A mesoporous superparamagnetic iron oxide nanoparticle as a generic drug delivery system for tumor ferroptosis therapy.

As a famous drug delivery system (DDS), mesoporous organosilica nanoparticles (MON) are degraded slowly in vivo and the degraded components are not useful for cell nutrition or cancer theranostics, and superparamagnetic iron oxide nanoparticles (SPION) are not mesoporous with low drug loading content (DLC). To overcome the problems of MON and SPION, we developed mesoporous SPIONs (MSPIONs) with an average diameter of 70 nm and pore size of 3.9 nm. Sorafenib (SFN) and/or brequinar (BQR) were loaded into the mesopores of MSPION, generating SFN@MSPION, BQR@MSPION and SFN/BQR@MSPION with high DLC of 11.5% (SFN), 10.1% (BQR) and 10.0% (SNF + BQR), demonstrating that our MSPION is a generic DDS. SFN/BQR@MSPION can be used for high performance ferroptosis therapy of tumors because: (1) the released Fe2+/3+ in tumor microenvironment (TME) can produce •OH via Fenton reaction; (2) the released SFN in TME can inhibit the cystine/glutamate reverse transporter, decrease the intracellular glutathione (GSH) and GSH peroxidase 4 levels, and thus enhance reactive oxygen species and lipid peroxide levels; (3) the released BQR in TME can further enhance the intracellular oxidative stress via dihydroorotate dehydrogenase inhibition. The ferroptosis therapeutic mechanism, efficacy and biosafety of MSPION-based DDS were verified on tumor cells and tumor-bearing mice.

Double-Layered Hollow Mesoporous Cuprous Oxide Nanoparticles for Double Drug Sequential Therapy of Tumors.

Cancer stem cells (CSCs) are one of the determinants of tumor heterogeneity and are characterized by self-renewal, high tumorigenicity, invasiveness, and resistance to various therapies. To overcome the resistance of traditional tumor therapies resulting from CSCs, a strategy of double drug sequential therapy (DDST) for CSC-enriched tumors is proposed in this study and is realized utilizing the developed double-layered hollow mesoporous cuprous oxide nanoparticles (DL-HMCONs). The high drug-loading contents of camptothecin (CPT) and all-trans retinoic acid (ATRA) demonstrate that the DL-HMCON can be used as a generic drug delivery system. ATRA and CPT can be sequentially loaded in and released from CPT3@ATRA3@DL-HMCON@HA. The DDST mechanisms of CPT3@ATRA3@DL-HMCON@HA for CSC-containing tumors are demonstrated as follows: 1) the first release of ATRA from the outer layer induces differentiation from CSCs with high drug resistance to non-CSCs with low drug resistance; 2) the second release of CPT from the inner layer causes apoptosis of non-CSCs; and 3) the third release of Cu+ from DL-HMCON itself triggers the Fenton-like reaction and glutathione depletion, resulting in ferroptosis of non-CSCs. This CPT3@ATRA3@DL-HMCON@HA is verified to possess high DDST efficacy for CSC-enriched tumors with high biosafety.

MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis.

Triple negative breast cancer (TNBC) cells have a high demand for oxygen and glucose to fuel their growth and spread, shaping the tumor microenvironment (TME) that can lead to a weakened immune system by hypoxia and increased risk of metastasis. To disrupt this vicious circle and improve cancer therapeutic efficacy, a strategy is proposed with the synergy of ferroptosis, immunosuppression reversal and disulfidptosis. An intelligent nanomedicine GOx-IA@HMON@IO is successfully developed to realize this strategy. The Fe release behaviors indicate the glutathione (GSH)-responsive degradation of HMON. The results of titanium sulfate assay, electron spin resonance (ESR) spectra, 5,5'-Dithiobis-(2-nitrobenzoic acid (DTNB) assay and T1 -weighted magnetic resonance imaging (MRI) demonstrate the mechanism of the intelligent iron atom (IA)-based cascade reactions for GOx-IA@HMON@IO, generating robust reactive oxygen species (ROS). The results on cells and mice reinforce the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis triggered by the GOx-IA@HMON@IO with the following steps: 1) GSH peroxidase 4 (GPX4) depletion by disulfidptosis; 2) IA-based cascade reactions; 3) tumor hypoxia reversal; 4) immunosuppression reversal; 5) GPX4 depletion by immunotherapy. Based on the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis, the intelligent nanomedicine GOx-IA@HMON@IO can be used for MRI-guided tumor therapy with excellent biocompatibility and safety.

