Highly-Efficient Gallium-Interference Tumor Therapy Mediated by Gallium-Enriched Prussian Blue Nanomedicine.

Prussian blue (PB)-based nanomedicines constructed from metal ion coordination remain restricted due to their limited therapeutic properties, and their manifold evaluation complexity still needs to be unraveled. Owing to the high similarities of its ionic form to iron (Fe) and the resulting cellular homeostasis disruption performance, physiologically unstable and low-toxicity gallium (Ga) has garnered considerable attention clinically as an anti-carcinogen. Herein, Ga-based nanoparticles (NPs) with diverse Ga contents are fabricated in one step using PB with abundant Fe sites as a substrate for Ga substitution, which aims to overcome the deficiencies of both and develop an effective nanomedicine. A systematic comparison of their physicochemical properties effectively reveals the saturated Ga introduction state during the synthesis process, further identifying the most Ga-enriched PB NPs with a substitution content of >50% as a nanomedicine for subsequent exploration. It is verified that the Ga interference mechanisms mediated by the most Ga-enriched PB NPs are implicated in metabolic disorders, ionic homeostasis disruption, cellular structure dysfunction, apoptosis, autophagy, and target activation of the mammalian target of the rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways. This study provides significant guidance on exploiting clinically approved agents for Ga interference and lays the foundation for the next generation of PB-based theranostic agents.

Gold nanorods with iron oxide dual-modal bioprobes in SERS-MRI enable accurate programmed cell death ligand-1 expression detection in triple-negative breast cancer.

The efficiency of immunotherapy for triple-negative breast cancer (TNBC) is relatively low due to the difficulty in accurately detecting immune checkpoints. The detection of TNBC-related programmed cell death ligand-1 (PD-L1) expression is important to guide immunotherapy and improve treatment efficiency. Surface-enhanced Raman spectroscopy (SERS) and magnetic resonance (MR) imaging exhibit great potential for early TNBC diagnosis. SERS, an optical imaging mode, has the advantages of high detection sensitivity, good spatial resolution, and "fingerprint" spectral characteristics; however, the shallow detection penetration of SERS bioprobes limits its application in vivo. MR has the advantages of allowing deep penetration with no radiation; however, its spatial resolution needs to be improved. SERS and MR have complementary imaging features for tumor marker detection. In this study, gold nanorod and ultrasmall iron oxide nanoparticle composites were developed as dual-modal bioprobes for SERS-MRI to detect PD-L1 expression. Anti-PD-L1 (aPD-L1) was utilized to improve the targeting ability and specificity of PD-L1 expression detection. TNBC cells expressing PD-L1 were accurately detected via the SERS imaging mode in vitro, which can image at the single-cell level. In addition, bioprobe accumulation in PD-L1 expression-related tumor-bearing mice was simply and dynamically monitored and analyzed in vivo using MR and SERS. To the best of our knowledge, this is the first time a SERS-MRI dual-modal bioprobe combined with a PD-L1 antibody has been successfully used to detect PD-L1 expression in TNBC. This work paves the way for the design of high-performance bioprobe-based contrast agents for the clinical immunotherapy of TNBC.

Dual-infinite coordination polymer-engineered nanomedicines for dual-ion interference-mediated oxidative stress-dependent tumor suppression.

Recently, nanomedicine design has shifted from simple nanocarriers to nanodrugs with intrinsic antineoplastic activities for therapeutic performance optimization. In this regard, degradable nanomedicines containing functional inorganic ions have blazed a highly efficient and relatively safe ion interference paradigm for cancer theranostics. Herein, given the potential superiorities of infinite coordination polymers (ICPs) in degradation peculiarity and functional integration, a state-of-the-art dual-ICP-engineered nanomedicine is elaborately fabricated via integrating ferrocene (Fc) ICPs and calcium-tannic acid (Ca-TA) ICPs. Thereinto, Fc ICPs, and Ca-TA ICPs respectively serve as suppliers of ferrous iron ions (Fe2+) and calcium ions (Ca2+). After the acid-responsive degradation of ICPs, released TA from Ca-TA ICPs facilitated the conversion of released ferric iron (Fe3+) from Fc ICPs into highly active Fe2+. Owing to the dual-path oxidative stress and neighboring effect mediated by Fe2+ and Ca2+, such a dual-ICP-engineered nanomedicine effectively induces dual-ion interference against triple-negative breast cancer (TNBC). Therefore, this work provides a novel antineoplastic attempt to establish ICP-engineered nanomedicines and implement ion interference-mediated synergistic therapy.

