Endogenous Fe2+-triggered self-targeting nanomicelles for self-amplifying intracellular oxidative stress.

BACKGROUND: Artesunate (ASA) acts as an •O2- source through the breakdown of endoperoxide bridges catalyzed by Fe2+, yet its efficacy in ASA-based nanodrugs is limited by poor intracellular delivery. METHODS: ASA-hyaluronic acid (HA) conjugates were formed from hydrophobic ASA and hydrophilic HA by an esterification reaction first, and then self-targeting nanomicelles (NM) were developed using the fact that the amphiphilic conjugates of ASA and HA are capable of self-assembling in aqueous environments. RESULTS: These ASA-HA NMs utilize CD44 receptor-mediated transcytosis to greatly enhance uptake by breast cancer cells. Subsequently, endogenous Fe2+ from the tumor catalyzes the released ASA to produce highly toxic •O2- radicals to kill tumor cells, although sustained tumor growth inhibition can be achieved via in vivo experiments. CONCLUSIONS: Self-targeting NMs represent a promising strategy for enhancing ASA-based treatments, leveraging clinically approved drugs to expedite drug development and clinical research in oncology.

Amino acid-based metallo-supramolecular nanoassemblies capable of regulating cellular redox homeostasis for tumoricidal chemo-/photo-/catalytic combination therapy.

Nanozymes, as nanomaterials with natural enzyme activities, have been widely applied to deliver various therapeutic agents to synergistically combat the progression of malignant tumors. However, currently common inorganic nanozyme-based drug delivery systems still face challenges such as suboptimal biosafety, inadequate stability, and inferior tumor selectivity. Herein, a super-stable amino acid-based metallo-supramolecular nanoassembly (FPIC NPs) with peroxidase (POD)- and glutathione oxidase (GSHOx)-like activities was fabricated via Pt4+-driven coordination co-assembly of l-cysteine derivatives, the chemotherapeutic drug curcumin (Cur), and the photosensitizer indocyanine green (ICG). The superior POD- and GSHOx-like activities could not only catalyze the decomposition of endogenous hydrogen peroxide into massive hydroxyl radicals, but also deplete the overproduced glutathione (GSH) in cancer cells to weaken intracellular antioxidant defenses. Meanwhile, FPIC NPs would undergo degradation in response to GSH to specifically release Cur, causing efficient mitochondrial damage. In addition, FPIC NPs intrinsically enable fluorescence/photoacoustic imaging to visualize tumor accumulation of encapsulated ICG in real time, thereby determining an appropriate treatment time point for tumoricidal photothermal (PTT)/photodynamic therapy (PDT). In vitro and in vivo findings demonstrated the quadruple orchestration of catalytic therapy, chemotherapeutics, PTT, and PDT offers conspicuous antineoplastic effects with minimal side reactions. This work may provide novel ideas for designing supramolecular nanoassemblies with multiple enzymatic activities and therapeutic functions, allowing for wider applications of nanozymes and nanoassemblies in biomedicine.

Mechanism of Self-Oxidative Copolymerization and its Application with Polydopamine-pyrrole Nano-copolymers.

Currently, the copolymer of dopamine (DA) and pyrrole (PY) via chemical and electrochemical oxidation usually requires additional oxidants, and lacks flexibility in regulating the size and morphology, thereby limiting the broad applications of DA-PY copolymer in biomedicine. Herein, the semiquinone radicals produced by the self-oxidation of DA is ingeniously utilized as the oxidant to initiate the following copolymerization with PY, and a series of quinone-rich polydopamine-pyrrole copolymers (PDAm -nPY) with significantly enhanced absorption in near-infrared (NIR) region without any additional oxidant assistance is obtained. Moreover, the morphology and size of PDAm -nPY can be regulated by changing the concentration of DA and PY, thereby optimizing nanoscale PDA0.05 -0.15PY particles (≈ 150 nm) with excellent NIR absorption and surface modification activity are successfully synthesized. Such PDA0.05 -0.15PY particles show effective photoacoustic (PA) imaging and photothermal therapy (PTT) against 4T1 tumors in vivo. Furthermore, other catechol derivatives can also copolymerize with PY under the same conditions. This work by fully utilizing the semiquinone radical active intermediates produced through the self-oxidation of DA reduces the dependence on external oxidants in the synthesis of composite materials and predigests the preparation procedure, which provides a novel, simple, and green strategy for the synthesis of other newly catechol-based functional copolymers.