Synergistic Glutathione Depletion and STING Activation to Potentiate Dendritic Cell Maturation and Cancer Vaccine Efficacy.

Dendritic cell (DC) maturation and antigen presentation are key factors for successful vaccine-based cancer immunotherapy. This study developed manganese-based layered double hydroxide (Mn-LDH) nanoparticles as a self-adjuvanted vaccine carrier that not only promoted DC maturation through synergistically depleting endogenous glutathione (GSH) and activating STING signaling pathway, but also facilitated the delivery of model antigen ovalbumin (OVA) into lymph nodes and subsequent antigen presentation in DCs. Significant therapeutic-prophylactic efficacy of the OVA-loaded Mn-LDH (OVA/Mn-LDH) nanovaccine was determined by the tumor growth inhibition in the mice bearing B16-OVA tumor. Our results showed that the OVA/Mn-LDH nanoparticles could be a potent delivery system for cancer vaccine development without the need of adjuvant. Therefore, the combination of GSH exhaustion and STING pathway activation might be an advisable approach for promoting DC maturation and antigen presentation, finally improving cancer vaccine efficacy.

Ultrathin Clay Nanoparticles-Mediated Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

Ferroptosis-triggered immunogenic cell death (ICD) is widely adopted to potentiate the body's antitumor immunity by catalyzing the production of toxic reactive oxygen species (ROS). However, the efficacy of ferroptosis and immunotherapy is greatly restricted by intracellular abundant glutathione (GSH) and immunosuppressive tumor microenvironment (TME). Herein, a facile bottom-up method for solvent-free synthesis of ultrathin manganese (Mn)-based layered double hydroxide nanosheets with high loading efficiency for pro-inflammatory cytokine interferon (IFNγ) (IFNγ/uMn-LDHs) is proposed to mutually reinforce the ferroptosis and systemic immunity. The introduction of manganese ions significantly contributes to GSH depletion and hydroxyl radical generation, which can be further enhanced by IFNγ delivery-induced SLC7A11 downregulation. The ICD effect after cell ferroptosis cooperates with the intrinsic immunomodulatory property of IFNγ/uMn-LDHs to facilitate the maturation of dendritic cells (DCs) and the priming of T cells. IFNγ secretion from activated CD8+ T cells in turn involves cascade immunogenic ferroptosis, thus constructing a closed-loop therapy. Remarkably, a potent abscopal effect is observed in the growth inhibition of both primary and distant tumors. Overall, the ultrathin Mn-based clay nanoplatform provides a simple approach for mutual regulation between ferroptosis and antitumor immune response, overcoming the obstacles of current cancer immunotherapy.

Gadolinium Oxide Nanoparticles Reinforce the Fractionated Radiotherapy-Induced Immune Response in Tri-Negative Breast Cancer via cGAS-STING Pathway.