Navigating zinc-involved nanomedicine in oncotherapy.

Zinc (Zn), extolled as "the flower of life" in modern medicine, has been extensively highlighted with its physiological functions to maintain growth, development, and metabolism homeostasis. Driven by the substantial advancement of nanotechnology and oncology, Zn-involved nanomedicines integrating the intrinsic bioactivity of Zn species and the physiochemical attributes of Zn-composed nanosystems have blazed a highly efficient and relatively biosafe antineoplastic path. In this review, we aim to highlight and discuss the recent representative modalities of emerging Zn-involved oncology nanomedicine, mainly emphasizing the rational design, biological effect and biosafety, and therapeutic strategies. In addition, we provide the underlying critical obstacles and future perspectives of Zn-involved oncology nanomedicines, primarily focusing on the chances and challenges of clinical translation. Furthermore, we hope the review can give rise to opportunities within oncology nanomedicine and other biomedical fields, promoting the prosperity and progress of the "Zincic Age".

Multifunctional Modulation of High-Performance Znx Fe3-x O4 Nanoparticles by Precisely Tuning the Zinc Doping Content.

The possibility to precisely control important properties of nanoparticles (NPs) such as their size, morphology, surface charge, or doping content is crucial for enhancing the performance of existing solutions beyond the state-of-the-art and for enabling novel applications. In this work, custom-tailored Znx Fe3- x O4 NPs are synthesized at different Zn doping concentrations to augment and expand their usefulness for high-performance applications in nanomedicine. By precisely increasing the Zn2+ content in the range of 0 ≤ x ≤ 2.0, the discussed NPs can sequentially acquire valuable properties enabling magnetic resonance imaging, near-infrared (NIR) photothermal effects, NIR photocatalytic and photoelectric effects, depending on the variation of substitution position of the Zn2+ in the magnetite structure and the emergence of a ZnO/ZnFe2 O4 heterostructure at high doping concentrations. The presented work demonstrates and explainsa facile route for the synthesis and modulation of multifunctional nanomaterials with manifold roles in disease diagnostics and therapy, and provides helpful guidance in designing divalent transition metal ion-doped nanomaterials.

Controllable synthesis of layered black bismuth oxidechloride nanosheets and their applications in internal tumor ablation.

The recently emerging bismuth oxyhalide (BiOX) nanomaterials are promising indirect band gap photosensitizer for ultraviolet (UV) light-triggered phototherapy due to their unique layered nanosheet structure. However, the low absorption and poor photothermal conversion efficiency have always impeded their further applications in cancer clinical therapy. Herein, BiOCl rich in oxygen vacancies has been reported to have full-spectrum absorption properties, making it possible to achieve photothermal property under near-infrared laser. Under 808 nm irradiation, the photothermal conversion efficiency of black BiOCl nanosheets (BBNs) is up to 40%. BBNs@PEG can effectively clear primary subcutaneous tumors and prevent recurrence, achieving good synergistic treatment effect. These results not only broke the limitation of UV on the BiOCl material and provided a good template for other semiconductor materials, but also represent a promising approach to fabricate BBN@PEG a novel, potent and multifunctional theranostic platform for precise photothermal therapy and prognostic evaluation.

An intelligent tumor microenvironment responsive nanotheranostic agent for T1/T2 dual-modal magnetic resonance imaging-guided and self-augmented photothermal therapy.

