Search

Oxygen is known as an irreplaceable gas in the lives of most eukaryotic cells, yet researchers underestimate its importance, as in the case in many studies of tumors. The variable oxygen content of malignant solid tumors increases the difficulty of treatment. Thus, it could be reasonably inferred that the tumor oxygen microenvironment, if efficiently and completely regulated, could bring certain changes to existing therapies. Based on this speculation, an acid-responsive, oxygen-scavenging and anaerobic-sensitizing nanoparticle was designed to regulate the oxygen level of solid tumor by creating an artificial anaerobic environment in our study. The Mg2Si core, which acted as a deoxygenating agent, was able to consume tumor oxygen and cause cell dormancy, while the incorporated hydrophobic tirapazamin (TPZ) helped to kill the now-dormant tumor cells. This simple and nontoxic nanoparticle achieved controllable factitious anaerobic circumstance in solid tumor for the first time, displaying the considerable potential and promising application of tumor gaseous microenvironment regulation therapy.

The "partial matching" between upconversion nanoparticle (UCNP) emission and absorption by photosensitizers (PSs) often leads to a theoretically reduced therapeutic efficiency in UC-based photodynamic therapy (PDT) strategies in which the chosen PSs have limited capabilities and are unable to utilize all the near-infrared-upconverted light. In this study, needle-like SnWO4 nanocrystals (SWs) with a broad UV-vis absorption region were synthesized to solve the problem. After covalent conjugation with UCNPs, all the UCNP-emitted light was effectively absorbed by SWs, triggering the type-I PDT process to activate ROS maxima. The unique nanostructure of the as-formed UCNP-SnWO4 nanohybrids (USWs) also enhanced the receiving light intensities of SW, which further boosted the antitumor efficacy. Meanwhile, the strong X-ray attenuation capacity of both tungsten and tin elements qualified the USWs as excellent radio-sensitizers for radiotherapy (RT) enhancement, which played a complementary role with PDT treatment because PDT-mediated induction arrested the cells in the G0-G1 cell cycle phase, and RT was more damaging toward cells in the G2/M phase. The remarkably enhanced UC-PDT/RT efficiency of USWs was next validated in vitro and in vivo, and the combined NIR light and ionizing irradiation treatment completely suppressed tumor growth, revealing its great potential as an efficient anticancer therapeutic agent against solid tumors.

The strong dependence on oxygen level, low ultraviolet/visible (UV/vis) light penetration depth and the extremely short lifetime of reactive oxygen species (ROS) are the major challenges of photodynamic therapy (PDT) for tumors. Fenton reaction can produce abundant ROS such as reactive hydroxyl radicals (OH) with significantly higher oxidation performance than singlet oxygen (1O2), which, however, has been rarely used in biomedical fields due to strict reaction conditions (favorably in pH range of 3–4, mostly under UV/vis light catalysis). Herein we propose and demonstrate a photochemotherapy (PCT) strategy of cancer therapy using near-infrared (NIR)-assisted tumor-specific Fenton reactions. NIR light-upconverted UV/vis light by upconversion nanoparticles (UCNPs) catalyze the intra-mitochondrial Fenton reaction between the delivered Fe2+ and H2O2 species over-expressed in cancer cell's mitochondria to in-situ kill the cancer cells. The intra-mitochondrial ROS generation of enabled by directly targeting the mitochondrial DNA (mtDNA) helix minimized the distance between the ROS and mtDNA molecules, thus the present PCT strategy showed much enhanced and tumor-specific therapeutic efficacy, as demonstrated by the intratumoral-accelerated OH burst and elevated cytotoxicity. Following the direct intratumoral injection, the PCT revealed marked tumor regression effect in vivo. This constructed PCT-agent is the first paradigm of NIR-upconversion catalyzed intra-mitochondrial Fenton reaction in response to tumoral microenvironment, establishing a novel photochemotherapy strategy for efficient cancer therapy.