Introduction: Radiotherapy is a widely recognized first-line clinical treatment for cancer, but its efficacy may be impeded by the radioresistance of advanced tumors. It is urgent to improve the sensitivity of radioresistant tumors to radiotherapy. In this work, gadolinium oxide nanocrystals (GONs) were utilized as radiosensitizers to enhance the killing effect and reinforce the immune activation of X-ray irradiation on 4T1 breast cancer cells in vitro and in vivo. Methods: 1.0 T small animal MR imaging (MRI) system was employed to trace GONs in vivo, while 225 kVp X-ray irradiation equipment was utilized for investigating the radiosensitization of GONs in 4T1 breast cancer cells in vitro and in vivo. Western blot, quantitative real-time PCR (RT-qPCR), immunohistochemistry, immunofluorescence, clonal survival assay, flow cytometry and reactive oxygen species assay were used to explore the biological mechanism of GON sensitization. Results: GONs exhibited exceptional utility as contrast agents for both in vivo and in vitro MRI imaging. Interestingly, a single dose of 8.0 Gy X-rays together with GONs failed to confer superior therapeutic effects in tumor-bearing mice, while only 3.0 Gy × 3 fractions X-rays combined with GONs exhibited effective tumor growth inhibition. Moreover, fractionated X-ray irradiation with GONs demonstrated a superior capacity to activate the cGAS-STING pathway. Discussion: Fractionated X-ray irradiation in the presence of GONs has demonstrated the most significant activation of the anti-tumor immune response by boosting the cGAS-STING pathway.

Ultrasmall Self-Cascade AuNP@FeS Nanozyme for H2S-Amplified Ferroptosis Therapy.

Recently, nanozymes with peroxidase (POD)-like activity have shown great promise for ferroptosis-based tumor therapy, which are capable of transforming hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals (•OH). However, the unsatisfactory therapeutic performance of nanozymes due to insufficient endogenous H2O2 and acidity at tumor sites has always been a conundrum. Herein, an ultrasmall gold (Au) @ ferrous sulfide (FeS) cascade nanozyme (AuNP@FeS) with H2S-releasing ability constructed with an Au nanoparticle (AuNP) and an FeS nanoparticle (FeSNP) is designed to increase the H2O2 level and acidity in tumor cells via the collaboration between cascade reactions of AuNP@FeS and the biological effects of released H2S, achieving enhanced •OH generation as well as effective ferroptosis for tumor therapy. The cascade reaction in tumor cells is activated by the glucose oxidase (GOD)-like activity of AuNP in AuNP@FeS to catalyze intratumoral glucose into H2O2 and gluconic acid; meanwhile, the released H2S from AuNP@FeS reduces H2O2 consumption by inhibiting intracellular catalase (CAT) activity and promotes lactic acid accumulation. The two pathways synergistically boost H2O2 and acidity in tumor cells, thus inducing a cascade to generate abundant •OH by catalyzing H2O2 through the POD-like activity of FeS in AuNP@FeS and ultimately causing amplified ferroptosis. In vitro and in vivo experiments demonstrated that AuNP@FeS presents a superior tumor therapeutic effect compared to that of AuNP or FeS alone. This strategy represents a simple but powerful method to amplify ferroptosis with H2S-releasing cascade nanozymes and will pave a new way for the development of tumor therapy.

An AND Logic Gate for Magnetic-Resonance-Imaging-Guided Ferroptosis Therapy of Tumors.

To improve the magnetic resonance imaging (MRI) efficiency and ferroptosis therapy efficacy of exceedingly small magnetic iron oxide nanoparticles (IO, <5 nm) for tumors via enhancing the sensitivity of tumor microenvironment (TME) responsiveness, inspired by molecular logic gates, a self-assembled IO with an AND logic gate function is designed and constructed. Typically, cystamine (CA) is conjugated onto the end of poly(2-methylthio-ethanol methacrylate) (PMEMA) to generate PMEMA-CA. The PMEMA-CA is grafted onto the surface of brequinar (BQR)-loaded IO to form IO-BQR@PMEMA. The self-assembled IO-BQR@PMEMA (SA-IO-BQR@PMEMA) is obtained due to the hydrophobicity of PMEMA. The carbon-sulfur single bond of PMEMA-CA can be oxidized by reactive oxygen species (ROS) in the TME to a thio-oxygen double bond, resulting in the conversion from being hydrophobic to hydrophilic. The disulfide bond of PMEMA-CA can be broken by the glutathione (GSH) in the TME, leading to the shedding of PMEMA from the IO surface. Under the dual actions of ROS and GSH in TME (i.e., AND logic gate), SA-IO-BQR@PMEMA can be disassembled to release IO, Fe2+/3+ , and BQR. In vitro and in vivo results demonstrate the AND logic gate function and mechanism, the high T1 MRI performance and exceptional ferroptosis therapy efficacy for tumors, and the excellent biosafety of SA-IO-BQR@PMEMA.

