Comprehensive pulmonary metabolic responses to silica nanoparticles exposure in Fisher 344 rats.

Silica nanoparticles (SiNPs) could induce adverse pulmonary effects, but the mechanism was not clear enough. Metabolomics is a sensitive and high-throughput approach that could investigate the intrinsic causes of adverse health effects caused by SiNPs. The current investigation represented the first in vivo metabolomics study examining the chronic pulmonary toxicity of SiNPs at a low dosage, mimicking real human exposure situation. The recovery process after the cessation of exposure was also taken into consideration. Fisher 344 rats were treated with either saline or SiNPs for 6 months. Half of the animals in each group received an additional six-month period for recovery. The findings indicated that chronic low-level exposure to SiNPs resulted in notable alterations in pulmonary metabolism of amino acids, lipids, carbohydrates, and nucleotides. SiNPs exerted an impact on various metabolites and metabolic pathways which are linked to oxidative stress, inflammation and tumorigenesis. These included but were not limited to L-carnitine, spermidine, taurine, xanthine, and glutathione metabolism. The metabolic alterations caused by SiNPs exhibited a degree of reversibility. However, the interference of SiNPs on two metabolic pathways related to tumorigenesis was observed to persist after a recovery period. The two metabolic pathways are glycerophospholipid metabolism as well as phenylalanine, tyrosine and tryptophan biosynthesis. This study elucidated the metabolic alterations induced by chronic low-level exposure to SiNPs and presented novel evidence of the chronic pulmonary toxicity and carcinogenicity of SiNPs, from a metabolomic perspective.

Redox-Active Ferrocene Quencher-Based Supramolecular Nanomedicine for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Real-time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe-integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self-consumption of ⋅OH. Here, we report the facile fabrication of a self-monitored chemodynamic agent (denoted as Fc-CD-AuNCs) by incorporating ferrocene (Fc) into ß-cyclodextrin (CD)-functionalized gold nanoclusters (AuNCs) via host-guest molecular recognition. The water-soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron-donating ability to effectively quench the second near-infrared (NIR-II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc-CD-AuNCs by cancer cells, Fenton reaction between redox-active Fc quencher and endogenous hydrogen peroxide (H2 O2 ) caused Fc oxidation and subsequent NIR-II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc-CD-AuNCs to in situ self-report ⋅OH generation without undesired ⋅OH consumption. Such a NIR-II fluorescence-monitored CDT enabled the use of renal-clearable Fc-CD-AuNCs for efficient tumor growth inhibition with minimal side effects in vivo.

Engineering Single-Atom Nanozymes for Catalytic Biomedical Applications.

Nanomaterials with enzyme-mimicking properties, coined as nanozymes, are a promising alternative to natural enzymes owing to their remarkable advantages, such as high stability, easy preparation, and favorable catalytic performance. Recently, with the rapid development of nanotechnology and characterization techniques, single atom nanozymes (SAzymes) with atomically dispersed active sites, well-defined electronic and geometric structures, tunable coordination environment, and maximum metal atom utilization are developed and exploited. With superior catalytic performance and selectivity, SAzymes have made impressive progress in biomedical applications and are expected to bridge the gap between artificial nanozymes and natural enzymes. Herein, the recent advances in SAzyme preparation methods, catalytic mechanisms, and biomedical applications are systematically summarized. Their biomedical applications in cancer therapy, oxidative stress cytoprotection, antibacterial therapy, and biosensing are discussed in depth. Furthermore, to appreciate these advances, the main challenges, and prospects for the future development of SAzymes are also outlined and highlighted in this review.

Real-Time Recognition Method for Key Signals of Rock Fracture Acoustic Emissions Based on Deep Learning.

