Cyclodextrin Polymer-Loaded Micro-Ceramic Balls for Solid-Phase Extraction of Triazole Pesticides from Water.

A citric acid cross-linked ß-cyclodextrin (ß-CD) polymer was synthesized and loaded on micro-ceramic balls to fabricate the solid-phase adsorbents (P-MCB) for adsorption and extraction of triazole pesticides from water. The stability of ß-CD polymer and P-MCB was investigated in solutions with different pH values at different temperatures. The adsorption properties and the influence of kinetics, sorbent amount, pesticide concentration, and temperature on the adsorption capacity were evaluated. The results showed P-MCB had favorable adsorption of 15.98 mg/g flutriafol in 3.5 h. The equilibrium data followed the Freundlich equation, and the adsorption of flutriafol and diniconazole followed the second-order kinetics. The recovery rate of P-MCB for triazole pesticides in water was satisfactory, and the recovery rate was still 80.1%, even at the 10th cycle. The P-MCB had good stability, with a degradation rate of 0.2% ± 0.08 within 10 days, which could ensure extraction and recycling.

Recent Advances in Boosting EGFR Tyrosine Kinase Inhibitors-Based Cancer Therapy.

Epidermal growth factor receptor (EGFR) plays a key role in signal transduction pathways associated with cell proliferation, growth, and survival. Its overexpression and aberrant activation in malignancy correlate with poor prognosis and short survival. Targeting inhibition of EGFR by small-molecular tyrosine kinase inhibitors (TKIs) is emerging as an important treatment model besides of chemotherapy, greatly reshaping the landscape of cancer therapy. However, they are still challenged by the off-targeted toxicity, relatively limited cancer types, and drug resistance after long-term therapy. In this review, we summarize the recent progress of oral, pulmonary, and injectable drug delivery systems for enhanced and targeting TKI delivery to tumors and reduced side effects. Importantly, EGFR-TKI-based combination therapies not only greatly broaden the applicable cancer types of EGFR-TKI but also significantly improve the anticancer effect. The mechanisms of TKI resistance are summarized, and current strategies to overcome TKI resistance as well as the application of TKI in reversing chemotherapy resistance are discussed. Finally, we provide a perspective on the future research of EGFR-TKI-based cancer therapy.

Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer.

The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.

PDT-Enhanced Ferroptosis by a Polymer Nanoparticle with pH-Activated Singlet Oxygen Generation and Superb Biocompatibility for Cancer Therapy.

In this study, we reported a nanocomplex (PAF) of PEGylated polygalacturonic acid, 5,10,15,20-tetrakis (4-aminophenyl) porphyrin (TAPP), and Fe3+ for photodynamic therapy (PDT)-enhanced ferroptosis in cancer treatment. PAF exhibited a size of 135 nm and a TAPP and Fe3+ loading content of 6.99 and 0.77%, respectively. The singlet oxygen (1O2) generation capacity of TAPP can be activated and significantly enhanced at acidic pH (4.5-5.0). Besides, the enhanced near-infrared absorption of TAPP at acidic pH enabled a further increase in 1O2 generation capability by a near-infrared laser (760 nm). The polysaccharide-based polymer carrier offers excellent biocompatibility, and PAF displayed a proliferative effect in both normal (L929) and cancer (B16) cells. However, upon light irradiation, PAF exhibited high toxicity to B16 melanoma cells by intracellular reactive oxygen species elevation, glutathione depletion, and lipid peroxidation. PAF displayed a much better anticancer effect than the nanocomplex containing Fe3+ or TAPP alone, indicating the PDT-enhanced ferroptosis in PAF. This study suggested that PDT-enhanced ferroptosis could be a facile and robust strategy of nanotherapeutics with high potency, tumor selectivity, and excellent biocompatibility.

α-Selective C(sp3)-H Thio/Selenocyanation of Ketones with Elemental Chalcogen.

A facile method is disclosed for the synthesis of α-thio/selenocyanato ketones through regioselective C-H thio/selenocyanation of ketones. The advantages include the use of easily available starting materials, high efficiency, simple operation, and easy scale-up. Control experiments provide evidence that the reaction proceeded via a radical way, while kinetic isotope effect experiments reveal that the cleavage of the C-H bond serves as the rate-limiting step.

Ag2O-promoted ring-opening reactions of cyclopropenones with oximes.

Ag2O-promoted ring-opening reactions of cyclopropenones with oximes is disclosed in this work, providing a direct route to 1,3-oxazinones. This method highlights a new reactivity of cyclopropenones which undergo 1,4-addition with oximes followed by ß-carbon elimination to in situ generate a α-carbonyl ketene intermediate.

Cinnamaldehyde-Based Poly(ester-thioacetal) To Generate Reactive Oxygen Species for Fabricating Reactive Oxygen Species-Responsive Nanoparticles.