A STING pathway-activatable contrast agent for MRI-guided tumor immunoferroptosis synergistic therapy.

The immunotherapy efficiency of stimulator of interferon genes (STING)-activatable drugs (e.g., 7-ethyl-10-hydroxycamptothecin, SN38) is limited by their non-specificity to tumor cells and the slow excretion of the DNA-containing exosomes from the treated cancer cells. The efficacy of tumor ferroptosis therapy is always limited by the elimination of lipid peroxides (LPO) by the pathways of glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH) and ferroptosis suppressor protein 1(FSP1). To solve these problems, in this study, we developed a STING pathway-activatable contrast agent (i.e., FeGd-HN@TA-Fe2+-SN38 nanoparticles) for magnetic resonance imaging (MRI)-guided tumor immunoferroptosis synergistic therapy. The remarkable in vivo MRI performance of FeGd-HN@TA-Fe2+-SN38 is attributed to its high accumulation at tumor location, the high relaxivities of FeGd-HN core, and the pH-sensitive TA-Fe2+-SN38 layer. The effectiveness and biosafety of the immunoferroptosis synergistic therapy induced by FeGd-HN@TA-Fe2+-SN38 are demonstrated by the in vivo investigations on the 4T1 tumor-bearing mice. The mechanisms of in vivo immunoferroptosis synergistic therapy by FeGd-HN@TA-Fe2+-SN38 are demonstrated by measurements of in vivo ROS, LPO, GPX4 and SLC7A11 levels, the intratumor matured DCs and CD8+ T cells, the protein expresion of STING and IRF-3, and the secretion of IFN-ß and IFN-γ.

Exceedingly Small Magnetic Iron Oxide Nanoparticles for T1 -Weighted Magnetic Resonance Imaging and Imaging-Guided Therapy of Tumors.

Magnetic iron oxide nanoparticles (MIONs) based T2 -weighted magnetic resonance imaging (MRI) contrast agents (CAs) are liver-specific with good biocompatibility, but have been withdrawn from the market and replaced with Eovist (Gd-EOB-DTPA) due to their inherent limitations (e.g., susceptibility to artifacts, high magnetic moment, dark signals, long processing time of T2 imaging, and long waiting time for patients after administration). Without the disadvantages of Gd-chelates and MIONs, the recently emerging exceedingly small MIONs (ES-MIONs) (<5 nm) are promising T1 CAs for MRI. However, there are rare review articles focusing on ES-MIONs for T1 -weighted MRI. Herein, the recent progress of ES-MIONs, including synthesis methods (the current basic synthesis methods and improved methods), surface modifications (artificial polymers, natural polymers, zwitterions, and functional protein), T1 -MRI visual strategies (structural remodeling, reversible self-assemblies, metal ions doped, T1 /T2 dual imaging modes, and PET/MRI strategy), and imaging-guided cancer therapy (chemotherapy, gene therapy, ferroptosis therapy, photothermal therapy, photodymatic therapy, radiotherapy, immuotherapy, sonodynamic therapy, and multimode therapy), is summarized. The detailed description of synthesis methods and applications of ES-MIONs in this review is anticipated to attract extensive interest from researchers in different fields and promote their participation in the establishment of ES-MIONs based nanoplatforms for tumor theranostics.

Tumor-Generated Reactive Oxygen Species Storm for High-Performance Ferroptosis Therapy.

