron donor (D) and acceptor (A) units. Different from conventional conjugated D-A polymers with through-bond charge transfer effect, the nonconjugated architecture avoids direct conjugation between D and A units, enabling blue emission. Meanwhile, spatial π-π interaction between the physically separated D and A units results in both small singlet-triplet energy splitting (0.019 eV) and high photoluminescence quantum yield (up to 60% in film state). The resulting polymer with 5 mol % acceptor unit gives efficient blue electroluminescence with Commission Internationale de l'Eclairage coordinates of (0.176, 0.269), together with a high external quantum efficiency of 12.1% and low efficiency roll-off of 4.9% (at 1000 cd m-2), which represents the first example of blue TADF nonconjugated polymer.

Maximizing Synergistic Activity When Combining RNAi and Platinum-Based Anticancer Agents.

RNAi approaches have been widely combined with platinum-based anticancer agents to elucidate cellular responses and to target gene products that mediate acquired resistance. Recent work has demonstrated that platination of siRNA prior to transfection may negatively influence RNAi efficiency based on the position and sequence of its guanosine nucleosides. Here, we used detailed spectroscopic characterization to demonstrate rapid formation of Pt-guanosine adducts within 30 min after coincubation of oxaliplatin [OxaPt(II)] or cisplatin [CisPt(II)] with either guanosine monophosphate or B-cell lymphoma 2 (BCL-2) siRNA. After 3 h of exposure to these platinum(II) agents, >50% of BCL-2 siRNA transcripts were platinated and unable to effectively suppress mRNA levels. Platinum(IV) analogues [OxaPt(IV) or CisPt(IV)] did not form Pt-siRNA adducts but did display decreased in vitro uptake and reduced potency. To overcome these challenges, we utilized biodegradable methoxyl-poly(ethylene glycol)-block-poly(ε-caprolactone)-block-poly(l-lysine) (mPEG-b-PCL-b-PLL) to generate self-assembled micelles that covalently conjugated OxaPt(IV) and/or electrostatically complexed siRNA. We then compared multiple strategies by which to combine BCL-2 siRNA with either OxaPt(II) or OxaPt(IV). Overall, we determined that the concentrations of siRNA (nM) and platinum(II)-based anticancer agents (µM) that are typically used for in vitro experiments led to rapid Pt-siRNA adduct formation and ineffective RNAi. Coincorporation of BCL-2 siRNA and platinum(IV) analogues in a single micelle enabled maximal suppression of BCL-2 mRNA levels (to <10% of baseline), augmented the intracellular levels of platinum (by ∼4×) and the numbers of resultant Pt-DNA adducts (by >5×), increased the cellular fractions that underwent apoptosis (by ∼4×), and enhanced the in vitro antiproliferative activity of the corresponding platinum(II) agent (by 10-100×, depending on the cancer cell line). When combining RNAi and platinum-based anticancer agents, this generalizable strategy may be adopted to maximize synergy during screening or for therapeutic delivery.

Stimuli-Responsive Polymersomes for Biomedical Applications.

Polymersomes, the structural analogues of liposomes, are hollow structures enclosed by a bilayer membrane made from amphiphilic copolymers. Polymersomes have been proposed to mimic the structure and properties of cellular membranes and viral capsids. Excellent robustness and stability, chemical versatility for tunable membrane properties and surface functionalization make polymersomes attractive candidates for drug delivery, diagnostic imaging, nanoreactor vessels, and artificial organelles. In further biomimetic strategies, stimuli-responsive polymersomes that can recognize various external physical or internal biological environmental stimuli and conduct "on demand" release in dose-, spatial-, and temporal-controlled fashions have been widely developed. This Perspective focuses on recent advances in stimuli-responsive polymersomes and their potential biomedical applications. Representative examples of each stimulus, the advantages and limitations of different strategies, and the future opportunities and challenges are discussed.

Turning Ineffective Transplatin into a Highly Potent Anticancer Drug via a Prodrug Strategy for Drug Delivery and Inhibiting Cisplatin Drug Resistance.