Recent Advances in Targeted Drug Delivery Strategy for Enhancing Oncotherapy.

Targeted drug delivery is a precise and effective strategy in oncotherapy that can accurately deliver drugs to tumor cells or tissues to enhance their therapeutic effect and, meanwhile, weaken their undesirable side effects on normal cells or tissues. In this research field, a large number of researchers have achieved significant breakthroughs and advances in oncotherapy. Typically, nanocarriers as a promising drug delivery strategy can effectively deliver drugs to the tumor site through enhanced permeability and retention (EPR) effect-mediated passive targeting and various types of receptor-mediated active targeting, respectively. Herein, we review recent targeted drug delivery strategies and technologies for enhancing oncotherapy. In addition, we also review two mainstream drug delivery strategies, passive and active targeting, based on various nanocarriers for enhancing tumor therapy. Meanwhile, a comparison and combination of passive and active targeting are also carried out. Furthermore, we discuss the associated challenges of passive and active targeted drug delivery strategies and the prospects for further study.

Bioengineered nanogenerator with sustainable reactive oxygen species storm for self-reinforcing sono-chemodynamic oncotherapy.

Oxidative stress-based antitumor modalities derived from reactive oxygen species (ROS) storms have attracted increasing attention. Nevertheless, low delivery efficiency, poor selectivity, hypoxia and overexpressed glutathione (GSH) have severely restricted the sustainable generation of the ROS storm in tumor cells. Herein, we design a bioengineered nanogenerator by coordination-driven co-assembly of sonosensitizer indocyanine green (ICG), Fenton-like agent copper ion (CuⅡ) and mitochondrial respiratory inhibitor metformin (MET), which is then camouflaged by a cancer cytomembrane to induce a sustainable intracellular ROS storm for on-demand self-reinforcing sono-chemodynamic oncotherapy. Such a nanogenerator with a core-shell structure, suitable diameter and outstanding stability can efficiently accumulate in tumor regions and then internalize into tumor cells through the camouflaging and homologous targeting strategy of the cancer cytomembrane. The nanogenerator shows an exceptional instability under the triple stimulations of acidic lysosomes, overexpressed GSH and ultrasound (US) radiation, thereby resulting in the rapid disassembly and burst drug release. Interestingly, the released MET significantly enhances the sonodynamic therapy (SDT) efficacy of the released ICG by inhibiting mitochondrial respiration and meanwhile the released CuⅡ obviously reduces ROS elimination by downregulating overexpressed GSH for self-amplifying and self-protecting the intracellular ROS storm. Moreover, such a nanogenerator almost completely achieves the tumor ablation in vivo in a single therapy cycle. Taken together, our bioengineered nanogenerator with a sustainable ROS storm can provide a promising strategy for ROS storm-based oncotherapy.

TME-triggered copper-coordinated engineered programmable nanogenerators for on-demand cascade-amplifying oxidative stress.

Although oxidative stress-based antitumor modality derived from reactive oxygen species (ROS) storm has attracted considerable attention in copper-based nanomaterials, its efficiency is still weakened by the insufficient hydrogen peroxide (H2O2) and overexpressed glutathione (GSH) in a tumor microenvironment (TME). In view of this, we designed an engineered programmable spike-like nanogenerator via the coordination-driven co-assembly of Evans Blue (EB), copper ions (CuII), and 5-hydroxy-p-naphthoquinone (HND). For programmable nanogenerators, the introduction of EB as a stabilizer-like component can not only adjust its morphology but also achieve its visual tracking. Interestingly, such programmable nanogenerators can be efficiently enriched in tumor regions and then internalized into tumor cells due to ECH with spike-like morphology. Notably, once the nanogenerator is disintegrated and burst to release the drug upon acidic lysosome and endogenous GSH triggering, the released HND can not only efficiently amplify endogenous H2O2 by intracellular oxidoreductases but also down-regulate the peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin 1) activity. In addition, the released CuII ions can efficiently catalyze the degradation of the endogenous H2O2 to amplify hydroxyl radicals (˙OH) and down-regulate the overexpressed GSH to reduce ˙OH elimination for on-demand cascade-amplifying oxidative stress. Importantly, such programmable nanogenerators show an excellent antitumor effect via down-regulating the Pin 1 activity and cascade-amplifying oxidative stress. In this study, we propose a spatiotemporally programmable cascade nanogenerator for oxidative stress-based antitumor therapy.