Ferroptosis therapy (FT) efficacy of tumors suffers from a relatively low concentration of Fenton agents, limited hydrogen peroxide (H2O2) content, and insufficient acidity in the tumor environment (TME), which are unfavorable for reactive oxygen species (ROS) generation based on Fenton or Fenton-like reactions. The glutathione (GSH) overexpression in TME can scavenge ROS and abate the FT performance. In this study, a strategy of ROS storm generation specifically initiated by the TME and our developed nanoplatforms (TAF-HMON-CuP@PPDG) is proposed for high-performance FT of tumors. The GSH in the TME initiates HMON degradation, resulting in tamoxifen (TAF) and copper peroxide (CuP) release from TAF3-HMON-CuP3@PPDG. The released TAF leads to enhanced acidification within tumor cells, which reacts with the released CuP producing Cu2+ and H2O2. The Fenton-like reaction between Cu2+ and H2O2 generates ROS and Cu+, and that between Cu+ and H2O2 generates ROS and Cu2+, forming a cyclic catalysis effect. Cu2+ reacts with GSH to generate Cu+ and GSSG. The increased acidification by TAF can accelerate the Fenton-like reaction between Cu+ and H2O2. The GSH consumption decreases the glutathione peroxidase 4 (GPX4) expression. All of the above reactions generate a ROS storm in tumor cells for high-performance FT, which is demonstrated in cancer cells and tumor-bearing mice.

Nanoparticle-Based MRI-Guided Tumor Microenvironment Heating via the Synergistic Effect of Ferroptosis and Inhibition of TGF-ß Signaling.

Although induction of ferroptosis and inhibition of transforming growth factor-ß (TGF-ß) signaling are both effective ways to reform the tumor microenvironment (TME) and render low-immunogenic tumors responsive to immune checkpoint inhibitor therapy, dose-limiting side effects remain major obstacles hindering their clinical application. Herein, novel sorafenib and anti-TGF-ß antibody loaded Fe3 O4 /Gd2 O3 hybrid nanoparticles with conjugation of arginine-glycine-aspartic dimer (FeGd-HN@Sorafenib@TGF-ß-antibody@RGD2, FG-STR) are developed. Sorafenib significantly enhances FeGd-HN-triggered ferroptosis and improves maturation and phagocytosis of dendritic cells (DCs) by inducing damage-associated molecular patterns released from ferroptotic cancer cells, while the anti-TGF-ß antibody further synergizes with enhanced ferroptosis to promote DC maturation and the recruitment of CD8+ T cells, thus heating the TME. Moreover, the incorporation of RGD2 facilitates the uptake of the FG-STR in tumor cells which lead to a significant dosage reduction of both sorafenib and anti-TGF-ß antibody to avoid dose-limiting toxicities. Finally, in vitro and in vivo experiments show that FG-STR has significantly superior intrinsic magnetic resonance imaging (MRI) capability than that of Gadovist, effectively inhibits tumor growth and lung metastasis, and increases the efficacy of anti-programmed cell death-1 treatment. Taken together, this study provides a promising strategy for new advanced MRI-guided TME heating therapies.

A Strategy of Fenton Reaction Cycloacceleration for High-Performance Ferroptosis Therapy Initiated by Tumor Microenvironment Remodeling.

The emerging tumor ferroptosis therapy confronts impediments of the tumor microenvironment (TME) with weak intrinsic acidity, inadequate endogenous H2 O2 , and a powerful intracellular redox balance system that eliminates toxic reactive oxygen species (ROS). Herein, a strategy of Fenton reaction cycloacceleration initiated by remodeling the TME for magnetic resonance imaging (MRI)-guided high-performance ferroptosis therapy of tumors is proposed. The synthesized nanocomplex exhibits enhanced accumulation at carbonic anhydrase IX (CAIX)-positive tumors based on the CAIX-mediated active targeting, and increased acidification via the inhibition of CAIX by 4-(2-aminoethyl) benzene sulfonamide (ABS) (remodeling TME). This accumulated H+ and abundant glutathione in TME synergistically trigger biodegradation of the nanocomplex to release the loaded cuprous oxide nanodots (CON), ß-lapachon (LAP), Fe3+ , and gallic acid-ferric ions coordination networks (GF). The Fenton and Fenton-like reactions are cycloaccelerated via the catalytic loop of Fe-Cu, and the LAP-triggered and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase1-mediated redox cycle, generating robust ROS and plenitudinous lipid peroxides accumulation for ferroptosis of tumor cells. The detached GF network has improved relaxivities in response to the TME. Therefore, the strategy of Fenton reaction cycloacceleration initiated by remodeling the TME is promising for MRI-guided high-performance ferroptosis therapy of tumors.