Clinically ineffective transplatin is highly potent against cancer cells when transformed into a transplatin(IV) prodrug nanoparticle. Herein, a hydrophobic transplatin(IV) was synthesized by H2O2-oxidization of transplatin and attachment of two hydrophobic aliphatic chains. Transplatin(IV) was subsequently encapsulated by a biodegradable amphiphilic copolymer, MPEG-PLA, forming a well-defined spherical micelles (M(TransPt)). Transplatin(IV) was protected efficiently and could be released under a simulated cancerous intracellular condition. Compared to the cisplatin and transplatin, M(TransPt) showed the highest Pt uptake and a clathrin-dependent endocytosis pathway. Most importantly, M(TransPt) displayed a nanomolar IC50 on A2780 cells and a great potency on cisplatin resistant A2780DDP cell line. Overall, this nanoplatform for delivering trans-geometry platinum(IV) drug exhibits excellent characteristics for enhancing efficacy and overcoming cisplatin drug resistance, and holds a strong promise for clinical use in the near future.

Amphiphilic Polycarbonates from Carborane-Installed Cyclic Carbonates as Potential Agents for Boron Neutron Capture Therapy.

Carboranes with rich boron content have showed significant applications in the field of boron neutron capture therapy. Biodegradable derivatives of carborane-conjugated polymers with well-defined structure and tunable loading of boron atoms are far less explored. Herein, a new family of amphiphilic carborane-conjugated polycarbonates was synthesized by ring-opening polymerization of a carborane-installed cyclic carbonate monomer. Catalyzed by TBD from a poly(ethylene glycol) macroinitiator, the polymerization proceeded to relatively high conversions (>65%), with low polydispersity in a certain range of molecular weight. The boron content was readily tuned by the feed ratio of the monomer and initiator. The resultant amphiphilic polycarbonates self-assembled in water into spherical nanoparticles of different sizes depending on the hydrophilic-to-hydrophobic ratio. It was demonstrated that larger nanoparticles (PN150) were more easily subjected to protein adsorption and captured by the liver, and smaller nanoparticles (PN50) were more likely to enter cancer cells and accumulate at the tumor site. PN50 with thermal neutron irradiation exhibited the highest therapeutic efficacy in vivo. The new synthetic method utilizing amphiphilic biodegradable boron-enriched polymers is useful for developing more-selective and -effective boron delivery systems for BNCT.

Effect of Molecular Structure on Stability of Organic Nanoparticles Formed by Bodipy Dimers.

The objective was to evaluate the stability of organic nanoparticles made from Bodipy dimers. Bodipy dimers with different length of linkers were synthesized via multicomponent Passerini reaction, and could form the fluorescent nanoparticles (FNPs) through nanoprecipitation. Bodipy-dimers FNPs with long chain linker indicated better stability in biological condition than those with short one as revealed by changes of diameter and size distribution. The FNPs possessed high physical homogeneity and low cytotoxicity. The molecular structure dependent stability was also validated by confocal laser scanning microscope based on the dissociation-induced fluorescence recovering. Importantly, stable FNPs also could be used to load hydrophobic cargoes and deliver them into cytoplasm. We believe this systematic study between structure and stability might open new opportunities for designing stable nanoparticles for various applications.

Nanoparticle-mediated delivery of multinuclear platinum(IV) prodrugs with enhanced drug uptake and the activity of overcoming drug resistance.

Here, a nanoparticle-mediated delivery of multinuclear platinum(IV) prodrugs [biodegradable polymer-di-cisPt(IV)] for overcoming cisplatin drug resistance is reported. From the MTT assays, lower IC50 values of polymer-di-cisPt(IV) on A2780DDP cells than A2780 were observed with the lowest resistance factor of 0.7. Inductively coupled plasma mass spectroscopy results showed that more drugs were delivered into cancer cells and greater number of Pt-DNA adducts were formed with the use of the polymer-di-cisPt(IV) conjugate nanoparticles. By a mechanistic study with endocytosis inhibitors to treat A2780 cells, we proved that polymer-di-cisPt(IV) conjugate nanoparticles were internalized by the cancer cells through endocytosis rather than through passive diffusion or copper transporter 1-mediated active transportation. This well illustrates the way how the polymer-di-cisPt(IV) micelles overcome cisplatin resistance.

