A Paclitaxel Prodrug with Copper Depletion for Combined Therapy toward Triple-Negative Breast Cancer.

Tuning the content of copper is of great significance for the treatment of cancer and neurodegenerative diseases. Herein, we synthesized a redox-responsive paclitaxel (PTX) prodrug by conjugating PTX with a copper chelator through a disulfide bond. The as-fabricated prodrug (PSPA) showed specific chelation toward copper ions and could assemble with distearoyl phosphoethanolamine-PEG2000 to form stable nanoparticles (PSPA NPs) in aqueous media. Upon being internalized by tumor cells, PSPA NPs could respond to high levels of redox-active species inside cells and efficiently release PTX. The copper chelator could increase oxidative stress- and abnormal metabolism-induced cell death through intracellular copper depletion. The combination of chemotherapy and copper depletion therapy generated an enhanced therapeutic outcome toward triple-negative breast cancer with an ignorable systemic toxicity. Our work may provide insight into the combination of metabolic regulation and chemotherapy for combating malignant tumors.

Hypoxia-Activated PEGylated Paclitaxel Prodrug Nanoparticles for Potentiated Chemotherapy.

Developing controlled drug-release systems is imperative and valuable for increasing the therapeutic index. Herein, we synthesized hypoxia-responsive PEGylated (PEG = poly(ethylene glycol)) paclitaxel prodrugs by utilizing azobenzene (Azo) as a cleavable linker. The as-fabricated prodrugs could self-assemble into stable nanoparticles (PAP NPs) with high drug content ranging from 26 to 44 wt %. The Azo group in PAP NPs could be cleaved at the tumorous hypoxia microenvironment and promoted the release of paclitaxel for exerting cytotoxicity toward cancer cells. In addition, comparative researches revealed that the PAP NPs with the shorter methoxy-PEG chain (molecular weight = 750) possessed enhanced tumor suppression efficacy and alleviated off-target toxicity. Our work demonstrates a promising tactic to develop smart and simple nanomaterials for disease treatment.

Indocyanine green potentiated paclitaxel nanoprodrugs for imaging and chemotherapy.

Self-assembled prodrug nanoparticles with tumor-responsive capacity have great potential in tumor visualization and treatment. However, the nanoparticle formulas usually contain multiple components, especially polymeric materials, which result in various potential issues. Herein, we report an indocyanine green (ICG)-driven assembly of paclitaxel prodrugs integrating near-infrared fluorescence imaging and tumor-specific chemotherapy. By feat of the hydrophilic merit of ICG, paclitaxel dimer could form more uniformly monodispersed nanoparticles. This two-in-one strategy reinforces the complementary advantages, resulting in superior assembly behavior, robust colloidal stability, enhanced tumor accumulation as well as desirable near-infrared imaging and in vivo feedback of chemotherapy. The in vivo experiments validated the prodrug activation at tumor sites as evidenced by enhanced fluorescence intensity, potent tumor growth suppression, and reduced systemic toxicity compared with commercial Taxol. The universality of ICG potentiated strategy toward photosensitizers and fluorescence dyes was confirmed. This presentation provides deep insight into the feasibility of constructing clinical-close alternatives for improving antitumor efficacy.

Intracellular Enzyme-Responsive Profluorophore and Prodrug Nanoparticles for Tumor-Specific Imaging and Precise Chemotherapy.

Responsive drug delivery systems possess great potential in disease diagnosis and treatment. Herein, we develop an activatable prodrug and fluorescence imaging material by engineering the endogenous NAD(P)H:quinone oxidoreductase-1 (NQO1) responsive linker. The as-prepared nanomaterials possess the NQO1-switched drug release and fluorescence enablement, which realizes the tumor-specific chemotherapy and imaging in living mice. The enzyme-sensitive prodrug nanoparticles exhibit selectively potent anticancer performance to NQO1-positive cancer and ignorable off-target toxicity. This work provides an alternative strategy for constructing smart prodrug nanoplatforms with precision, selectivity, and practicability for advanced cancer imaging and therapy.

Hyperfluorescent polymers enabled by through-space charge transfer polystyrene sensitizers for high-efficiency and full-color electroluminescence.

Fluorescent polymers are suffering from low electroluminescence efficiency because triplet excitons formed by electrical excitation are wasted through nonradiative pathways. Here we demonstrate the design of hyperfluorescent polymers by employing through-space charge transfer (TSCT) polystyrenes as sensitizers for triplet exciton utilization and classic fluorescent chromophores as emitters for light emission. The TSCT polystyrene sensitizers not only have high reverse intersystem crossing rates for rapid conversion of triplet excitons into singlet ones, but also possess tunable emission bands to overlap the absorption spectra of fluorescent emitters with different bandgaps, allowing efficient energy transfer from the sensitizers to emitters. The resultant hyperfluorescent polymers exhibit full-color electroluminescence with peaks expanding from 466 to 640 nm, and maximum external quantum efficiencies of 10.3-19.2%, much higher than those of control fluorescent polymers (2.0-3.6%). These findings shed light on the potential of hyperfluorescent polymers in developing high-efficiency solution-processed organic light-emitting diodes and provide new insights to overcome the electroluminescence efficiency limitation for fluorescent polymers.