Synergistic Functional Nanomedicine Enhances Ferroptosis Therapy for Breast Tumors by a Blocking Defensive Redox System.

The upregulation of dihydroorotate dehydrogenase (DHODH) redox systems inside tumor cells provides a powerful shelter against lipid peroxidation (LPO), impeding ferroptosis-induced antitumor responses. To solve this issue, we report a strategy to block redox systems and enhance ferroptotic cancer cell death based on a layered double hydroxide (LDH) nanoplatform (siR/IONs@LDH) co-loaded with ferroptosis agent iron oxide nanoparticles (IONs) and the DHODH inhibitor (siR). siR/IONs@LDH is able to simultaneously release IONs and siR in a pH-responsive manner, efficiently generate toxic reactive oxygen species (ROS) via an Fe2+-mediated Fenton reaction, and synergistically induce cancer cell death upon the acceleration of LPO accumulation. In vivo therapeutic evaluations demonstrate that this nanomedicine has excellent performance for tumor growth inhibition without any detectable side effects. This work thus provides a new insight into nanomaterial-mediated tumor ferroptosis therapy.

Improved cancer immunotherapy strategies by nanomedicine.

Cancer immunotherapy agents fight cancer via immune system stimulation and have made significant advances in minimizing side effects and prolonging the survival of patients with solid tumors. However, major limitations still exist in cancer immunotherapy, including the inefficiency of immune response stimulation in specific cancer types, therapy resistance caused by the tumor microenvironment (TME), toxicities by the immune imbalance, and short lifetime of stimulator of interferon genes (STING) agonist. Recent advances in nanomedicine have shown significant potential in overcoming the obstacles of cancer immunotherapy. Several nanoscale agents have been reported for cancer immunotherapy, including nanoscale cancer vaccines impacting the STING pathway, nanomaterials reprogramming TME, nano-agents triggering immune response with immune checkpoint inhibitor synergy, ferroptosis-mediated and indoleamine-2,3-dioxygenase immunosuppression-mediated cancer immunotherapy, and nanomedicine-meditated chimeric antigen receptor-T-cell therapy. Herein, we summarize the major advances and innovations in nanomedicine-based cancer immunotherapy, and outline the opportunities and challenges to integrate more advanced nanomaterials into cancer immunotherapy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Nanoprobes for Tumor Theranostics.

This Special Issue of Biosensors, entitled "Nanoprobes for Tumor Theranostics", aims to report the research progress of using nanoprobes for the diagnosis and therapy of tumors, and promote their applications [...].

Cycloacceleration of Reactive Oxygen Species Generation Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for Tumor Ferroptosis Therapy.

Because of the insufficiency of hydrogen peroxide, the relatively low rate of Fenton reaction, and the active glutathione (GSH) peroxidase 4 (GPX4) in tumor cells, it is difficult to achieve a desirable efficacy of ferroptosis therapy (FT) for tumors based on nanomaterials. Inspired by the concept of "cyclotron" in physics, in this study, a new concept of cycloacceleration of reactive oxygen species (ROS) generation in tumor cells to realize high-performance FT of tumors is proposed. Typically, a magnetic resonance imaging (MRI) contrast agent of dotted core-shell Fe3 O4 /Gd2 O3 hybrid nanoparticles (FGNPs) is prepared based on exceedingly small magnetic iron oxide nanoparticles (ES-MIONs). Sorafenib (SFN) is loaded and poly(ethylene glycol) methyl ether-poly(propylene sulfide)-NH2 (mPEG-PPS-NH2 ) is grafted on the surface of FGNP to generate SA-SFN-FGNP via self-assembly. The results of in vitro and in vivo demonstrate SA-SFN-FGNP can work with the acidic tumor microenvironment and endosomal conditions, Fenton reaction and system XC - , and generate cyclic reactions in tumor cells, resulting in specific cycloacceleration of ROS generation for high-performance FT of tumors. The very high longitudinal relaxivity (r1 , 33.43 mM-1 s-1 , 3.0 T) makes sure that the SA-SFN-FGNP can be used for MRI-guided FT of tumors.