Dual-Sensitive Charge-Conversional Polymeric Prodrug for Efficient Codelivery of Demethylcantharidin and Doxorubicin.

A tumor is a complicated system, and tumor cells are typically heterogeneous in many aspects. Polymeric drug delivery nanocarriers sensitive to a single type of biosignals may not release cargos effectively in all tumor cells, leading to low therapeutic efficacy. To address the challenges, here, we demonstrated a pH/reduction dual-sensitive charge-conversional polymeric prodrug strategy for efficient codelivery. Reduction-sensitive disulfide group and acid-labile anticancer drug (demethylcantharidin, DMC)-conjugated ß-carboxylic amide group were repeatedly and regularly introduced into copolymer chain simultaneously via facile CuAAC click polymerization. The obtained multifunctional polymeric prodrug P(DMC), mPEG-b-poly(disulfide-alt-demethylcantharidin)-b-mPEG was further utilized for DOX encapsulation. Under tumor tissue/cell microenvironments (pH 6.5 and 10 mM GSH), the DOX-loaded polymeric prodrug nanoparticles (P(DMC)@DOX NPs) performed surface negative-to-positive charge conversion and accelerated/sufficient release of DMC and DOX. The remarkably enhanced cellular internalization and cytotoxicity in vitro, especially against DOX-resistant SMMC-7721 cells, were demonstrated. P(DMC)@DOX NPs in vivo also exhibited higher tumor accumulation and improved antitumor efficiency compared to P(SA)@DOX NPs with one drug and without charge-conversion ability. The desired multifunctional polymeric prodrug strategy brings a new opportunity for cancer chemotherapy.

Single-Stimulus Dual-Drug Sensitive Nanoplatform for Enhanced Photoactivated Therapy.

Photoactivated therapy has become a complementary and attractive modality for traditional cancer treatment. Herein, we demonstrated a novel single-stimulus dual-drug sensitive nanoplatform, Cur-loaded Dex-Pt(N3) nanoparticles (Cur@DPNs) for enhanced photoactivated therapy. The developed Cur@DPNs could be photoactivated by UVA light to simultaneously generate instant reactive oxygen species from Cur for fast photodynamic therapy and release lasting Pt(II) from Pt(N3) for long-acting photochemotherapy. Compared with small free drugs and individual photoactivated therapy, Cur@DPNs exhibited enhanced photoactivated cytotoxicity and in vivo antitumor efficacy with low systemic toxicity accompanied. Therefore, the single-stimulus dual-drug sensitive nanoplatform is convinced to be a promising strategy for multidrug delivery, site-selective and combinational photoactivated therapy in the near future.

A hybrid platinum drug dichloroacetate-platinum(II) overcomes cisplatin drug resistance through dual organelle targeting.

A hybrid drug dichloroacetate-platinum(II) [DCA-Pt(II)] was found to overcome cisplatin drug resistance of ovarian cancer through a dual targeting mode, which is different from the mode of action of the present platinum (Pt) drugs used in clinics. DCA-Pt(II) exhibited remarkable cytotoxicity against both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780DDP) ovarian cancer cells. The Pt and Pt-DNA adduct content test showed that there was less Pt cellular uptake and fewer Pt-DNA adducts were present after DCA-Pt(II) treatment compared with treatment with cisplatin, carboplatin, and some other drugs. In the study, the effects of DCA-Pt(II) on the cell cycle and apoptosis were also investigated, which showed that DCA-Pt(II) induced G2/M phase arrest and mitochondria-mediated apoptosis in both sensitive and resistant cells lines. Interestingly, DCA-Pt(II) had much greater effects on mitochondria in A2780DDP cell lines than in A2780 cell lines.

Doxorubicin-Loaded Carborane-Conjugated Polymeric Nanoparticles as Delivery System for Combination Cancer Therapy.