The stability and safety of magnetic resonance imaging (MRI) contrast agents (CAs) are crucial for accurate diagnosis and real-time monitor of tumor development. Paramagnetic Mn

Glutathione (GSH) plays a vital role in maintaining biological redox homeostasis. Accordingly, accurate imaging of glutathione in vivo is of great significance. Herein, we propose a magnetic resonance energy transfer (MRET) strategy based on a distance-dependent magnetic exchange coupling effect (MECE), which can realize GSH detection within tumors in vivo by susceptibility weighted imaging (SWI). Fe3O4 nanoparticles (NPs) and CoFe2O4 NPs linked with cystamine (Fe3O4-S-S-CoFe2O4) have been successfully designed as SWI nanoprobes. After the disulfide bonds are broken by excess GSH in the tumor, the increase in the distance between Fe3O4 NPs and CoFe2O4 NPs will induce a decrease of MECE and magnetic susceptibility. As a result, the changes in the SWI signals are used for tumor GSH detection in vivo. Experimental results in vitro and in vivo demonstrate that the Fe3O4-S-S-CoFe2O4 SWI nanoprobe can sensitively detect concentrations of GSH in tumors. Hence, this strategy not only improves the sensitivity of the GSH response in SWI but also provides a powerful basis for the design of other responsive functional MRI nanoprobes.

As a distinct feature of Alzheimer's disease (AD), the presence of excess metal ions in the brain is most probably one of the main causative factors for the aggregation of β-Amyloid (Aβ) proteins. The design of nanoprobes for detection and control of ion concentrations will be of great importance in predicting the progression of AD and simultaneously providing effective treatments. Herein, we report the design and synthesis of a novel yet smart nanoprobe that can sensitively detect the Cu 2+ concentration and concurrently capture Cu 2+ both in vitro and in vivo . The designed nanoprobe (UCHQ) combines two main components: upconversion nanoparticles (UCNPs) used for the detection and upconversion luminescence (UCL) imaging of Cu 2+ upon 980 nm exposure and the chelator 8-hydroxyquinoline-2-carboxylic acid (HQC) used for chelating Cu 2+ and AD therapy. The results show that the emission intensity of UCHQ is highly dependent on the Cu 2+ concentrations due to the luminescence resonance energy transfer (LRET) from UCNPs to HQC-bonded Cu 2+ . Fascinatingly, the as-constructed UCHQs could be used for UCL imaging of Aβ both in cells and AD mice. Most importantly, UCHQs could not only inhibit the Aβ aggregation-induced apoptosis via capturing overmuch Cu 2+ but also accelerate the nontoxic structural transformation of Aβ.

CT angiography (CTA) and CT perfusion (CTP) imaging can play important roles in the workup of acute ischemic stroke. However, these techniques are hindered by the large amounts of contrast agents (CAs) required, high doses of X-ray radiation exposure, and nephrotoxicity of the clinical used iodinated CAs. To address these problems, we synthesized and validated a novel class of CT CAs, PEGylated BaHoF5 nanoparticles (NPs), for CTA and CTP imaging, which can greatly enhance the diagnostic sensitivity and accuracy of ischemic stroke. These agents have unique advantages over conventional iodinated CT agents, including much lower dosage required, major metabolism through liver and better imaging efficiency at different voltages. Once translated, these PEGylated BaHoF5 NPs can replace iodine-based CAs for diagnostic contrast-enhanced imaging of patients with kidney/heart diseases and improve the overall diagnostic index with negligible side effects.