The characteristics of acoustic emission signals generated in the process of rock deformation and fission contain rich information on internal rock damage. The use of acoustic emissions monitoring technology can analyze and identify the precursor information of rock failure. At present, in the field of acoustic emissions monitoring and the early warning of rock fracture disasters, there is no real-time identification method for a disaster precursor characteristic signal. It is easy to lose information by analyzing the characteristic parameters of traditional acoustic emissions to find signals that serve as precursors to disasters, and analysis has mostly been based on post-analysis, which leads to poor real-time recognition of disaster precursor characteristics and low application levels in the engineering field. Based on this, this paper regards the acoustic emissions signal of rock fracture as a kind of speech signal generated by rock fracture uses this idea of speech recognition for reference alongside spectral analysis (STFT) and Mel frequency analysis to realize the feature extraction of acoustic emissions from rock fracture. In deep learning, based on the VGG16 convolutional neural network and AlexNet convolutional neural network, six intelligent real-time recognition models of rock fracture and key acoustic emission signals were constructed, and the network structure and loss function of traditional VGG16 were optimized. The experimental results show that these six deep-learning models can achieve the real-time intelligent recognition of key signals, and Mel, combined with the improved VGG16, achieved the best performance with 87.68% accuracy and 81.05% recall. Then, by comparing multiple groups of signal recognition models, Mel+VGG-FL proposed in this paper was verified as having a high recognition accuracy and certain recognition efficiency, performing the intelligent real-time recognition of key acoustic emission signals in the process of rock fracture more accurately, which can provide new ideas and methods for related research and the real-time intelligent recognition of rock fracture precursor characteristics.

Amplification of Lipid Peroxidation by Regulating Cell Membrane Unsaturation To Enhance Chemodynamic Therapy.

Lipid peroxidation (LPO) is one of the most damaging processes in chemodynamic therapy (CDT). Although it is well known that polyunsaturated fatty acids (PUFAs) are much more susceptible than saturated or monounsaturated ones to LPO, there is no study exploring the effect of cell membrane unsaturation degree on CDT. Here, we report a self-reinforcing CDT agent (denoted as OA@Fe-SAC@EM NPs), consisting of oleanolic acid (OA)-loaded iron single-atom catalyst (Fe-SAC)-embedded hollow carbon nanospheres encapsulated by an erythrocyte membrane (EM), which promotes LPO to improve chemodynamic efficacy via modulating the degree of membrane unsaturation. Upon uptake of OA@Fe-SAC@EM NPs by cancer cells, Fe-SAC-catalyzed conversion of endogenous hydrogen peroxide into hydroxyl radicals, in addition to initiating the chemodynamic therapeutic process, causes the dissociation of the EM shell and the ensuing release of OA that can enrich cellular membranes with PUFAs, enabling LPO amplification-enhanced CDT.

Iron-siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation.

Ferrous iron (Fe2+ ) has more potent hydroxyl radical (⋅OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe2+ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe0 nanoparticles (Fe0 -siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe0 -siRNA NPs are degraded to release Fe2+ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O2 ). The accompanied O2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe0 -siRNA NPs. In addition to initiating chemodynamic process, Fe2+ -catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT.

Melatonin alleviates PM2.5 -induced glucose metabolism disorder and lipidome alteration by regulating endoplasmic reticulum stress.

Exposure to fine particulate matter (PM2.5 ) was associated with an increased incidence of liver metabolic disease. Melatonin has been shown to prevent liver glucolipid metabolism disorders. However, whether melatonin could rescue PM2.5 -induced liver metabolic abnormalities remains uncertain. This study was to evaluate the mitigating effect of melatonin on PM2.5 -accelerated hepatic glucose metabolism imbalance in vivo and in vitro. Schiff periodic acid shiff staining and other results showed that PM2.5 led to a decrease in hepatic glycogen reserve and an increase in glucose content, which was effectively alleviated by melatonin. Targeted lipidomics is used to identify lipid biomarkers associated with this process, including glycerolipids, glycerophospholipids, and sphingolipids. In addition, gene microarray and quantitative polymerase chain reaction analysis of ApoE-/- mice liver suggested that PM2.5 activated the miR-200a-3p and inhibited DNAJB9, and the targeting relationship was verified by luciferase reports for the first time. Further investigation demonstrated that DNAJB9 might motivate endoplasmic reticulum (ER) stress by regulating Ca2+ homeostasis, thus altering the protein expression of GSK3B, FOXO1, and PCK2. Meanwhile, melatonin effectively inhibited miR-200a-3p and glucose metabolism disorder. Knockout of miR-200a-3p in L02 cells revealed that miR-200a-3p is indispensable in the damage of PM2.5 and the therapeutic effect of melatonin. In summary, melatonin alleviated PM2.5 -induced liver metabolic dysregulation by regulating ER stress via miR-200a-3p/DNAJB9 signaling pathway. Our data provide a prospective targeted therapy for air pollution-related liver metabolism disorders.