Platinum-Coordinated Engineered Nanoreactors with O2 Self-Amplificationand On-Demand Cascade Chemo-Drug Synthesis for Self-Reinforcing Hypoxic Oncotherapy.

How to efficiently synthesize toxic chemo-drugs in the hypoxia tumor microenvironment still faces a huge challenge. Herein, we have tailored engineered vehicle-free nanoreactors by coordination-driven co-assembly of photosensitizer indocyanine green (ICG), transition metal platinum (Pt), and nontoxic 1,5-dihydroxynaphthalene (DHN) to self-amplify O2 and cascade chemo-drug synthesis in tumor cells for self-reinforcing hypoxic oncotherapy. Once vehicle-free nanoreactors are internalized into tumor cells, they show a serious instability that results in rapid disassembly and on-demand drug release under the stimuli of acidic lysosome and laser radiation. Notably, the released Pt can efficiently decompose the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia, which is conducive to enhancing the photodynamic therapy (PDT) efficiency of the released ICG. Complementarily, a large amount of the 1O2 generated by PDT can efficiently oxidize the released nontoxic DHN into the highly toxic chemo-drug juglone. Therefore, such vehicle-free nanoreactors can achieve intracellular on-demand cascade chemo-drug synthesis and self-reinforce photo-chemotherapeutic efficacy on the hypoxic tumor. On the whole, such a simple, flexible, efficient, and nontoxic therapeutic strategy will broaden the study of on-demand chemo-drug synthesis and hypoxic oncotherapy.

Biomimetic dual-responsive bioengineered nanotheranostics for intracellular cascade-synthesizing chemo-drugs and efficient oncotherapy.

Intracellular-synthesized chemo-drugs based on the inherent characteristics of the tumor microenvironment (TME) have been extensively applied in oncotherapy. However, combining other therapeutic strategies to convert nontoxic small molecules into toxic small-molecule chemo-drugs in the TME is still a huge challenge. To address this issue, herein we have developed a biomimetic dual-responsive bioengineered nanotheranostics system via the supramolecular co-assembly of the nontoxic small-molecule 1,5-dihydroxynaphthalene (DHN) and small-molecule photosensitizer indocyanine green (ICG) followed by surface cloaking through red blood cell membranes (RBCs) for intracellular cascade-synthesizing chemo-drugs and efficient oncotherapy. Such nanotheranostics with a suitable diameter, core-shell structure, ultrahigh dual-drug payload rate, and excellent stability can efficiently accumulate in tumor regions and then internalize into tumor cells. Under the dual stimulations of near-infrared laser irradiation and acidic lysosomes, the nanotheranostics system exhibited exceptional instability under heat-primed membrane rupture and pH decrease, thereby achieving rapid disassembly and on-demand drug release. Furthermore, the released ICG can efficiently convert 3O2 into 1O2. After that, the generated 1O2 can efficiently oxidize the released nontoxic DHN into the highly toxic chemo-drug juglone, thereby realizing intracellular cascade-synthesizing chemo-drugs and synergistic photodynamic-chemotherapy while reducing detrimental side effects on normal cells or tissues. Overall, it is envisioned that RBC-cloaked nanotheranostics with intracellular cascade-synthesizing chemo-drugs can provide a promising strategy for intracellular chemo-drug synthesis-based oncotherapy.

Aß-responsive metformin-based supramolecular synergistic nanodrugs for Alzheimer's disease via enhancing microglial Aß clearance.