Photothermal therapy (PTT), as a promising antineoplastic therapeutic strategy, has been harnessed to restrain tumor growth through near-infrared (NIR) irradiation mediated thermal ablation. Nevertheless, its biological applications are hampered by thermal diffusion and up-regulated heat shock proteins (HSPs). Herein, a versatile nanotheranostic agent is developed via integrating Zn0.2Fe2.8O4 nanoparticles (NPs), polydopamine (PDA), and MnO2 NPs for T1/T2 dual-modal magnetic resonance (MR) imaging-guided and self-augmented PTT. The as-designed Zn0.2Fe2.8O4@PDA@MnO2 NPs adequately serve as a PTT agent to realize effective photothermal conversion and obtain local hyperthermia. Additionally, the Zn0.2Fe2.8O4@PDA@MnO2 NPs can significantly consume overexpressed glutathione (GSH) and generate Mn2+ in the tumor microenvironment (TME), thus destroying redox homeostasis and catalytically generating hydroxyl radicals (˙OH) for HSP suppression and PTT enhancement. Meanwhile, Mn2+ and Zn0.2Fe2.8O4 NPs significantly strengthen T1- and T2-weighted MR contrast for tumor imaging and PTT guidance. Hence, this study offers proof of concept for self-augmented PTT and T1/T2 dual-modal MR imaging for tumor elimination.

An intelligent T1-T2 switchable MRI contrast agent for the non-invasive identification of vulnerable atherosclerotic plaques.

Unlike stable atherosclerotic plaques, vulnerable plaques are very likely to cause serious cardio-cerebrovascular diseases. Meanwhile, how to non-invasively identify vulnerable plaques at early stages has been an urgent but challenging problem in clinical practices. Here, we propose a macrophage-targeted and in situ stimuli-triggered T1-T2 switchable magnetic resonance imaging (MRI) nanoprobe for the non-invasive diagnosis of vulnerable plaques. Precisely, single-dispersed iron oxide nanoparticles (IONPs) modified with hyaluronic acid (HA), denoted as IONP-HP, show macrophage targetability and T1 MRI enhancement (r2/r1 = 3.415). Triggered by the low pH environment of macrophage lysosomes, the single-dispersed IONP-HP transforms into a cluster analogue, which exhibits T2 MRI enhancement (r2/r1 = 13.326). Furthermore, an in vivo switch of T1-T2 enhancement modes shows that the vulnerable plaques exhibit strong T1 enhancement after intravenous administration of the nanoprobe, followed by a switch to T2 enhancement after 9 h. In contrast, stable plaques show only slight T1 enhancement but without T2 enhancement. It is therefore imperative that the intelligent and novel nanoplatform proposed in this study achieves a substantial non-invasive diagnosis of vulnerable plaques by means of a facile but effective T1-T2 switchable process, which will significantly contribute to the application of materials science in solving clinical problems.

Metal-Free Organo-Theranostic Nanosystem with High Nitroxide Stability and Loading for Image-Guided Targeted Tumor Therapy.

The desire for all-organic-composed nanoparticles (NPs) of considerable biocompatibility to simultaneously diagnose and treat cancer is undeniably interminable. Heretofore, metal-based agents dominate the landscape of available magnetic resonance imaging (MRI) contrast agents and photothermal therapeutic agents, but with associated metal-specific downsides. Here, an all-organic metal-free nanoprobe, whose appreciable biocompatibility is synergistically contributed by its tetra-organo-components, is developed as a viable alternative to metal-based probes for MRI-guided tumor-targeted photothermal therapy (PTT). This rationally entails a glycol chitosan (GC)-linked polypyrrole (PP) nanoscaffold that provides abundant primary and secondary amino groups for amidation with the carboxyl groups in a nitroxide radical (TEMPO) and folic acid (FA), to obtain GC-PP@TEMPO-FA NPs. Advantageously, the appreciably benign GC-PP@TEMPO-FA features high nitroxide loading (r1 = 1.58 mM-1 s-1) and in vivo nitroxide-reduction resistance, prolonged nitroxide-systemic circulation times, appreciable water dispersibility, potential photodynamic therapeutic and electron paramagnetic resonance imaging capabilities, considerable biocompatibility, and ultimately achieves a 17 h commensurate MRI contrast enhancement. Moreover, its GC component conveys a plethora of PP to tumor sites, where FA-mediated tumor targeting enables substantial NP accumulation with consequential near-complete tumor regression within 16 days in an MRI-guided PTT. The present work therefore promotes the engineering of organic-based metal-free biocompatible NPs in synergism, in furtherance of tumor-targeted image-guided therapy.

Maltodextrin-Conjugated Gd-Based MRI Contrast Agents for Specific Diagnosis of Bacterial Infections.