Global association between atmospheric particulate matter and obesity: A systematic review and meta-analysis.

BACKGROUND: Among various air pollutants, particulate matter (PM) is the most harmful and representative pollutant. Although several studies have shown a link between particulate pollution and obesity, the conclusions are still inconsistent. METHODS: We conducted a systematic review and meta-analysis to pool the effect of PM exposure on obesity. Five databases (including PubMed, Web of Science, Scopus, Embase, and Cochrane) were searched for relevant studies up to Jan 2022. Adjusted risk ratio (RR) with corresponding 95% confidence interval (CI) were retrieved from individual studies and pooled with random effect models by STATA software. Besides, we tested the stability of results by Egger's test, Begg's test, funnel plot, and using the trim-and-fill method to modify the possible asymmetric funnel graph. The NTP-OHAT guidelines were followed to assess the risk of bias. Then the GRADE was used to evaluate the certainty of evidence. RESULTS: 26 studies were included in this meta-analysis. 19 studies have shown that PM2.5 can increase the risk of obesity per 10 µg/m3 increment (RR: 1.159, 95% CI: 1.111-1.209), while 15 studies have indicated that PM10 increase the risk of obesity per 10 µg/m3 increment (RR: 1.092, 95% CI: 1.070-1.116). Besides, 5 other articles with maternal exposure showed that PM2.5 increases the risk of obesity in children (RR: 1.06, 95% CI: 1.02-1.11). And we explored the source of heterogeneity by subgroup analysis, which suggested associations between PM and obesity tended to vary by region, age group, participants number, etc. The analysis results showed publication bias and other biases are well controlled, but most certainties of the evidence were low, and more research is required to reduce these uncertainties. CONCLUSION: Exposure to PM2.5 and PM10 with per 10 µg/m3 increment could increase the risk of obesity in the global population.

Silica nanoparticles induce pulmonary autophagy dysfunction and epithelial-to-mesenchymal transition via p62/NF-κB signaling pathway.

It has been reported that silica nanoparticles (SiNPs) could cause epithelial-to-mesenchymal transition (EMT), but the specific mechanism is still unclear. Thus, the purpose of this study was to investigate the underlying mechanisms of pulmonary EMT after subacute exposure to SiNPs. The results showed intratracheal instillation of SiNPs increased the pulmonary MDA content, while decreased the activity of SOD and GSH-Px in rats. Western blot analysis demonstrated that SiNPs induced autophagy dysfunction via the upregulation of p62. Meanwhile, the inflammation cytokines (TNF-α, IL-18, IL-1ß) were released in rat lung. Immunohistochemistry and western blot assays both showed that SiNPs could regulate the related protein biomarkers of EMT through decreasing E-cadherin and increasing vimentin in a dose-dependent manner. Besides, SiNPs activated the proteins expression involved in p62/NF-κB signaling pathway, whereas the pulmonary EMT induced by SiNPs was significantly dampened after the knock down of p62. In this study, we illustrated that subacute exposure to SiNPs could trigger the autophagy dysfunction and pulmonary inflammation, further lead to EMT via activating the p62/NF-κB signaling pathway. Our findings provide new molecular evidence for SiNPs-induced pulmonary toxicity.

The relationship between long-term exposure to PM2.5 and hypertension in women：A meta-analysis.

OBJECTIVE: Gender difference and PM2.5 exposure all have effects on hypertension, change of estrogen level in different women's stage bring complex influence on blood pressure. Then we conduct this meta-analysis to investigate the association between long-term exposure (at least one year) to fine particulate matter (PM2.5) and hypertension in adult non-pregnant women. METHOD: Four major databases: PubMed, Cochrane Library, Web of Science and Embase were searched with specific search terms, and 11 studies were finally selected. The meta-analysis module of software Stata 12.0 was used for data processing with the effect values hazard ratio (HR) and odds ratio (OR) respectively. RESULTS: After sensitivity analysis, we removed a study with highly heterogeneity and finally included 10 studies. Meta-analysis results showed that exposure to PM2.5 (per 10 µg/m3 increase) was associated with hypertension in non-pregnancy adult women, HR = 1.23, 95%CI: 1.08-1.40; OR = 1.07, 95%CI: 1.00-1.14. And subgroup analysis showed that menopause, non-White and diabetes are the key risk factors of hypertension when exposed to PM2.5. CONCLUSION: This is the first meta-analysis to explore the association between PM2.5 and non-pregnancy women, and calculate OR and HR respectively for the first time. Exposure to PM2.5 could increase the risk of hypertension in non-pregnancy women, and the combined 'HR' was much higher than 'OR'.