Here, inspired by the concept of supramolecular inclusion complex, we successfully fabricate metformin (Met)-based supramolecular nanodrugs with the Aß-responsive on-demand drug release for synergistic Alzheimer's disease (AD) therapy via enhancing microglial Aß clearance. Interestingly, the introduction of low-dosage Met (1.1 mg/kg) can not only significantly improve the structural stability of nanodrugs but also exert a synergistic anti-dementia effect with donepezil (Don). Besides, such nanodrugs with outstanding physiological stability can selectively penetrate the blood-brain barrier (BBB), target brain, increase efficient uptake of microglia and neurons, and then achieve simultaneous spatiotemporal on-demand drug release under stimuli of the overexpressed amyloid-beta (Aß). Furthermore, Met and Don released from nanodrugs exhibit a superior synergistic anti-dementia effect by enhancing microglial phagocytosis and Aß clearance through the lysosomal pathway. Taken together, we report a synergistic strategy based on Aß-responsive supramolecular nanodrugs for AD therapy, which can be expected to provide a novel clinical therapeutic idea for ameliorating central nervous system disease.

A Novel Yolk-Shell Fe3O4@ Mesoporous Carbon Nanoparticle as an Effective Tumor-Targeting Nanocarrier for Improvement of Chemotherapy and Photothermal Therapy.

Owing to their good stability and high photothermal conversion efficiency, the development of carbon-based nanoparticles has been intensively investigated, while the limitation of unsatisfactory cellular internalization impedes their further clinical application. Herein, we report a novel strategy for fabrication of Fe3O4 yolk-shell mesoporous carbon nanocarriers (Fe3O4@hmC) with monodispersity and uniform size, which presented significantly higher cell membrane adsorption and cellular uptake properties in comparison with common solid silica-supported mesoporous carbon nanoparticles with core-shell structure. Moreover, the MRI performance of this novel Fe-based nanoparticle could facilitate precise tumor diagnosis. More importantly, after DOX loading (Fe3O4@hmC-DOX), owing to synergistic effect of chemo-phototherapy, this therapeutic agent exhibited predominant tumor cell ablation capability under 808 nm NIR laser irradiation, both in vitro and in vivo. Our work has laid a solid foundation for therapeutics with hollowed carbon shell for solid tumor diagnosis and therapy in clinical trials.

Trojan-Horse Diameter-Reducible Nanotheranostics for Macroscopic/Microscopic Imaging-Monitored Chemo-Antiangiogenic Therapy.

Although nanotheranostics have displayed striking potential toward precise nanomedicine, their targeting delivery and tumor penetration capacities are still impeded by several biological barriers. Besides, the current antitumor strategies mainly focus on killing tumor cells rather than antiangiogenesis. Enlightened by the fact that the smart transformable self-targeting nanotheranostics can enhance their targeting efficiency, tumor penetration, and cellular uptake, we herein report carrier-free Trojan-horse diameter-reducible metal-organic nanotheranostics by the coordination-driven supramolecular sequential co-assembly of the chemo-drug pemetrexed (PEM), transition-metal ions (FeIII), and antiangiogenesis pseudolaric acid B. Such nanotheranostics with both a high dual-drug payload efficiency and outstanding physiological stability are responsively decomposed into numerous ultra-small-diameter nanotheranostics under stimuli of the moderate acidic tumor microenvironment and then internalized into tumor cells through tumor-receptor-mediated self-targeting, synergistically enhancing tumor penetration and cellular uptake. Besides, such nanotheranostics enable visualization of self-targeting capacity under the macroscopic monitor of computed tomography/magnetic resonance imaging, thereby realizing efficient oncotherapy. Moreover, tumor microvessels are precisely monitored by optical coherence tomography angiography/laser speckle imaging during chemo-antiangiogenic therapy in vivo, visually verifying that such nanotheranostics possess an excellent antiangiogenic effect. Our work will provide a promising strategy for further tumor diagnosis and targeted therapy.

Natural Killer Cell Membrane-Cloaked Virus-Mimicking Nanogenerator with NIR-Triggered Shape Reversal and •C/•OH Storm for Synergistic Thermodynamic-Chemodynamic Therapy.