Bacterial infections are one of the most serious health risks worldwide, and their rapid diagnosis remains a major challenge in clinic. To enhance the relaxivity and bacterial specificity of magnetic resonance imaging (MRI) contrast agents, here, a kind of gadolinium-based nanoparticles (NPs) of impressive biocompatibility is constructed as a contrast agent for maltodextrin-mediated bacteria-targeted diagnosis. To realize this, positively charged ultrasmall gadolinium oxide (Gd2O3, 2-3 nm) NPs are embedded in mesoporous silica NPs (MSN) with pore size around 6.38 nm. The resulting Gd2O3@MSN exhibits enhanced r1 value and T1-weighted MRI performance. Interestingly, upon conjugation of Gd2O3@MSN with maltodextrin to produce Gd2O3@MSN-Malt NPs, a remarkable decrease in internalization by osteosarcoma cells, alongside an increased adsorption toward E. coli and S. aureus, is achieved. It is therefore conceivable that the bacteria-targeted Gd2O3@MSN-Malt might be a promising MRI contrast agent for effective discrimination of bacterial infections from tumor.

pH-Responsive metal-organic framework encapsulated gold nanoclusters with modulated release to enhance photodynamic therapy/chemotherapy in breast cancer.

Gold nanoclusters (AuNCs) with an ultra-small size, as new inorganic photosensitizers, have been shown to be promising in photodynamic therapy (PDT), but their application has been restricted due to short blood circulation. It is therefore important to develop stimuli-responsive AuNC-based nanoprobes to achieve highly efficient PDT. Here, metal-organic framework (MOF, ZIF-8) encapsulated AuNCs (AuNCs@MOF) were synthesized, and then they were loaded with doxorubicin (DOX) to obtain pH-responsive nanoprobes (AuNCs@MOF-DOX) with modulated release for enhanced PDT/chemotherapy. In an acidic tumor microenvironment, the structure of ZIF-8 collapsed, accelerating the release of the AuNCs and DOX in the tumor cells, and enhancing the performance of PDT/chemotherapy. Under irradiation with a 670 nm laser, a large amount of singlet oxygen was generated, and the release rate of DOX increased to 77.1% at a pH value of 5.5. By single PDT and single chemotherapy, the tumors were only partially inhibited, but they completely disappeared using the combination of PDT and chemotherapy. The prepared pH-responsive AuNCs@MOF-DOX nanoprobes with modulated release showed excellent PDT/chemotherapy performance, and will be important bi-functional nanoprobes for synergistic therapy.

Radiosensitizing Effect of Gadolinium Oxide Nanocrystals in NSCLC Cells Under Carbon Ion Irradiation.

Gadolinium-based nanomaterials can not only serve as contrast agents but also contribute to sensitization in the radiotherapy of cancers. Among radiotherapies, carbon ion irradiation is considered one of the superior approaches with unique physical and biological advantages. However, only a few metallic nanoparticles have been used to improve carbon ion irradiation. In this study, gadolinium oxide nanocrystals (GONs) were synthesized using a polyol method to decipher the radiosensitizing mechanisms in non-small cell lung cancer (NSCLC) cell lines irradiated by carbon ions. The sensitizer enhancement ratio at the 10% survival level was correlated with the concentration of Gd in NSCLC cells. GONs elicited an increase in hydroxyl radical production in a concentration-dependent manner, and the yield of reactive oxygen species increased obviously in irradiated cells, which led to DNA damage and cell cycle arrest. Apoptosis and cytostatic autophagy were also significantly induced by GONs under carbon ion irradiation. The GONs may serve as an effective theranostic material in carbon ion radiotherapy for NSCLC.

A pH-sensitive polymer based precise tumor targeting strategy with reduced uptake of nanoparticles by non-cancerous cells.