Endoplasmic Reticulum Targeting to Amplify Immunogenic Cell Death for Cancer Immunotherapy.

Immunogenic cell death (ICD) elicited by photodynamic therapy (PDT) is mediated through generation of reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress. However, the half-life of ROS is very short and the intracellular diffusion depth is limited, which impairs ER localization and thus limits ER stress induction. To solve the problem, we synthesized reduction-sensitive Ds-sP NPs (PEG-s-s-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] nanoparticles) loaded with an efficient ER-targeting photosensitizer TCPP-TER (4,4',4″,4'″-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(2-((4-methylphenyl)sulfonamido)ethyl)benzamide). The resulting Ds-sP/TCPP-TER NPs could selectively accumulate in the ER and locally generate ROS under near-infrared (NIR) laser irradiation, which induced ER stress, amplified ICD, and activated immune cells, leading to augmented immunotherapy effect. This study presents a novel ICD amplifying, ER-targeting PDT strategy that can effectively eradicate primary tumors under NIR exposure, as well as distant tumors through an abscopal effect.

Singlet Oxygen Generation in Dark-Hypoxia by Catalytic Microenvironment-Tailored Nanoreactors for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Singlet oxygen (1 O2 ) has a potent anticancer effect, but photosensitized generation of 1 O2 is inhibited by tumor hypoxia and limited light penetration depth. Despite the potential of chemodynamic therapy (CDT) to circumvent these issues by exploration of 1 O2 -producing catalysts, engineering efficient CDT agents is still a formidable challenge since most catalysts require specific pH to function and become inactivated upon chelation by glutathione (GSH). Herein, we present a catalytic microenvironment-tailored nanoreactor (CMTN), constructed by encapsulating MoO42- catalyst and alkaline sodium carbonate within liposomes, which offers a favorable pH condition for MoO42- -catalyzed generation of 1 O2 from H2 O2 and protects MoO42- from GSH chelation owing to the impermeability of liposomal lipid membrane to ions and GSH. H2 O2 and 1 O2 can freely cross the liposomal membrane, allowing CMTN with a built-in NIR-II ratiometric fluorescent 1 O2 sensor to achieve monitored tumor CDT.

Endogenous Labile Iron Pool-Mediated Free Radical Generation for Cancer Chemodynamic Therapy.

Current chemodynamic therapy (CDT) primarily relies on the delivery of transition metal ions with Fenton activity to trigger hydroxyl radical production from hydrogen peroxide. However, administration of an excess amount of exogenous Fenton-type heavy metals may cause potential adverse effects to human health, including acute and chronic damages. Here, we present a new CDT strategy that uses intracellular labile iron pool (LIP) as the endogenous source of Fenton-reactive metals for eliciting free radical generation, and the discovery of hydroperoxides (R'OOH) as an optimal LIP-mediated chemodynamic agent against cancer. By simulating the metabolic fates of peroxo compounds within cells, R'OOH was found to have excellent free radical-producing ability in the presence of labile iron(II) and to suffer only moderate elimination by glutathione/glutathione peroxidase, which contributes to its superior chemodynamic efficacy. The LIP-initiated nontoxic-to-toxic transition of R'OOH, together with increased LIP levels in tumor cells, enabled efficient and specific CDT of cancer. Moreover, pH/labile iron(II) cascade-responsive nanomedicines comprising encapsulated methyl linoleate hydroperoxide and LIP-increasing agent in pH-sensitive polymer particles were fabricated to realize enhanced CDT. This work not only paves the way to using endogenous Fenton-type metals for cancer therapy but also offers a paradigm for the exploration of high-performance chemodynamic agents activated by intracellular LIP.

Particulate matter exposure and biomarkers associated with blood coagulation: A meta-analysis.