Free radical-based anticancer modality has been widely applied to cancer therapies. However, it still faces challenges of low delivery efficiency and poor selectivity of free radical generation specifically toward tumors. Herein, a virus-mimicking hollow mesoporous disulfide-bridged organosilica is designed to encapsulate •C precursor 2, 2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), which is then enclosed by tannic acid (TA)/FeIII photothermal assembly and further cloaked by natural killer (NK) cell membrane to achieve synergistic thermodynamic-chemodynamic therapy. The nanogenerator can first evade immune surveillance via NK cell membrane "cloaking" mechanism to strongly accumulate in tumors. Interestingly, the NIR laser-induced heat can trigger NK cell membrane rupture for "shape reversal" to expose a virus-like surface to amplify the cellular uptake, and simultaneously break the azo bonds of AIPH for in situ controlled •C generation. Then upon glutathione (GSH) triggering, the nanogenerator disintegrates via disulfide-thiol exchange and efficiently generates •OH by lysosomal pH-initiated TA-FeIII reaction; notably, the consumption of GSH can amplify oxidative stress to enhance free radical therapy by weakening the self-defense mechanism of tumor cells. It is envisioned that the NK cell membrane-cloaked virus-mimicking and NIR/GSH sequentially activated •C/•OH radical nanogenerator can provide a promising strategy for oxidative stress-based anticancer therapy.

Shuttle-Shape Carrier-Free Platinum-Coordinated Nanoreactors with O2 Self-Supply and ROS Augment for Enhanced Phototherapy of Hypoxic Tumor.

The synergistic nanotheranostics of reactive oxygen species (ROS) augment or phototherapy has been a promising method within synergistic oncotherapy. However, it is still hindered by sophisticated design and fabrication, lack of a multimodal synergistic effect, and hypoxia-associated poor photodynamic therapy (PDT) efficacy. Herein, a kind of porous shuttle-shape platinum (IV) methylene blue (Mb) coordination polymer nanotheranostics-loaded 10-hydroxycamptothecin (CPT) is fabricated to address the abovementioned limitations. Our nanoreactors possess spatiotemporally controlled O2 self-supply, self-sufficient singlet oxygen (1O2), and outstanding photothermal effect. Once they are taken up by tumor cells, nanoreactors as a cascade catalyst can efficiently catalyze degradation of the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia. The production of O2 can ensure enhanced PDT. Subsequently, under both stimuli of external red light irradiation and internal lysosomal acidity, nanoreactors can achieve the on-demand release of CPT to augment in situ mitochondrial ROS and highly efficient tumor ablation via phototherapy. Moreover, under the guidance of near-infrared (NIR) fluorescent imaging, our nanoreactors exhibit strongly synergistic potency for treatment of hypoxic tumors while reducing damages against normal tissues and organs. Collectively, shuttle-shape platinum-coordinated nanoreactors with augmented ROS capacity and enhanced phototherapy efficiency can be regarded as a novel tumor theranostic agent and further promote the research of synergistic oncotherapy.

Self-targeting nanotherapy based on functionalized graphene oxide for synergistic thermochemotherapy.

Nanotherapy based on thermochemotherapy has boomed as a promising alternative for oncotherapy due to the enhanced permeability and retention (EPR) effect. However, a lack of self-targeting capacity prevents nanotherapy from efficiently accumulating in tumor tissue and internalizing into tumor cells, resulting in a suboptimal therapeutic effect. To overcome these bottlenecks, a kind of methotrexate (MTX)-soybean phospholipid (SPC) inclusion complex (MTX-SPC)-modified graphene oxide (CGO) nanotherapy (CGO-MTX-SPC) is constructed by CGO nanosheets as a supporter for MTX-SPC, thereby realizing active-targeting and synergistic thermochemotherapy. As an FDA-approved chemotherapeutic drug, MTX can be regarded as a tumor-targeting enhancer against the folate receptor on account of its similar structure to folic acid (FA). The fabricated CGO-MTX-SPC has a sheet shape with a size of ca. 109 nm and tumor microenvironment-responsive on-demand drug release. It is worth noting that the physiological stability of CGO-MTX-SPC is better than that of CGO while displaying an improved photothermal effect. In addition, CGO-MTX-SPC can specifically recognize tumor cells and then achieve on-demand drug burst release by dual stimuli of internal lysosomal acidity and an external laser. Moreover, in vivo experimental results further demonstrate that CGO-MTX-SPC displays significant enrichment at the tumor location by active targeting mechanisms due to the introduction of MTX-SPC, endowing the synergistic thermochemotherapy effect upon 808 nm laser irradiation and almost thorough tumor elimination while significantly erasing undesirable side effects. Taken together, the design idea of our nanotherapy not only provides a potential tumor-targeting therapeutic strategy but also broadens the drug payload method of two-dimensional nanomaterials.