Currently, reactive oxygen species (ROS)-induced apoptosis systems have drawn increasing attention in cancer therapy, owing to their specific tumor inhibition ability and great biocompatibility. Herein, we developed a highly dispersed nano-enzyme based on the assembly of natural glucose oxidase (GOD) onto CoFe-layered double hydroxides (CoFe-LDHs) monolayer nanosheets. By virtue of the high dispersion of Fe3+ within the host layer, the CoFe-LDHs nanosheets exhibit a collaborative enhanced Fenton catalytic activity with a rate constant of 3.26 × 10−4 s−1, which is 1–3 orders of magnitude higher than other iron-containing Fenton reaction agents. Subsequently, with a massive H2O2 triggered by GOD, GOD/CoFe-LDHs nanohybrid converts a cascade of glucose into hydroxyl radicals under tumor acid conditions, which is validated by a high maximum velocity (Vmax = 2.23 × 10−6 M) and low Michaelis–Menten constant (KM = 5.40 mM). Through the intracellular catalytic Fenton reaction within the tumor environment, both in vitro and in vivo results demonstrate the excellent antitumor effect of GOD/CoFe-LDHs. Therefore, a self-supplied, ultra-efficient and sequential catalytic tumor-specific therapy has been achieved based on GOD/CoFe-LDHs nano-enzyme, which holds great promise in clinical cancer therapy with minimum side effects.

The stability and safety of magnetic resonance imaging (MRI) contrast agents (CAs) are crucial for accurate diagnosis and real-time monitor of tumor development. Paramagnetic Mn2+ as nonlanthanide metal ion has been widely studied for use in T1-MRI CAs, but unfortunately, Mn2+ can be oxidized by H2O2 in tumor to nonparamagnetic Mn4+ via a Fenton-like reaction. The concurrent loss of paramagnetism and production of toxic hydroxyl radical ( OH) go against the basic requirment of CAs, thus restricting the further development of Mn2+-based CAs. Based on the different standard potential of W6+/W5+ (~0.26 V) and Mn4+/Mn2+ (~1.2 V), a “cathodic protection” strategy was exploited in Mn2+-doped NaxWO3 nanorods (NaxMnWO3), with W5+ as the sacrificial anode and Mn2+ as the protected cathode, to protect Mn2+ from oxidation in tumor for stable MR contrast performance, as well as repress its Fenton-like reaction activity for good biosafety. Moreover, the tungsten bronze crystal structure endows NaxMnWO3 with excellent near-infrared (NIR)-photothermal properties for effective tumor hyperthermia, without effect from the changed oxidation state of W. This “cathodic protection” strategy offers a new method for the development of reliable and hypotoxic biomaterials for stable imaging and therapeutic applications in clinic.

Accurate and noninvasive monitoring of nanoparticles' (NPs) distribution and metabolism in organism is important, especially for NPs at low-dosage, but remains challenging due to the insufficient sensitivity and resolution of the existing imaging techniques. Herein, Fe3O4 NPs with different sizes were synthesized for low-dosage NPs' metabolism study with susceptibility weighted imaging (SWI) technique. SWI, as a functional MRI technique with phase postprocessing, can sensitively detect the differences of magnetic susceptibilities between tissues, so can measure the Fe3O4 contents even at low dosage in tissues. After in vivo intravenous injection, Fe3O4 NPs could be visually distinguished in major organs (kidney, liver, spleen) by SWI, and the corresponding content changes over time were also sensitively detected, but cannot be achieved via the conventional T2-weighted imaging (T2WI). With the SWI technique, the metabolic pathways of Fe3O4 NPs in body were mapped, revealing the critical dependence on the sizes of NPs. This is significant for the assessment of NPs' metabolic time, toxicity risk, and application potentiality. Undoubtedly, SWI is a powerful tool for real-time metabolism low-dose NPs with designed characteristics (shapes, sizes, surface properties, etc.), and noninvasive detection of targets with magnetic nano-sensors in vivo.