Due to the high oxidative stress of the tumor microenvironment, more and more researchers have been devoted to reactive oxygen species (ROS)-responsive nanodrug delivery systems for anticancer therapy. Herein, a ROS-responsive moiety, thioacetal, was synthesized, and cinnamaldehyde (CA) was introduced in the polymer chain to trigger the generation of ROS to expect the enhancement of the ROS-responsive effect. The poly(ester-thioacetal) mPEG2k - b-(NTA-HD)12 polymer, its self-assembled micelles, and the ROS-responsive behavior were characterized by 1H NMR and DLS. The anticancer drug doxorubicin (DOX) was adopted to prepare DOX-loaded poly(ester-thioacetal) micelles. The intracellular ROS detection indicated that the mPEG2k - b-(NTA-HD)12 polymer could degrade via the high concentration of ROS in cancer cells, and the released CA stimulated mitochondria to regenerate additional ROS. The flow cytometry results indicated that the ROS-responsive polymeric micelles showed faster cellular uptake compared to the control mPEG2k - b-PCL5k micelles. The ROS responsive DOX/mPEG2k - b-(NTA-HD)12 micelles exhibited much better anticancer efficiency on both 4T1 and HeLa cancer cells than DOX/mPEG2k - b-PCL5k micelles.

Fabrication of Polymeric Micelles with Aggregation-Induced Emission and Forster Resonance Energy Transfer for Anticancer Drug Delivery.

With the aim of obtaining effective cancer therapy with simultaneous cellular imaging, dynamic drug-release monitoring, and chemotherapeutic treatment, a polymeric micelle with aggregation-induced emission (AIE) imaging and a Forster resonance energy transfer (FRET) effect was fabricated as the drug carrier. An amphiphilic conjugate of 1H-pyrrole-1-propanoicacid (MAL)-poly(ethylene glycol) (PEG)-Tripp-bearing AIE molecules were synthesized and self-assembled into micelles to load the anticancer drug doxorubicin (DOX). Spherical DOX-loaded micelles with the mean size of 106 nm were obtained with good physiological stability (CMC, 12.5 µg/mL), high drug-loading capacity (10.4%), and encapsulation efficiency (86%). The cellular uptake behavior of DOX-loaded MAL-PEG-Tripp micelles was visible for high-quality intracellular imaging due to the AIE property. The delivery of DOX from the drug-loaded micelles was dynamic monitored by the FRET effect between the DOX and MAL-PEG-Tripp. Both in vitro (IC50, 2.36 µg/mL) and in vivo anticancer activity tests revealed that the DOX-loaded MAL-PEG-Tripp micelles exhibited promising therapeutic efficacy to cancer with low systematic toxicity. In summary, this micelle provided an effective way to fabricate novel nanoplatform for intracellular imaging, drug-delivery tracing, and chemotherapy.

Copper-Catalyzed Three-Component Coupling Reaction of Azoles, Se Powder, and Aryl Iodides.

A copper-catalyzed three-component coupling reaction of azoles, Se powder, and aryl iodide is described for the first time. This transformation provides a straightforward and facile pathway to synthesis 2-arylselanyl-azoles via a copper-catalyzed double C-Se bonds formation process. This reaction is attractive and practical since the cheap copper catalyst is employed and it does not require ligands, proceeds in generally good yields, and has a broad range of functional groups tolerance.

Copper-catalyzed ipso-selenation of aromatic carboxylic acids.

The copper-catalyzed decarboxylative selenation of aromatic carboxylic acids with diselenide is reported. This transformation tolerated a diverse set of functional groups on the substrates, including pentafluorobenzoic acid and heteroaromatic acids, delivering diaryl and methyl aryl selenides in good to excellent yields. Mechanistic studies indicated that the copper catalyst is essential in the activation of the Se-Se bond and the decarboxylation of aromatic acids. The utility of the products has been demonstrated in the facile synthesis of 10H-phenoselenazine and 11-methyldibenzo-(b,f)-1,4-selenazepine.

A ROS-responsive polymeric micelle with a π-conjugated thioketal moiety for enhanced drug loading and efficient drug delivery.

As the implications of reactive oxygen species (ROS) are elucidated in many diseases, ROS-responsive nanoparticles are attracting great interest from researchers. In this work, a ROS sensitive thioketal (TK) moiety with a π-conjugated structure was introduced into biodegradable methoxy poly(ethylene glycol)-thioketal-poly(ε-caprolactone)mPEG-TK-PCL micelles as a linker, which was designed to speed up the drug release and thus enhance the therapeutic efficacy. The micelle showed a high drug loading content of 12.8% and excellent stability under physiological conditions because of the evocation of π-π stacking and hydrophobic interactions with the anticancer drug doxorubicin (DOX). The polymeric micelle presented a better drug carrier capacity and higher in vitro anticancer efficacy towards cancer cells. The in vivo study showed that DOX-loaded mPEG-TK-PCL micelles displayed lower toxicity towards normal cells and remarkably enhanced antitumor efficacy. This research provides a way to design potential drug carriers for efficient cancer chemotherapy.

