We first establish the existence of global strong solutions to the 3D inviscid incompressible magneto-micropolar equations with a velocity damping in Sobolev spaces H-K (K >= 3), where the H-3 norm of initial data is small, but its higher order derivatives could be large. Combining the. (H) over dot(-s) norm (0 <= s < 3/2) or (B) over dot(2,infinity)(-s) norm (0<s <= 3/2) of the initial magnetic field is finite with some tricky interpolation estimates, we show parallel to del B-n(t)parallel to (L2) <= C-0(1 + t)(-n/2 - 3/2p + 3/4) and two faster decay rates for the velocity and the micro-rotation field parallel to del(n)(U, w)(t)parallel to (L2) <= C-0(1 + t)(-n/2 - 3/2p + 1/4), which are shown to be the usual L-p - L-2 (1 <= p <= 2) type of the optimal time decay rates for 3D inviscid incompressible magneto-micropolar equations with damping. We then conclude the damping term contributes to weaken the assumption of initial condition and enhance the decay rate of velocity compared to the classical incompressible viscous magneto-micropolar equations. Meanwhile, for the 3D inviscid compressible magneto-micropolar fluid, the damping term also has the same effect on the decay rate of the velocity.
In this paper, we consider the stability of the Couette flow for the Cauchy problem to the parabolic-parabolic chemotaxis-Navier–Stokes system in T×R, we prove that the Couette flow is stable under the extra smallness assumption, where the amplitude is large enough. This result was inspired by Zeng et al. (2021), they investigated the suppression of blow-up in Patlak–Keller–Segel-Navier–Stokes system via the Couette flow. Compared with their work, our chemical equation has different nonlinear term, which leads to the difficulty of estimates of chemical gradient.
Boron neutron capture therapy (BNCT) is an emerging approach for treating malignant tumors with binary targeting. However, its clinical application has been hampered by insufficient B-10 accumulation in tumors and low B-10 concentration ratios of tumor-to-blood (T/B) and tumor-to-normal tissue (T/N). Herein, we developed fluorinated BPA derivatives with different fluorine groups as boron delivery agents for enabling sufficient B-10 accumulation in tumors and enhancing T/B and T/N ratios. Our findings demonstrated that fluorinated BPA derivatives had good biological safety. Furthermore, fluorinated BPA derivatives showed improved B-10 accumulation in tumors and enhanced T/B and T/N ratios compared to the clinical boron drug fructose-BPA (f-BPA). In particular, in B16-F10 tumor-bearing mice, fluorinated BPA derivatives met the requirements for clinical BNCT even at half of the clinical dose. Thus, fluorinated BPA derivatives are potentially effective boron delivery agents for clinical BNCT in melanoma.
In this paper, we consider the initial boundary value problem of the chemotaxis-Navier- Stokes system with low regularity, and we show that the system has a global generalized solution, which was first introduced by M. Winkler [SIAM J. Math. Anal., 47(4):3092-3115, 2015].
Paramagnetic complexes containing gadolinium ions have been widely used for magnetic resonance imaging (MRI) in clinic. However, these paramagnetic complexes pose some safety concerns. There is still a demand for the development of stable MRI contrast agents that exhibit higher sensitivity and superior functionality to existing contrast agents. Here, we develop carbonized paramagnetic complexes of manganese (II) (Mn@CCs) to encapsulate Mn2+ in sealed carbonized shells with superhigh r1 relaxivity. Compared to the most common clinical contrast agent Magnevist, investigations in vivo demonstrate that the Mn@CCs cross the intact blood-brain barrier of normal health mice with minor metal deposition; preferentially target the glioma tissues distribute homogeneously with high penetration in an intracranial mouse model; delineate clear tumor margins in MRIs of ultrasmall single-nodule brain tumors, and multi-nodular liver tumors. The sensitivity, accuracy and low toxicity offer by Mn@CCs provides new opportunities for early molecular diagnostics and imaging-guided biomedical applications.
Background: Asymmetric intracellular and extracellular ionic gradients are critical to the survivability of mammalian cells. Given the importance of manganese (Mn2+), calcium (Ca2+), and bicarbonate (HCO3-) ions, any alteration of the ion-content balance could induce a series of cellular responses. HCO3- plays an indispensable role for Mn-mediated Fenton-like reaction, but this is difficult to achieve because bicarbonates are tightly regulated by live cells, and are limited in anticancer efficacy. Methods: A responsive and biodegradable biomineral, Mn-doped calcium carbonate integrated with dexamethasone phosphate (DEX) (Mn:CaCO3-DEX), was reported to enable synergistic amplification of tumor oxidative stress, reduce inflammation, and induce Ca-overload cell apoptosis by elevating the intracellular and extracellular ionic gradients. Results: Under the acidic environment in tumor region, the ions (Mn2+, CO32-, Ca2+) were released by the degradation of Mn:CaCO3-DEX and then escalated oxidative stresses by triggering a HCO3--indispensable Mn-based Fenton-like reaction and breaking Ca2+ ion homeostasis to cause oxidative stress in cells and calcification. The released anti-inflammatory and antitumor drug, DEX, could alleviate the inflammatory environment. The investigations in vitro and in vivo demonstrated that the synergistic oncotherapy could effectively inhibit the growth of subcutaneous tumors and orthotopic liver tumors. Notably, normal cells showed greater tolerance of the synergistic influences. Conclusion: As an ion drug, Mn:CaCO3-DEX is an excellent potential diagnostic agent for precise orthotopic tumor management by the generation in situ of toxic ion and drug pools in the environment of tumor region, with synergistic effects of enhanced chemodynamic therapy, calcification, and anti-inflammation effects.