A novel self-targeting theranostic nanoplatform for photoacoustic imaging-monitored and enhanced chemo-sonodynamic therapy.

Sonodynamic therapy has attracted wide attention as a noninvasive therapy due to deep tissue penetration. However, majority sonosensitizers often suffer from poor physiological stability, rapid blood clearance and nonspecific targeting, which seriously hinders their further practical applications. Inspired by the concept of active targeting drug delivery, both dual-functional chemo-drug pemetrexed (PEM, emerges an innate affinity toward the folate receptor) and amphiphilic d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected to be covalently linked by an esterase-responsive ester linkage. The synthesized self-targeting TPGS-PEM prodrug and indocyanine green (ICG) as functional motifs can be self-assembled into a TPGS-PEM-ICG nanoplatform within an aqueous medium. The TPGS-PEM-ICG nanoplatform with outstanding structural and physiological stability not only protects the sonosensitizer from reticular endothelial system clearance but also achieves active targeting drug delivery and efficient tumor enrichment. Moreover, TPGS-PEM-ICG nanoplatform can selectively recognize tumor cells and then realize on-demand drug burst release by multiple stimuli of internal lysosomal acidity, esterase and external ultrasound, which guarantee low side effects toward normal tissues and organs. It is also worth noting that our nanoplatform exhibits protruding tumor enrichment under the precise guidance of photoacoustic/fluorescence imaging. Further in vitro and in vivo experimental results well confirmed that the TPGS-PEM-ICG nanoplatform possesses enhanced chemo-sonodynamic effects. Interestingly, the highly toxic reactive oxygen species can remarkably reduce the blood oxygen saturation signal of the tumor microenvironment via precise, multifunctional and high-resolution photoacoustic imaging. Taken together, the TPGS-PEM-ICG nanoplatform can be expected to hold enormous potential for diagnosis, prognosis and targeted therapy for tumor.

Correction: Tumor acidity-responsive carrier-free nanodrugs based on targeting activation via ICG-templated assembly for NIR-II imaging-guided photothermal-chemotherapy.

Correction for 'Tumor acidity-responsive carrier-free nanodrugs based on targeting activation via ICG-templated assembly for NIR-II imaging-guided photothermal-chemotherapy' by Kaihang Xue et al., Biomater. Sci., 2021, DOI: 10.1039/D0BM01864C.

Tumor acidity-responsive carrier-free nanodrugs based on targeting activation via ICG-templated assembly for NIR-II imaging-guided photothermal-chemotherapy.

Carrier-free nanodrugs composed of photosensitizers and chemotherapeutic drugs show great potential in synergistic photothermal-chemotherapy. However, the targeting specificity to tumor cells is still a major obstacle for carrier-free nanodrugs. Meanwhile, almost all exogenous tumor-targeting ligands show no therapeutic effect by themselves. Here, a tumor microenvironment-driven self-targeting supramolecular nanodrug was successfully constructed via an indocyanine green (ICG)-templated small-molecule self-assembly strategy with methotrexate (MTX, folic acid-like antitumor drug) followed by post-insertion of weak acidity-responsive PEG for synergistic photothermal-chemotherapy. Interestingly, the size and morphology could be adjusted by changing the ICG-to-MTX ratio. Notably, the dynamic introduction of PEG not only could temporarily shield self-targeting function in blood to prolong the circulation time, but also could trigger the activation of self-targeting via re-exposing MTX ligands within the tumor microenvironment to enhance cellular uptake. Furthermore, the dePEGylated nanodrug would be disassembled to release MTX on-demand for chemotherapy via both stimuli of stronger lysosomal acidity and an external NIR laser. Moreover, the elimination of tumors could be realized through NIR-II fluorescence/PA imaging-guided synergistic photothermal-chemotherapy. The tumor microenvironment-driven carrier-free nanodrug based on self-targeting activation via ICG-templated assembly might provide a brand-new idea for synergistic photothermal-chemotherapy.

Selective antitumor activity of drug-free TPGS nanomicelles with ROS-induced mitochondrial cell death.