Copper-Catalyzed Three-Component Reaction for Regioselective Aryl- and Heteroarylselenation of Indoles using Selenium Powder.

A new and efficient copper-catalyzed C3 aryl- and heteroarylselenation of indoles employing selenium powder has been developed. The advantages of this chemistry involve the use of cheap selenating reagents, tolerance of a variety of functional groups, and practicality. In addition, this protocol has been further elaborated in an intramolecular phenylselenation of a (hetero) aryl C-H bond to construct an important motif of benzoselenopheno[3,2-b]indole. A preliminary mechanism study suggests that the reaction starts with a Ullman-type selenation between aryl iodides and selenium, followed by an oxidative cross-coupling with indole. The utility of this method has been demonstrated in an efficient gram-scale synthesis and an application to the synthesis of tubulin polymerization inhibitor.

Copper-Catalyzed Oxirane-Opening Reaction with Aryl Iodides and Se Powder.

Using Se powder as the selenating reagent, the copper-catalyzed double C-Se cross-coupling of aryl iodides, epoxides, and elemental selenium has been developed. This strategy provides a straightforward approach to the synthesis of ß-hydroxy phenylselenides with excellent regioselectivity of the ring opening reaction. This process proceeds in generally good yields and is compatible with a broad range of functional groups.

Palladium-Catalyzed Cascade Reaction of 2-Amino-N'-arylbenzohydrazides with Triethyl Orthobenzoates To Construct Indazolo[3,2-b]quinazolinones.

A palladium-catalyzed sequential cyclization/C-H activation cascade reaction of 2-amino-N'-arylbenzohydrazides with triethyl orthobenzoates has been developed, providing indazolo[3,2-b]quinazolinones in good to high yields. Two key intermediates of the reaction, 2-phenyl-3-(phenylamino)quinazolinone and C-H insertion palladacycle, were isolated, and their structures were unambiguously confirmed by X-ray crystallography. This method represents an unprecedented example of a halogen-free protocol to access indazolo[3,2-b]quinazolinones. Moreover, this chemistry also provides a useful tool for the discovery of fluorescent materials.

An Engineered Butyrate-Derived Polymer Nanoplatform as a Mucosa-Healing Enhancer Potentiates the Therapeutic Effect of Magnolol in Inflammatory Bowel Disease.

Colonic epithelial damage and dysregulated immune response are crucial factors in the progression and exacerbation of inflammatory bowel disease (IBD). Nanoenabled targeted drug delivery to the inflamed intestinal mucosa has shown promise in inducing and maintaining colitis remission, while minimizing side effects. Inspired by the excellent antioxidative and anti-inflammatory efficacy of naturally derived magnolol (Mag) and gut homeostasis regulation of microbiota-derived butyrate, we developed a pH/redox dual-responsive butyrate-rich polymer nanoparticle (PSBA) as an oral Mag delivery system for combinational therapy of IBD. PSBA showed a high butyrate content of 22% and effectively encapsulated Mag. The Mag-loaded nanoparticles (PSBA@Mag) demonstrated colonic pH and reduction-responsive drug release, ensuring efficient retention and adhesion in the colon of colitis mice. PSBA@Mag not only normalized the level of reactive oxygen species and inflammatory effectors in inflamed colonic mucosa but also restored the epithelial barrier function in both ulcerative colitis and Crohn's disease mouse models. Importantly, PSBA promoted the migration and healing ability of intestinal epithelial cells in vitro and in vivo, sensitizing the therapeutic efficacy of Mag in animal models. Moreover, transcriptomics and metabolism analyses revealed that PSBA@Mag mitigated inflammation by suppressing the production of pro-inflammatory cytokines and chemokines and restoring the lipid metabolism. Additionally, this nanomedicine modulated the gut microbiota by inhibiting pathogenic Proteus and Escherichia-Shigella and promoting the proliferation of beneficial probiotics, including Lachnoclostridium, Lachnospiraceae_NK4A136_group and norank_f_Ruminococcaceae. Overall, our findings highlight the potential of butyrate-functionalized polymethacrylates as versatile and effective nanoplatforms for colonic drug delivery and mucosa repair in combating IBD and other gastrointestinal disorders.

A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy.