Hypoxia, as an inevitable characteristic of solid tumors, has been regarded as a noticeably causative factor to therapeutic resistance and metastatic variants. Exploring novel theranostics to realize the accurate diagnosis of hypoxia and the simultaneous implementation of effective therapy is a promising prospect for the successful treatment of tumors. In the present study, we designed and synthesized a multifunctional rattle-structured nanotheranostic, with the inner core coated by hollow mesoporous silica for chemical drug Doxorubicin (DOX) storage and hypoxia-sensitive MnO2 enrichment. In various acidic micro-environments caused by hypoxia, MnO2 nanosheets could be degraded into manganese ions (Mn2+), which were chelated by the modified Tetraxetanum (DOTA) ligands for real-time T1-magnetic resonance imaging (T1-MRI), with on-demand DOX release to realize both normoxia and hypoxia-sensitive chemotherapy by overcoming hypoxia. Nanotheranostics integrating hypoxia-driven T1-MRI with synergetic chemotherapy have tremendous potential in the intelligent diagnosis, personalized treatment and excellent prognosis of solid tumors in the future.

Tumor resistance to ionizing irradiation and cancer cell's metastasis stimulated by radiation often lead to anti-cancer failure, and can be negatively caused by a key role--cellular hypoxia. In this regard, the exploitation of hypoxia-specific cytotoxic agents which assist to potentiate the anti-tumor effect of radiotherapy (RT) as well as efficiently counteract radiation-/hypoxia-induced cancer cell metastasis, becomes especially important, but has been widely overlooked. Herein, a core/shell-structured multifunctional nanoradiosensitizer with upconversion nanoparticle (UCNP) as an inside core, mesoporous silica as the shell and a cavity in between, has been constructed, in which UCNP core serves as radiation dose amplifiers and bio-reductive pro-drug--tirapazamine (TPZ) loaded in cavity is an hypoxia-selective cytotoxin and the silica shell provides the protection and diffusion path for TPZ. Such nanoradiosensitizer has been employed to inhibit the hypoxia-reoxygenation and the subsequent replication of cancer cells that often occurs after a single unaccompanied RT at low doses, and to silence the expression of transcription factors that support the progression of malignancy in cancer. This study confirms the radiotherapeutic benefits of utilizing nanoradiosensitizer as adjuvant to low-dose RT, and the results demonstrate the highly efficient hypoxia-specific killing in oxygen-dependent anti-tumor therapies.

The "partial matching" between upconversion nanoparticle (UCNP) emission and absorption by photosensitizers (PSs) often leads to a theoretically reduced therapeutic efficiency in UC-based photodynamic therapy (PDT) strategies in which the chosen PSs have limited capabilities and are unable to utilize all the near-infrared-upconverted light. In this study, needle-like SnWO

To address the intractable issues such as the low performance or biocompatibility frequently encountered in previous CT, magnetic resonance (MR) and fluorescence trimodal imaging nanoprobes, a nanocomposite has been constructed by decorating gadolinium ions doped upconversion nanoparticle (Gd-doped UCNP) with radiopaque but fluorescence-transparent tantalum oxide (TaO(x), x ≈ 1). The as-synthesized water-soluble nanoparticle showed a litchi-like shape with an average size of ~30 nm and demonstrated extraordinarily high longitudinal and transverse relaxivity values (r(1) = 11.45 mM(-1)s(-1) and r(2) = 147.3 mM(-1)s(-1)) compared with the reported Gd-doped UCNPs to date. Obvious CT contrast enhancement was obtained by the combined effect between the radiopaque TaO(x) shell and the Gd-doped UCNP inner core. Strong upconversion luminescence (UCL) signal could unobstructedly penetrate out in virtue of high transparency of the TaO(x) shell. No mutual interference among different modalities of the upconversion nanolitchi (UCNL) was found, which ensured that the individual merits of every imaging modality could be brought into full play, demonstrated by in vitro and in vivo imagings. Furthermore, UCNLs showed only a slight effect on macrophages and RBCs in vitro and tissue in vivo.