OBJECTIVE: Find the correlation between particulate matter (PM) and biomarkers related to blood coagulation, offer medical evidence to sensitive indicators and carry out early diagnosis of cardiovascular diseases. METHOD: A combination of computer and manual retrieval was used to search for the keywords in PubMed (584 records), Cochrane Library (28 records), Web of Science (162 records) and Embase (163 records). Finally, a total of 25 articles were included in this meta-analysis. Stata 13.0 was applied to examine the heterogeneity among the studies and to calculate the combined effect estimates, percent variation (%) and 95% CI by selecting corresponding models. Additionally, sensitivity analysis and publication bias test were also conducted. RESULTS: Meta-analysis indicated that there was an association between PM2.5 exposure (per 10 µg/m3 increase) and fibrinogen. With the increase of PM2.5 exposure (per 10 µg/m3 increase), the content of fibrinogen revealed a high level (2.26%; 95% CI: 1.08-3.44%); and the increase of UFPs exposure (per 5000/cm3 increase) was correlated with some biomarkers such as cell surface antigen and protein ligand including ICAM-1, sCD40L, P-selectin, E-selectin and PAI-1 that indirectly related to blood coagulation, yielding a percent variation of 10.83% (95% CI: 3.49%-18.17%). CONCLUSION: This meta-analysis expounded that PM-related biomarkers were associated with blood coagulation, and the relationship with fibrinogen was much stronger.

Self-Assembled Responsive Bilayered Vesicles with Adjustable Oxidative Stress for Enhanced Cancer Imaging and Therapy.

In the present study, we report the development of magnetic-plasmonic bilayer vesicles assembled from iron oxide-gold Janus nanoparticles (Fe3O4-Au JNPs) for reactive oxygen species (ROS) enhanced chemotherapy. The amphiphilic Fe3O4-Au JNPs were grafted with poly(ethylene glycol) (PEG) on the Au surface and ROS-generating poly(lipid hydroperoxide) (PLHP) on the Fe3O4 surface, respectively, which were then assembled into vesicles containing two closely attached Fe3O4-Au NPs layers in opposite directions. The self-assembly mechanism of the bilayered vesicles was elucidated by performing a series of numerical simulations. The enhanced optical properties of the bilayered vesicles were verified by the calculated results and experimental data. The vesicles exhibited enhanced T2 relaxivity and photoacoustic properties over single JNPs due to the interparticle magnetic dipole interaction and plasmonic coupling. In particular, the vesicles are pH responsive and disassemble into single JNPs in the acidic tumor environment, activating an intracellular biochemical reaction between the grafted PLHP and released ferrous ions (Fe2+) from Fe3O4 NPs, resulting in highly efficient local ROS generation and increased intracellular oxidative stress. In combination with the release of doxorubicin (DOX), the vesicles combine ROS-mediated cytotoxicity and DOX-induced chemotherapy, leading to greatly improved therapeutic efficacy than monotherapies. High tumor accumulation efficiency and fast vesicle clearance from the body were also confirmed by positron emission tomography (PET) imaging of radioisotope 64Cu-labeled vesicles.

Synthesis of Copper Peroxide Nanodots for H2O2 Self-Supplying Chemodynamic Therapy.

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (•OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.

Hybrid Nanomedicine Fabricated from Photosensitizer-Terminated Metal-Organic Framework Nanoparticles for Photodynamic Therapy and Hypoxia-Activated Cascade Chemotherapy.

During photodynamic therapy (PDT), severe hypoxia often occurs as an undesirable limitation of PDT owing to the O2 -consuming photodynamic process, compromising the effectiveness of PDT. To overcome this problem, several strategies aiming to improve tumor oxygenation are developed. Unlike these traditional approaches, an opposite method combining hypoxia-activated prodrug and PDT may provide a promising strategy for cancer synergistic therapy. In light of this, azido-/photosensitizer-terminated UiO-66 nanoscale metal-organic frameworks (UiO-66-H/N3 NMOFs) which serve as nanocarriers for the bioreductive prodrug banoxantrone (AQ4N) are engineered. Owing to the effective shielding of the nanoparticles, the stability of AQ4N is well preserved, highlighting the vital function of the nanocarriers. By virtue of strain-promoted azide-alkyne cycloaddition, the nanocarriers are further decorated with a dense PEG layer to enhance their dispersion in the physiological environment and improve their therapeutic performance. Both in vitro and in vivo studies reveal that the O2 -depleting PDT process indeed aggravates intracellular/tumor hypoxia that activates the cytotoxicity of AQ4N through a cascade process, consequently achieving PDT-induced and hypoxia-activated synergistic therapy. Benefiting from the localized therapeutic effect of PDT and hypoxia-activated cytotoxicity of AQ4N, this hybrid nanomedicine exhibits enhanced therapeutic efficacy with negligible systemic toxicity, making it a promising candidate for cancer therapy.