Engineering Paclitaxel Prodrug Nanoparticles via Redox-Activatable Linkage and Effective Carriers for Enhanced Chemotherapy.

The current clinical performance of chemotherapy is far from satisfactory, greatly limited by insufficient delivery efficacy and serious systemic side effects. Dimeric prodrug systems are emerging as valuable strategies for boosting the antitumor outcome. Here, dimeric paclitaxel prodrugs were synthesized with different bridged linkers, and the formed prodrug nanoparticles possessed excellent colloidal stability and ultrahigh drug content. The diselenide bond containing paclitaxel prodrugs could respond to a redox-heterogeneous intracellular microenvironment for on-demand drug release and subsequently show a selective cytotoxicity toward tumor cells against normal cells. Furthermore, the optimal carrier materials were screened out according to their contribution on stability, endocytosis, cytotoxicity, biodistribution, and antitumor efficacy. Compared with DSPE-PEG, human serum albumin, and Fe-tannic acid-based complex, F127 anchored dimeric paclitaxel nanoformulations exhibited preferential tumor accumulation and potent anticancer effect. Our present work provides deep insight into the development of advanced nanoformulations with comprehensive advantages for enhancing cancer therapy.

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.

Through-space charge transfer dendrimers employing oxygen-bridged triarylboron acceptors for efficient deep-blue electroluminescence.

Through-space charge transfer dendrimers consisting of dendritic triacridan donors and oxygen-bridged triarylboron acceptors are demonstrated to exhibit deep-blue thermally activated delayed fluorescence with the state-of-the-art external quantum efficiency of 14.6% for electroluminescence by a solution process.

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.

Nanoscale Covalent Organic Frameworks with Donor-Acceptor Structure for Enhanced Photothermal Ablation of Tumors.

Covalent organic frameworks (COFs) have shown great potential in catalysis and the biomedical fields, but monodisperse COFs with tunable sizes are hard to obtain. Herein, we successfully developed a series of COFs based on electron donor-acceptor strategy in mild conditions. The synthetic COFs exhibit excellent colloidal stability with uniform spherical morphology. The sizes can be flexibly adjusted by the amount of catalyst, and the absorption spectra also vary with the sizes. By changing the electron-donating ability of the monomers, the corresponding COFs possess a wide range of absorption spectra, which can be even extended to the second near-infrared biowindow. The obtained COFs possess potent photothermal activity under laser irradiation, and could inhibit the growth of tumors effectively. This work provides a strategy for the synthesis of monodisperse COFs with variable absorption for their potential applications.

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.

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.

Renal clearable Hafnium-doped carbon dots for CT/Fluorescence imaging of orthotopic liver cancer.

Carbon dots (CDs) are emerging as powerful nanoprobes for multiple-model bioimaging. Nowadays, orthotopic xenograft models attract increasing attention because of their superiorities of duplicating the tumor microenvironment. However, compared with the extensive study of subcutaneous xenograft tumors, less attention has been paid to CDs for in vivo orthotopic tumor imaging. Furthermore, it is very desirable for a nanoprobe to achieve preferential accumulation at the tumor site and efficient renal clearance. In this work, a novel kind of Hafnium-doped CDs (HfCDs) were successfully prepared via a simple one-pot pyrolysis method. The significant advantages including robust stability, good biocompatibility, excellent water solubility, remarkable computed tomography (CT) contrast performance and preferential tumor accumulation capability endow HfCDs with particular functions of CT/fluorescence imaging of orthotopic liver cancer initially. More importantly, HfCDs could locate at the tumor site and achieve the rapid imaging within 1 min. The findings of the current study represent a facile and universal approach to fabricate outstanding renal clearable multimodal imaging nanoprobes with great potential for clinical diagnosis.

Intestinal Bacteria Encapsulated by Biomaterials Enhance Immunotherapy.

The human intestine contains thousands of bacterial species essential for optimal health. Aside from their pathogenic effects, these bacteria have been associated with the efficacy of various treatments of diseases. Due to their impact on many human diseases, intestinal bacteria are receiving increasing research attention, and recent studies on intestinal bacteria and their effects on treatments has yielded valuable results. Particularly, intestinal bacteria can affect responses to numerous forms of immunotherapy, especially cancer therapy. With the development of precision medicine, understanding the factors that influence intestinal bacteria and how they can be regulated to enhance immunotherapy effects will improve the application prospects of intestinal bacteria therapy. Further, biomaterials employed for the convenient and efficient delivery of intestinal bacteria to the body have also become a research hotspot. In this review, we discuss the recent findings on the regulatory role of intestinal bacteria in immunotherapy, focusing on immune cells they regulate. We also summarize biomaterials used for their delivery.