Early diagnosis probes that combine fluorescence, X-ray computed tomography (CT) and magnetic resonance (MR) imagings are anticipated to give three dimensional (3D) details of tissues and cells of high resolution and sensitivity. However, how to combine these three modalities together within a sub-50 nm sized structure is technically challenging. Here we report a trimodal imaging probe of PEGylated NaY/GdF(4): Yb, Er, Tm @SiO(2)-Au@PEG(5000) nanopaticles of uniform size of less than 50 nm. The as-designed nanoprobes showed (1) strong emissions ranging from the visible (Vis) to near infrared (NIR) for fluorescent imaging, (2) T(1)-weighted MRI by shorting T(1) relaxation time and (3) enhanced HU value as a CT contrast agent. The structure was optimized based on a comprehensive investigation on the influence of the distance between the NaY/GdF(4): Yb, Er, Tm core and Au nanoparticles (NPs) at the surface. The potential of trimodal imaging for cancerous cells and lesions was further demonstrated both in vitro and in vivo.

Highly ordered MCM-41-type mesoporous silica nanoparticles (MSNs) with particle sizes of 150 +/- 20 nm were prepared and PEGylated by covalently grafting PEGxk chains of different molecular weights (x = 4, 6, 10, 20) and chain densities (0.05 wt%-3.75 wt%) on the outer surface. The influence of molecular weights and chain densities of PEGxk on the nonspecific binding of PEGylated MSNs to human serum protein (HSA) was investigated. The results revealed that the optimal molecular weights should be not less than 10k, and the corresponding optimal chain densities for PEG10k-MSNs and PEG20k-MSNs were 0.75 wt% and 0.075 wt%, respectively, and the resultant minimum HSA adsorbance (2.5%) on PEGxk-MSNs was far less than that on MSNs (18.7%) without PEGylation. Under the optimal conditions for the minimum HSA adsorbance, the phagocytosis of human THP-1 monocytic leukemia cell line-derived macrophages (THP-1 macrophages) and the hemolysis of human red blood cells (HRBCs) were investigated with MSNs and PEGylated MSNs. A minimum THP-1 phagocytosis percentage (0.1%) and a very low HRBCs hemolysis percentage (0.9%) of PEG10k-MSNs were obtained, which were much lower than those (8.6% and 14.2%, respectively) of MSNs.

Biophotonic technology that uses light and ionizing radiation for positioned cancer therapy is a holy grail in the field of biomedicine because it can overcome the systemic toxicity and adverse side effects of conventional chemotherapy. However, the existing biophotonic techniques fail to achieve the satisfactory treatment efficacy, which remains a big challenge for clinical implementation. Herein, we develop a novel theranostic technique of "intranuclear biophotonics" by the smart design of a nuclear-targeting biophotonic system based on photo-/radio-sensitizers covalently co-loaded upconversion nanoparticles. These nuclear-targeting biophotonic agents can not only generate a great deal of multiple cytotoxic reactive oxygen species in the nucleus by making full use of NIR/X-ray irradiation, but also produce greatly enhanced intranuclear synergetic radio-/photodynamic therapeutic effects under the magnetic/luminescent bimodal imaging guidance, which may achieve the optimal efficacy in treating radio-resistant tumors. We anticipate that the highly effective intranuclear biophotonics will contribute significantly to the development of biophotonic techniques and open new perspectives for a variety of cancer theranostic applications.

It is well-known that multimodal imaging can integrate the advantages of different imaging modalities by overcoming their individual limitations. As ultra-high field magnetic resonance imaging (MRI) will be inevitably used in future MRI/X-ray computed tomography (CT) scanner, it is highly expected to develop high-performance nano-contrast agents for ultra-high field MR and CT dual-modality imaging, which has not been reported yet. Moreover, specific behavior of nano-contrast agents for ultra-high field MRI is a challenging work and still remains unknown. Herein, a novel type of NaHoF4 nanoparticles (NPs) with varied particle sizes were synthesized and explored as high-performance dual-modality contrast agents for ultra-high field MR and CT imaging. The specific X-ray absorption and MR relaxivity enhancements with varied nanoparticle diameters (3 nm, 7 nm, 13 nm and 29 nm) under different magnetic field (1.5/3.0/7.0 T) are investigated. Based on experimental results and theoretical analysis, the Curie and dipolar relaxation mechanisms of NaHoF4 NPs are firstly separated. Our results will greatly promote the future medical translational development of the NaHoF4 nano-contrast agents for ultra-high field MR/CT dual-modality imaging applications.