Drug-loaded nanoparticles can be specifically uptaken by tumor cells to realize active targeting due to the conjugated ligands or antibodies on their surface. However, some non-cancerous cells express non-specific receptors or antigens on their surface, which can react with the ligands or antibodies conjugated on the nanoparticle surface and then result in non-specific uptake of the nanoparticles by non-cancerous cells. In order to reduce the non-specific uptake of nanoparticles by non-cancerous cells, in this study, we proposed a pH-sensitive polymer based precise tumor targeting strategy and synthesized superparamagnetic iron oxide nanoparticle (SPION) encapsulated albumin nanoparticles (AN) with conjugation of folic acid (FA) and mPEG-DCA (SPION-AN-FA@mPEG), in which mPEG can shield FA, avoiding the non-specific recognition by normal cells under physiological conditions, and can be shed to expose FA in tumor microenvironments. The pH-sensitivity of mPEG-DCA was verified by HPLC characterization and 1H-NMR spectroscopy. The graft density and length of mPEG-DCA were optimized via the cellular uptake of SPION-AN-FA@mPEG measured by flow cytometry analysis. The r2 value and r2/r1 ratio of the optimized SPION-AN-FA@mPEG (i.e., SPION-AN-FA@mPEG4) are 168.6 mM-1 s-1 and 42.8, respectively, which are both much higher than that of the commercial contrast agent Resovist®. The in vitro T2-weighted MR images and in vivo MRI performance demonstrate that our SPION-AN-FA@mPEG4 nanoparticles can be used as an effective T2-weighted MRI contrast agent.

Engineered nano-immunopotentiators efficiently promote cancer immunotherapy for inhibiting and preventing lung metastasis of melanoma.

Malignant melanoma, one of the most aggressive types of cancer easily metastasizes, making it extremely difficult to treat and unresponsive to current therapies. Recent breakthroughs in nanomaterials-based cancer immunotherapy have provided potential specific strategy for tumor and metastasis inhibition. With the development of nanotechnology, inorganic nanomaterials have been increasingly studied for their potential cancer therapeutic and molecular imaging functions. However, only iron-based nanomaterials have been approved by the Food and Drug Administration (FDA) in inorganic nanomedicines. For promising clinical application, a new type of nanocomposite is engineered by combining ultra-small iron oxide nanoparticles (Fe3O4 NPs) and ovalbumin (OVA), denoted as Fe3O4-OVA nanocomposites in this study. Interestingly, this is the first time that Fe3O4 NPs are found as nano-immunopotentiators helping nanocomposites efficiently stimulate dendritic cell-based immunotherapy and potentially-activate macrophages. These nanocomposites efficiently stimulate the maturation level of bone marrow derived dendritic cell (BMDCs) and corresponding activation of T cells and also potentially-activate macrophages. With the help of the Fe3O4 nano-immunopotentiators (Fe3O4 NPs), this therapeutic and prophylactic Fe3O4-OVA vaccine can not only efficiently inhibit the subcutaneous and metastatic B16-OVA tumor growth but also successfully prevent the formation of subcutaneous and metastatic tumor, providing a promising strategy for expanding the clinical use of Fe-based nanomaterials.

Colorimetric detection of Ba2+, Cd2+ and Pb2+ based on a multifunctionalized Au NP sensor.

In this work, we developed a colorimetric method for the detection of three kinds of ions with one kind of detection reagent. In detail, gold nanoparticles (Au NPs) multifunctionalized with 3-mercaptonicotinic acid and 4-aminobenzo-18-crown-6 (3-MPA-abc) were prepared and used as a colorimetric sensor for the simple and rapid detection of Ba2+, Cd2+ and Pb2+ ions. After adding Ba2+/Cd2+/Pb2+, the oxygen atom in the crown ether cavity and the carboxyl group of 3-mercaptopropionic acid can react with Ba2+/Cd2+/Pb2+ to form coordination bonds, resulting in the aggregation of the functionalized Au NPs and the color change of Au NP solution. The LOD of the colorimetric sensor for Ba2+/Cd2+/Pb2+ is 20 nM, 20 nM and 50 nM by the naked eye, respectively. A good linear relationship (R2 = 0.9984, R2 = 0.9917, R2 = 0.9934) between the absorbance ratio and Ba2+/Cd2+/Pb2+ concentrations indicates that our Au NP based colorimetric sensor can be used for the quantitative assay of Ba2+/Cd2+/Pb2+, and this detection method was successfully applied in the detection of Ba2+/Cd2+/Pb2+ in real environmental samples.

Ultra-small gadolinium oxide nanocrystal sensitization of non-small-cell lung cancer cells toward X-ray irradiation by promoting cytostatic autophagy.