D-a-tocopheryl polyethylene glycol succinate (TPGS) as a FDA-approved safe adjuvant has shown an excellent application in the targeting delivery of antitumor drugs and overcoming multidrug resistance. Beside, TPGS can result in apoptogenic activity toward many tumor types because it can induce mitochondrial dysfunction. Therefore, TPGS can serve as an antineoplastic agent. However, the current research on the selective antitumor activity of TPGS is ignored. To reveal the issue, herein we develop a mitochondria-targeting drug-free TPGS nanomicelles with the hydrodynamic diameter of about 100 nm and outstanding serum stability by weak interaction-driven self-assembly of the amphiphilic TPGS polymer. Moreover, such drug-free TPGS nanomicelles intravenously injected into tumor-bearing mice exhibit long blood circulation time, superior tumor enrichment, and inhibit the tumor growth via inducing excessive reactive oxygen species (ROS) generation within tumor cells. Further in vitro and in vivo researches jointly demonstrate that drug-free TPGS nanomicelles have more significant antitumor effect on HeLa cells compared with that of other tumor cells. On the contrary, drug-free TPGS nanomicelles display the low toxicity toward normal cells and tissues. Taken together, these new findings confirm that TPGS drug-free nanomicelles represent simple, multifunctional, safe, and efficient antineoplastic agents, which can be expected to bring new light on the development of drug-free polymers for tumor therapy.

Effects of green tea extract combined with brisk walking on lipid profiles and the liver function in overweight and obese men: A randomized, double-blinded, placebo-control trial.

This study was aimed to investigate the effect of green tea extract (GTE) combined with brisk walking on lipid profiles and the liver function in overweight and obese men. Twenty-four participants were randomized to either the GTE group or the placebo group for 12 weeks with a 4-week follow-up. The walking program consisted of four 60-min-sessions/week and all participants were asked to consume two GTE (150mg) or placebo tablets daily. After 12-week intervention, GTE group resulted in a significant difference in the low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels when compared to placebo group (P < 0.01). There was also a significant reduction in the aspartate aminotransferase levels (P < 0.01) in the GTE group, but no change in the placebo group (P >0.05). There was no change in the triglyceride or high-density lipoprotein cholesterol (HDL-C) levels in the placebo group, but a significant reduction was noted in the HDL-C levels in the GTE group (P < 0.05). GTE combined with brisk walking resulted in a significant change in the LDL-C and TC levels, however, a significant reduce in HDL-C in the GTE group. The study has a more positive effect on the liver function than brisk walking alone.

Self-Distinguishing and Stimulus-Responsive Carrier-Free Theranostic Nanoagents for Imaging-Guided Chemo-Photothermal Therapy in Small-Cell Lung Cancer.

Lack of tumor targeting and low drug payload severely impedes various nanoagents further employed in small-cell lung cancer (SCLC). Therefore, how to develop a new targeting ligand and enhance drug payload has been an urgent need for SCLC therapy. Herein, we first sift and verify that capreomycin (Cm) has a high affinity toward CD56 receptors overexpressed on SCLC cells. Motivated by the concept of self-targeted drug delivery, Cm is selected as the specific targeting ligand toward CD56 receptors and chemodrug doxorubicin (Dox) is adopted to be covalently linked via the redox-responsive disulfide linkage. The synthesized self-distinguishing prodrug (Dox-ss-Cm) and FDA-approved photosensitizer indocyanine green (ICG) as structural motifs can be self-assembled into theranostic nanoagents (ICG@Dox-ss-Cm NPs) within an aqueous solution. Such carrier-free nanoagents with high drug payload can exert targeted on-demand drug release under multiple stimuli of intracellular lysosomal acidity, glutathione (GSH), and an external near-infrared (NIR) laser. Besides, our nanoagents can be specifically self-targeted to SCLC sites in vivo and self-distinguishing via SCLC cells in vitro; thus, they decrease the undesirable effects on normal tissues and organs. Further in vitro and in vivo studies uniformly confirm that such nanoagents show highly synergistic effects for SCLC chemo-photothermal therapy (PTT) under the precise guidance of NIR fluorescence (NIRF)/photoacoustic (PA) imaging. Taken together, our work can provide a novel and promising strategy for the targeted treatment of SCLC.