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).

Through-space charge transfer hexaarylbenzene dendrimers with thermally activated delayed fluorescence and aggregation-induced emission for efficient solution-processed OLEDs.

Through-space electron interaction plays a critical role in determining the optical and charge transport properties of functional materials featuring π-stacked architectures. However, developing efficient organic luminescent materials with such interactions has been a challenge because of the lack of well-established prototypical molecules. Here we report the design of through-space charge transfer hexaarylbenzenes (TSCT-HABs) containing circularly-arrayed electron donors (acridan/dendritic triacridan) and acceptors (triazine), which exhibit both thermally activated delayed fluorescence (TADF) and aggregation-induced emission (AIE) effects for high-efficiency solution-processed organic light-emitting diodes (OLEDs). Spatial separation of donors and acceptors in the TSCT-HABs induces a small singlet-triplet energy splitting of 0.04-0.08 eV, leading to delayed fluorescence with microsecond-scale lifetimes. Meanwhile, the TSCT-HABs display the AIE effect with emission intensity enhanced by 6-17 fold from solution to the aggregation state owing to their propeller-shaped configuration. Solution-processed OLEDs based on the TSCT-HABs show maximum external quantum efficiency up to 14.2%, making them among the most efficient emitters for solution-processed TADF OLEDs.

Synthesis and Electroluminescent Properties of Through-Space Charge Transfer Polymers Containing Acridan Donor and Triarylboron Acceptors.

We report the design, synthesis and electroluminescent properties of three kinds of through-space charge transfer (TSCT) polymers consisting of non-conjugated polystyrene backbone, acridan donor and triarylboron acceptors having different substituents such as hydrogen (H), fluorine (F), and trifluoromethyl (CF3). Owing to the weak electron interaction between acridan donor and triarylboron acceptor through non-conjugated connection, blue emission with peaks in range of 429-483 nm can be achieved for the polymers in solid-state film, accompanied with photoluminescence quantum yields of 26-53%. The resulting TSCT polymers exhibit small ΔEST values below 0.1 eV owing to the separated HOMO and LUMO distributions, showing thermally activated delayed fluorescence with lifetimes in range of 0.19-0.98 µs. Meanwhile, the polymers show aggregation-induced emission (AIE) effect with the emission intensity increased by up to ~33 folds from solution to aggregation state. Solution-processed organic light-emitting diodes based on the polymers containing trifluoromethyl substituent exhibit promising electroluminescent performance with maximum luminous efficiency of 20.1 cd A-1 and maximum external quantum efficiency of 7.0%, indicating that they are good candidates for development of luminescent polymers.

Intracellular calcium ions and morphological changes of cardiac myoblasts response to an intelligent biodegradable conducting copolymer.

A novel biodegradable conducting polymer, PLA-b-AP-b-PLA (PAP) triblock copolymer of poly (l-lactide) (PLA) and aniline pentamer (AP) with electroactivity and biodegradability, was synthesized and its potential application in cardiac tissue engineering was studied. The PAP copolymer presented better biocompatibility compared to PANi and PLA because of promoted cell adhesion and spreading of rat cardiac myoblasts (H9c2 cell line) on PAP/PLA thin film. After pulse electrical stimulation (5 V, 1 Hz, 500 ms) for 6 days, the proliferation ratio, and intracellular calcium concentration of H9c2 cells on PAP/PLA were improved significantly. Meanwhile, cell morphology changed by varying the pulse electrical signals. Especially, the oriented pseudopodia-like structure was observed from H9c2 cells on PAP/PLA after electrical stimulation. It is regarded that the novel conducting copolymer could enhance electronic signals transferring between cells because of its special electrochemical properties, which may result in the differentiation of cardiac myoblasts.

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.

Ion-assisted fabrication of neutral protein crosslinked sodium alginate nanogels.

Protein crosslinked nanogels which combine the merits of nanogels and the specific biological activity from protein have emerged as fascinating protein delivery systems. However, the fragility and low density of reactive group in proteins, especially low electric density of neutral proteins seriously limited the fabrication of protein crosslinked nanogels without affecting their bioactivities. Here, we demonstrated a facile ion-assisted method to fabricate neutral protein crosslinked nanogels. Oxidized sodium alginate (OSA) with aldehyde groups and low viscosity was successfully synthesized, which could reversibly form nanogels via addition and removal of divalent cation. Subsequently, hemoglobin and myoglobin were used as representative neutral proteins to fabricate stable protein crosslinked OSA nanogels under the assist of divalent cation followed by in situ Schiff base formation between OSA and proteins. The mild fabrication condition guaranteed the structural integrity and bioactivity of proteins in the obtained protein crosslinked nanogels. This ion-assisted method was expected to bring a new opportunity for fabricating versatile functional biohybrid nanogels systems.