BACKGROUND: Gadolinium-based nanoparticles (GdNPs) have been used as theranostic sensitizers in clinical radiotherapy studies; however, the biomechanisms underlying the radio-sensitizing effects of GdNPs have yet to be determined. In this study, ultra-small gadolinium oxide nanocrystals (GONs) were employed to investigate their radiosensitizing effects and biological mechanisms in non-small-cell lung cancer (NSCLC) cells under X-ray irradiation. METHOD AND MATERIALS: GONs were synthesized using polyol method. Hydroxyl radical production, oxidative stress, and clonogenic survival after X-ray irradiation were used to evaluate the radiosensitizing effects of GONs. DNA double-strand breakage, cell cycle phase, and apoptosis and autophagy incidences were investigated in vitro to determine the radiosensitizing biomechanism of GONs under X-ray irradiation. RESULTS: GONs induced hydroxyl radical production and oxidative stress in a dose- and concentration-dependent manner in NSCLC cells after X-ray irradiation. The sensitizer enhancement ratios of GONs ranged between 19.3% and 26.3% for the NSCLC cells under investigation with a 10% survival rate compared with that of the cells treated with irradiation alone. Addition of 3-methyladenine to the cell medium decreased the incidence rate of autophagy and increased cell survival, supporting the idea that the GONs promoted cytostatic autophagy in NSCLC cells under X-ray irradiation. CONCLUSION: This study examined the biological mechanisms underlying the radiosensitizing effects of GONs on NSCLC cells and presented the first evidence for the radiosensitizing effects of GONs via activation of cytostatic autophagy pathway following X-ray irradiation.

ZD2-Engineered Gold Nanostar@Metal-Organic Framework Nanoprobes for T1 -Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple-Negative Breast Cancer.

Compared with other subtypes of breast cancer, triple-negative breast cancer (TNBC) is seriously threatening to human life. Therefore, it is a matter of urgency to develop multifunctional nanoprobes for visualized theranostics of TNBC, achieving specific targeting toward only TNBC, but not other subtypes. Nanoscale metal-organic frameworks (MOFs) show important potential in visualized theranostics of tumors, but it is critical to synthesize well-defined core-shell MOF-based nanocomposites by encapsulating a single nanoparticle within MOF. In this study, a TNBC-targeted peptide (ZD2)-engineered, and a single gold nanostar (AuNS) coated within MIL-101-NH2 (Fe) by coating MOF with four cycles, obtain well-defined core-shell AuNS@MOF-ZD2 nanocomposites, which are expected to achieve T1 -weighted magnetic resonance imaging and photothermal therapy (PTT) specifically targeting toward TNBC. The prepared AuNS@MOF-ZD2 nanocomposites possess good biocompatibility, efficient T1 -weighted magnetic resonance (MR) relaxivity and stable photothermal conversion ability with an efficiency of 40.5%. The in vitro and in vivo characterizations prove their performances of T1 -weighted MR and PTT with a low power density of 808 nm laser, achieving excellent theranostic efficacy in TNBC. Importantly, it is demonstrated that the prepared AuNS@MOF-ZD2 nanoprobes can specifically target TNBC cells (MDA-MB-231), but not other subtypes of breast cancer cells (MDA-MB-435, MDA-MB-468, and MCF-7), indicating their promising application in visualized theranostics of breast cancers with molecular classification.

Fenton-Reaction-Acceleratable Magnetic Nanoparticles for Ferroptosis Therapy of Orthotopic Brain Tumors.