Immune checkpoint blockade therapy provides a new strategy for tumor treatment; however, the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects. Herein, we reported a lipid/PLGA nanocomplex (RDCM) co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1MT to improve immunotherapy of colon cancer. Arginine-glycine-aspartic acid (RGD) as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol (PEG), and programmed cell death-ligand 1 (PD-L1) peptide inhibitor DPPA (sequence: CPLGVRGK-GGG-d(NYSKPTDRQYHF)) was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker. The Ce6 and 1MT were encapsulated in PLGA nanoparticles. The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes. When the nanocomplexes were delivered to tumor, DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding. RGD facilitated the cellular internalization of nanocomplexes via avß3 integrin. Strong immunogenic cell death was induced by 1O2 generated from Ce6 irradiation under 660 nm laser. 1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment. The RDCM facilitated the maturation of dendritic cells, inhibited the activity of IDO, and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice, triggering a robust immunological memory effect, thus effectively preventing tumor metastasis. The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

Oxidase-like manganese oxide nanoparticles: a mechanism of organic acids/aldehydes as electron acceptors and potential application in cancer therapy.

Identifying the underlying catalytic mechanisms of synthetic nanocatalysts or nanozymes is important in directing their design and applications. Herein, we revisited the oxidation process of 4,4'-diamino-3,3',5,5'-tetramethylbiphenyl (TMB) by Mn3O4 nanoparticles and revealed that it adopted an organic acid/aldehyde-triggered catalytic mechanism at a weakly acidic or neutral pH, which is O2-independent and inhibited by the pre-addition of H2O2. Importantly, similar organic acid/aldehyde-mediated oxidation was applied to other substrates of peroxidase in the presence of nanoparticulate or commercially available MnO2 and Mn2O3 but not MnO. The selective oxidation of TMB by Mn3O4 over MnO was further supported by density functional theory calculations. Moreover, Mn3O4 nanoparticles enabled the oxidation of indole 3-acetic acid, a substrate that can generate cytotoxic singlet oxygen upon single-electron transfer oxidation, displaying potential in nanocatalytic tumor therapy. Overall, we revealed a general catalytic mechanism of manganese oxides towards the oxidation of peroxidase substrates, which could boost the design and various applications of these manganese-based nanoparticles.

A novel glucose/pH responsive low-molecular-weight organogel of easy recycling.

A new phenylboronic acid based gelator was developed to prepare low-molecular-weight organogel (LMOG), which could interact with several solvents to assemble into a three-dimensional nanofiber network. (1)H NMR spectroscopy study suggests that the driving force for the gelation includes hydrogen bonding and π-π stacking. Evaluated by UV-spectroscopy, the gel showed a prompt initial response to glucose at low concentration of 0.012 mmol/mL, which is a critical concentration of venous plasma glucose for diabetes. Significantly, this organogel exhibits excellent sensitivity to glucose among seven sugars tested (i.e., mannitol, galactose, lactose, maltose, sucrose, and fructose). The proposed formation of hydrogen-bonded complexes during the glucose sensing was supported by our energy calculation. Meanwhile, this organogel exhibits pH-response. Importantly, this LMOG could be conveniently recycled and thus be reused.

Unexpected copper-catalyzed cascade synthesis of quinazoline derivatives.

The first example of a copper-catalyzed cascade reaction of (2-aminophenyl)methanols with aldehydes using the combination of cerium nitrate hexahydrate and ammonium chloride has been developed, leading to a wide range of 2-substituted quinazolines in moderate to excellent yields. The efficiency of this transformation was demonstrated by compatibility with a wide range of functional groups. Thus, the method represents a convenient and practical strategy for synthesis of 2-substituted quinazoline derivatives.

Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy.

Reactive oxygen species (ROS) play a crucial role in physiological and pathological processes, emerging as a therapeutic target in cancer. Owing to the high concentration of ROS in solid tumor tissues, ROS-based treatments, such as photodynamic therapy and chemodynamic therapy, and ROS-responsive drug delivery systems have been widely explored to powerfully and specifically suppress tumors. However, their anticancer efficacy is still hampered by the heterogeneous ROS levels, and thus comprehensively upregulating the ROS levels in tumor tissues can ensure an enhanced therapeutic effect, which can further sensitize and/or synergize with other therapies to inhibit tumor growth and metastasis. Herein, we review the recently emerging drug delivery strategies and technologies for increasing the H2O2, ˙OH, 1O2, and ˙O2- concentrations in cancer cells, including the efficient delivery of natural enzymes, nanozymes, small molecular biological molecules, and nanoscale Fenton-reagents and semiconductors and neutralization of intracellular antioxidant substances and localized input of mechanical and electromagnetic waves (such as ultrasound, near infrared light, microwaves, and X-rays). The applications of these ROS-upregulating nanosystems in enhancing and synergizing cancer therapies including chemotherapy, chemodynamic therapy, phototherapy, and immunotherapy are surveyed. In addition, we discuss the challenges of ROS-upregulating systems and the prospects for future studies.