Biodegradable and biocompatible exceedingly small magnetic iron oxide nanoparticles for T1-weighted magnetic resonance imaging of tumors.

Magnetic resonance imaging (MRI) has been widely using in clinical diagnosis, and contrast agents (CAs) can improve the sensitivity MRI. To overcome the problems of commercial Gd chelates-based T1 CAs, commercial magnetic iron oxide nanoparticles (MIONs)-based T2 CAs, and reported exceedingly small MIONs (ES-MIONs)-based T1 CAs, in this study, a facile co-precipitation method was developed to synthesize biodegradable and biocompatible ES-MIONs with excellent water-dispersibility using poly (aspartic acid) (PASP) as a stabilizer for T1-weighted MRI of tumors. After optimization of the synthesis conditions, the final obtained ES-MION9 with 3.7 nm of diameter has a high r1 value (7.0 ± 0.4 mM-1 s-1) and a low r2/r1 ratio (4.9 ± 0.6) at 3.0 T. The ES-MION9 has excellent water dispersibility because of the excessive -COOH from the stabilizer PASP. The pharmacokinetics and biodistribution of ES-MION9 in vivo demonstrate the better tumor targetability and MRI time window of ES-MION9 than commercial Gd chelates. T1-weighted MR images of aqueous solutions, cells and tumor-bearing mice at 3.0 T or 7.0 T demonstrate that our ES-MION9 has a stronger capability of enhancing the MRI contrast comparing with the commercial Gd chelates. The MTT assay, live/dead staining of cells, and H&E-staining indicate the non-toxicity and biosafety of our ES-MION9. Consequently, the biodegradable and biocompatible ES-MION9 with excellent water-dispersibility is an ideal T1-weighted CAs with promising translational possibility to compete with the commercial Gd chelates.

Corrigendum: PET/Ct Imaging of Activated Cancer-Associated Fibroblasts Predict Response to PD-1 Blockade in Gastric Cancer Patients.

[This corrects the article DOI: 10.3389/fonc.2021.802257.].

A tumor microenvironment dual responsive contrast agent for contrary contrast-magnetic resonance imaging and specific chemotherapy of tumors.

Development of magnetic resonance imaging (MRI) contrast agents (CAs) is still one of the research hotspots due to the inherent limitations of T1- or T2-weighted CAs and T1/T2 dual-mode CAs. To dramatically enhance the MRI contrast between tumors and normal tissues, we propose a new concept of contrary contrast-MRI (CC-MRI), whose specific definition is that CC-MRI CAs present a positive or negative signal at normal tissues, but show contrary signals at diseased tissues. To realize CC-MRI of tumors, we designed and developed a tumor microenvironment (TME) dual responsive CA (i.e., SA-FeGdNP-DOX@mPEG), which is almost not responsive under normal physiological conditions, but highly responsive to the acidic and reductive TME. Our SA-FeGdNP-DOX@mPEG shows a negative MRI signal under normal physiological conditions due to the high r2 value (336.9 mM-1 s-1) and high r2/r1 ratio (18.4), but switches to a positive MRI signal in the TME because of the high r1 value (20.32 mM-1 s-1) and low r2/r1 ratio (7.2). Our TME dual responsive SA-FeGdNP-DOX@mPEG significantly enhanced the contrast of MR images between tumors and livers, and the ΔSNR difference reached 501%. In addition, our SA-FeGdNP-DOX2@mPEG2 with tumor targetability and controlled DOX release responding to the TME was also used for tumor-specific chemotherapy with reduced side effects.