Cancer is one of the leading causes of morbidity and mortality in the world, but more cancer therapies are needed to complement existing regimens due to problems of existing cancer therapies. Herein, we term ferroptosis therapy (FT) as a form of cancer therapy and hypothesize that the FT efficacy can be significantly improved via accelerating the Fenton reaction by simultaneously increasing the local concentrations of all reactants (Fe2+, Fe3+, and H2O2) in cancer cells. Thus, Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin (CDDP)-loaded Fe3O4/Gd2O3 hybrid nanoparticles with conjugation of lactoferrin (LF) and RGD dimer (RGD2) (FeGd-HN@Pt@LF/RGD2), were exploited in this study for FT of orthotopic brain tumors. FeGd-HN@Pt@LF/RGD2 nanoparticles were able to cross the blood-brain barrier because of its small size (6.6 nm) and LF-receptor-mediated transcytosis. FeGd-HN@Pt@LF/RGD2 can be internalized into cancer cells by integrin αvß3-mediated endocytosis and then release Fe2+, Fe3+, and CDDP upon endosomal uptake and degradation. Fe2+ and Fe3+ can directly participate in the Fenton reaction, whereas the CDDP can indirectly produce H2O2 to further accelerate the Fenton reaction. The acceleration of Fenton reaction generates reactive oxygen species to induce cancer cell death. FeGd-HN@Pt@LF/RGD2 successfully delivered reactants involved in the Fenton reaction to the tumor site and led to significant inhibition of tumor growth. Finally, the intrinsic magnetic resonance imaging (MRI) capability of the nanoparticles was used to assess and monitor tumor response to FT (self-MRI monitoring).

Dotted Core-Shell Nanoparticles for T1 -Weighted MRI of Tumors.

Gd-based T 1 -weighted contrast agents have dominated the magnetic resonance imaging (MRI) contrast agent market for decades. Nevertheless, they are reported to be nephrotoxic and the U.S. Food and Drug Administration has issued a general warning concerning their use. In order to reduce the risk of nephrotoxicity, the MRI performance of the Gd-based T 1 -weighted contrast agents needs to be improved to allow a much lower dosage. In this study, novel dotted core-shell nanoparticles (FeGd-HN3-RGD2) with superhigh r 1 value (70.0 mM-1 s-1 ) and very low r 2 /r 1 ratio (1.98) are developed for high-contrast T 1 -weighted MRI of tumors. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and histological analyses show good biocompatibility of FeGd-HN3-RGD2. Laser scanning confocal microscopy images and flow cytometry demonstrate active targeting to integrin αv ß3 positive tumors. MRI of tumors shows high tumor ΔSNR for FeGd-HN3-RGD2 (477 ± 44%), which is about 6-7-fold higher than that of Magnevist (75 ± 11%). MRI and inductively coupled plasma results further confirm that the accumulation of FeGd-HN3-RGD2 in tumors is higher than liver and spleen due to the RGD2 targeting and small hydrodynamic particle size (8.5 nm), and FeGd-HN3-RGD2 is readily cleared from the body by renal excretion.

Y1-receptor-ligand-functionalized ultrasmall upconversion nanoparticles for tumor-targeted trimodality imaging and photodynamic therapy with low toxicity.

Achieving efficient photodynamic therapy (PDT) in deeper biological tissue is still the biggest bottleneck that limits its widespread application in clinic. Although deeper biological tissue PDT could be realized through a combination of upconversion nanoparticles with a photosensitizer, issues with particle-size-induced upconversion fluorescence (UF) reduction and the related in vivo toxicity still cannot be solved properly. In this study, we synthesized Y1Rs-ligand [Pro30, Nle31, Bpa32, Leu34]NPY(28-36) (NPY)-modified and photosensitizer MC540-loaded LiLuF4:Yb,Er@nLiGdF4@mSiO2 multifunctional nanocomposites (MNPs) with a core-multishell structure and ultrasmall size. Their in vitro and in vivo breast tumor targeting, trimodality imaging performance, PDT therapeutic efficacy, and acute toxicity were evaluated. Our results demonstrated that the core-multishell MNPs(MC540) could achieve excellent UF imaging, and that doping with Gd3+ and Lu3+ rare earth ions could enhance the MR and CT imaging performance. In addition, the mSiO2 shell provided a higher loading rate for the photosensitizer MC540, and the DSPE-PEG thin layer coating outside the MNPs(MC540) further improved the water solubility and biocompatibility, reducing the acute toxicity of the nanocomposites. Finally, the NPY modification enhanced the targetability of MNPs(MC540)/DSPE-PEG-NPY to breast tumors, improving the trimodality UF, CT, and MR imaging performance and PDT efficacy for Y1-receptor-overexpressed breast cancer. In general, our developed multifunctional nanocomposites can serve as a theranostic agent with low toxicity, providing great potential for their use in clinical breast cancer diagnosis and therapy.