Carborane-conjugated amphiphilic copolymer nanoparticles were designed to deliver anticancer drugs for the combination of chemotherapy and boron neutron capture therapy (BNCT). Poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2(2-dicarba-closo-dodecarborane)propyloxycarbonyl-propyne carbonate) (PLMB) was synthesized via the versatile reaction between decaborane and side alkynyl groups, and self-assembled with doxorubicin (DOX) to form drug-loaded nanoparticles. These DOX@PLMB nanoparticles could not only suppress the leakage of the boron compounds into the bloodstream due to the covalent bonds between carborane and polymer main chains, but also protect DOX from initial burst release at physiological conditions because of the dihydrogen bonds between DOX and carborane. It was demonstrated that DOX@PLMB nanoparticles could selectively deliver boron atoms and DOX to the tumor site simultaneously in vivo. Under the combination of chemotherapy and BNCT, the highest tumor suppression efficiency without reduction of body weight was achieved. This polymeric nanoparticles delivery system could be very useful in future chemoradiotherapy to obtain improved therapeutic effect with reduced systemic toxicity.

Use of asymmetric multilayer polylactide nanofiber mats in controlled release of drugs and prevention of liver cancer recurrence after surgery in mice.

Local tumor recurrence remains a major clinical problem following surgical treatment for most cancers such as hepatocellular carcinoma (HCC). An implantable local drug delivery system may be suitable for addressing this unmet clinical need. In this study, asymmetric multilayer polylactide nanofiber (AMPN) mats were prepared and a one-sided and prolonged release profile of hydrophilic dye or oxaliplatin was observed after they were sandwiched between two liver lobes in mice. Covering the surgery site by drug-loaded AMPN mat after tumor resection, in both subcutaneous and orthotopic HCC model in mice, the recurrence of HCC was significantly retarded and the survival time of mice was markedly prolonged. In conclusion, post-surgical therapy at tumor resection margins by drug-loaded AMPN mats may represent a suitable application of nanofiber-based local chemotherapy. FROM THE CLINICAL EDITOR: After cancer surgery, local recurrence remains a significant problem. In this study, the authors designed asymmetric multilayer PLA nanofiber (AMPN) mats and loaded them with anti-tumor drugs. Both in-vitro and in-vivo experiments showed good efficacy in preventing tumor recurrence. This novel product may point a way to the future and improve survival of cancer patients.

BODIPY fluorescent chemosensor for Cu2+ detection and its applications in living cells: fast response and high sensitivity.

Copper is an essential trace element for the proper functioning of organ and metabolic process in humans. However, both its excess and deficiency in the body can result in adverse health effects. A BODIPY containing 2,2'-bipyridyl group was synthesized and used as a fluorescent chemodosimeter for selective Cu2+ detection in mild condition. This BODIPY shows fast response (~1 min) and high sensitivity for Cu2+ in aqueous solution due to the photoinduced electron transfer from the excited state of fluorophore to the bipyridyl unit complexed to Cu2+. The fluorescence quenching mechanism revealed by MALDI-TOF Mass spectra showed one Cu2+ could coordinate with two BODIPY molecules, and this coordination is reversible. This simple BODIPY dyes also could be used for sensing the Cu2+ in living cell. This work contributes to extend the potential applications of BODIPY to the biological and environmental areas.

Self-host blue-emitting iridium dendrimer with carbazole dendrons: nondoped phosphorescent organic light-emitting diodes.

A blue-emitting iridium dendrimer, namely B-G2, has been successfully designed and synthesized with a secondgeneration oligocarbazole as the dendron, which is covalently attached to the emissive tris[2-(2,4-difluorophenyl)-pyridyl]iridium(III) core through a nonconjugated link to form an efficient self-host system in one dendrimer. Unlike small molecular phosphors and other phosphorescent dendrimers, B-G2 shows a continuous enhancement in the device efficiency with increasing doping concentration. When using neat B-G2 as the emitting layer, the nondoped device is achieved without loss in efficiency, thus giving a state-of-art EQE as high as 15.3% (31.3 cdA1, 28.9 lmW1) along with CIE coordinates of (0.16, 0.29).