Exceedingly Small Gadolinium Oxide Nanoparticles with Remarkable Relaxivities for Magnetic Resonance Imaging of Tumors.

Gd chelates have occupied most of the market of magnetic resonance imaging (MRI) contrast agents for decades. However, there have been some problems (nephrotoxicity, non-specificity, and low r1 ) that limit their applications. Herein, a wet-chemical method is proposed for facile synthesis of poly(acrylic acid) (PAA) stabilized exceedingly small gadolinium oxide nanoparticles (ES-GON-PAA) with an excellent water dispersibility and a size smaller than 2.0 nm, which is a powerful T1 -weighted MRI contrast agent for diagnosis of diseases due to its remarkable relaxivities (r1 = 70.2 ± 1.8 mM-1 s-1 , and r2 /r1 = 1.02 ± 0.03, at 1.5 T). The r1 is much higher and the r2 /r1 is lower than that of the commercial Gd chelates and reported gadolinium oxide nanoparticles (GONs). Further ES-GON-PAA is developed with conjugation of RGD2 (RGD dimer) (i.e., ES-GON-PAA@RGD2) for T1 -weighted MRI of tumors that overexpress RGD receptors (i.e., integrin αv ß3 ). The maximum signal enhancement (ΔSNR) for T1 -weighted MRI of tumors reaches up to 372 ± 56% at 2 h post-injection of ES-GON-PAA@RGD2, which is much higher than commercial Gd-chelates (<80%). Due to the high biocompatibility and high tumor accumulation, ES-GON-PAA@RGD2 with remarkable relaxivities is a promising and powerful T1 -weighted MRI contrast agent.

Enhanced Antitumor Efficacy by a Cascade of Reactive Oxygen Species Generation and Drug Release.

Reactive oxygen species (ROS) can be used not only as a therapeutic agent for chemodynamic therapy (CDT), but also as a stimulus to activate release of antitumor drugs, achieving enhanced efficacy through the combination of CDT and chemotherapy. Here we report a pH/ROS dual-responsive nanomedicine consisting of ß-lapachone (Lap), a pH-responsive polymer, and a ROS-responsive polyprodrug. In the intracellular acidic environment, the nanomedicine can realize pH-triggered disassembly. The released Lap can efficiently generate hydrogen peroxide, which will be further converted into highly toxic hydroxyl radicals via the Fenton reaction. Subsequently, through ROS-induced cleavage of thioketal linker, doxorubicin is released from the polyprodrug. In vivo results indicate that the cascade of ROS generation and antitumor-drug release can effectively inhibit tumor growth. This design of nanomedicine with cascade reactions offers a promising strategy to enhance antitumor efficacy.

Porphyrin Nanocage-Embedded Single-Molecular Nanoparticles for Cancer Nanotheranostics.

Single molecular nanoparticles (SMNPs) integrating imaging and therapeutic capabilities exhibit unparalleled advantages in cancer theranostics, ranging from excellent biocompatibility, high stability, prolonged blood lifetime to abundant tumor accumulation. Herein, we synthesize a sophisticated porphyrin nanocage that is further functionalized with twelve polyethylene glycol arms to prepare SMNPs (porSMNPs). The porphyrin nanocage embedded in porSMNPs can be utilized as a theranostic platform. PET imaging allows dynamic observation of the bio-distribution of porSMNPs, confirming their excellent circulation time and preferential accumulation at the tumor site, which is attributed to the enhanced permeability and retention effect. Moreover, the cage structure significantly promotes the photosensitizing effect of porSMNs by inhibiting the π-π stacking interactions of the photosensitizers, ablating of the tumors without relapse by taking advantage of photodynamic therapy.