The early diagnosis and simultaneous drug delivery monitored by non-invasive visualization are highly challenging but clinical-relevant for the diagnostics and therapy monitoring of serious diseases such as cancers. Herein, a Gd-doped layered double hydroxide (LDH)/Au nanocomposite has been developed as both a drug carrier and a diagnostic agent. The obtained nanocomposite shows high non-anionic anti-cancer drug DOX loading capacity and an interesting pH-responsive release profile of loaded DOX. The nanocomposite was found to be able to efficiently transport DOX into the cancer cell, release the DOX in the acidic cytoplasm and then cause death of cancer cells. Meanwhile, the nanocomposite demonstrates better in vitro CT and T(1)-weighted MR imaging capabilities than the commercial MRI and CT contrast agents and favorable in vivo CT and T(1)-weighted MR imaging performance. After being modified with heparin, the nanocomposite also demonstrates effective CT and MR imagings of tumors by intravenous administration in tumor-bearing mice. Furthermore, the nanocomposite shows negligible cytotoxicity and no detectable tissue damage on mice after injection of high dosage of nanocomposite. In conclusion, the synthetic nanocomposite is expected to be a potential theranostic agent for bimodal imagings of cancers and anti-cancer drug delivery as well.

Nuclear-targeted therapy by delivering anticancer drug directly into cancer cell nuclei can elicit synergistic therapeutic effects and kill these cancer cells with much enhanced efficiencies. Besides nuclear targeting, another difficulty in nuclear-targeted therapy is how to achieve real-time monitoring of the therapy process simultaneously. In this article we report on the development of multifunctional upconversion nanoparticles (UCNPs) which were able to target cancer cell nuclei, and thus deliver the anticancer drug directly to the nuclear region and simultaneously image cell nucleus by magnetic resonance (MR)/upconversion fluorescent for real-time guidance of their therapeutic action simultaneously. The Er/Yb-doped NaYF(4) core and NaGdF(4) shell endow the core/shell structured UCNPs with enhanced upconversion fluorescent imaging and more sensitive T(1)-MR imaging performances, and the surface conjugation of TAT peptide served as a key role in the nuclear targeting and nuclear transport process. This multifunctional UCNPs-based nano-theranostic was used to improve the efficacy of DOX in Hela humor tumor models, by direct DOX delivery to the nucleus under the synchronous monitoring of the nano-theranostics. Further development of this technology may provide more exciting opportunities in treating cancer disease by nuclear-targeted therapy.

Early diagnosis that combines the high-resolutional CT and sensitive NIR-fluorescence bioimaging could provide more accurate information for cancerous tissues, which, however, remain a big challenge. Here we report a simple bimodal imaging platform based on PEGylated NaYbF(4): Tm(3+) nanoparticles (NPs) of less than 20 nm in diameter for both CT and NIR-fluorescence bioimaging. The as-designed nanoprobes showed excellent in vitro and in vivo performances in the dual-bioimaging, very low cytotoxicity and no detectable tissue damage in one month. Remarkably, the Yb(3+) in the lattice of NaYbF(4): Tm(3+) NPs functions not only as a promising CT contrast medium due to its high X-ray absorption coefficiency, but also an excellent sensitizer contributing to the strong NIR-fluorescent emissions for its large NIR absorption cross-section. In addition, these NPs could be easily excreted mainly via feces without detectable remnant in the animal bodies.