Background Different from Fe ions in Fenton reaction, Mn ions can function both as catalyst for chemodynamic therapy and immune adjuvant for antitumor immune responses. In Mn-mediated Fenton-like reaction, bicarbonate ( HCO_3^ - ), as the most important component to amplify therapeutic effects, must be present, however, intracellular HCO_3^ - is strictly limited because of the tight control by live cells. Results Herein, Stimuli-responsive manganese carbonate-indocyanine green complexes (MnCO 3 -ICG) were designed for intracellular marriage of bicarbonate and Mn ions as “immune ion reactors” to regulate intracellular redox homeostasis and antitumor immune responses. Under the tumor acidic environment, the biodegradable complex can release “ion reactors” of Mn 2+ and HCO_3^ - , and ICG in the cytoplasm. The suddenly increased HCO_3^ - in situ inside the cells regulate intracellular pH, and accelerate the generation of hydroxyl radicals for the oxidative stress damage of tumors cells because HCO_3^ - play a critical role to catalyze Mn-mediated Fenton-like reaction. Investigations in vitro and in vivo prove that the both CDT and phototherapy combined with Mn 2+ -enhanced immunotherapy effectively suppress tumor growth and realize complete tumor elimination. Conclusions The combination therapy strategy with the help of novel immune adjuvants would produce an enhanced immune response, and be used for the treatment of deep tumors in situ.
The catalytic activities of currently developed peroxidase-mimic nanozymes are generally limited. Therefore, further efforts are still needed to improve the catalytic performance of peroxidase nanozymes. Herein, we synthesized Fe-coordinated carbon nanozyme dots (Fe-CDs) that can serve as both efficient peroxidase nanozymes and T2-magnetic resonance imaging (MRI) contrast agents. The intrinsic peroxidase-like activity of the Fe-CDs was explored by catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) with hydrogen peroxide (H2O2). The product showed better performance over natural horseradish peroxidase (HRP) and other mimetic peroxidases. Quantification of glucose and ascorbic acid detection showed that this nanozyme could be used to detect a minimum limit as low as 5 μM glucose. Moreover, the colorimetric detection technique was used to detect serum glucose in mice, and the detection result was comparable with autobiochemistry analyzer results using a glucose assay kit. Furthermore, the Fe-CDs showed good magnetism properties and provided promising MR imaging of tumors with excellent biocompatibility.
Both short-wave infrared (SWIR: 900-1700 nm) and near-infrared (NIR: 650-900 nm) luminescence possess lower optical scattering and higher signal-to-noise in deep tissues than conventional luminescence, gaining increasing attention in biomedicine. Herein, we designed mesoporous silica-coated Yb-doped magnesium germanate nanoparticles (mMGOs) with excellent two-in-one NIR and SWIR persistent luminescence after X-ray irradiation by simply regulating the valence of rare-earth ions, which also possess high cargo loading and a controlled release profile in the tumor region. The investigations in vitro and in vivo showed that mMGOs were repeatedly activated to realize rechargeable persistent luminescence imaging for tracking cargo delivery in mice. Moreover, the stimulative drug-release profile inhibited tumor growth effectively. Both of the X-ray excited two-in-one NIR and SWIR persistent luminescence imaging not only allowed for rechargeable imaging of deep tumors but also achieved long-term tracking with a remarkable tumor inhibition effect.
X-ray excited persistent luminescence (XEPL) imaging has attracted increasing attention in biomedical imaging due to elimination of autofluorescence, high signal-to-noise ratio and repeatable activation with high penetration. However, optical imaging still suffers from limited for high spatial resolution. Methods: Herein, we report Mn3+-rich manganese oxide (MnOx)-coated chromium-doped zinc gallogermanate (ZGGO) nanoparticles (Mn-ZGGOs). Enhanced XEPL and magnetic resonance (MR) imaging were investigated by the decomposition of MnOx shell in the environment of tumors. We also evaluated the tumor cell-killing mechanism by detection of reactive oxygen (ROS), lipid peroxidation and mitochondrial membrane potential changes in vitro. Furthermore, the in vivo biodistribution, imaging and therapy were studied by U87MG tumor-bearing mice. Results: In the tumor region, the MnOx shell is quickly decomposed to produce Mn3+ and oxygen (O2) to directly generate singlet oxygen (1O2). The resulting Mn2+ transforms endogenous H2O2 into highly toxic hydroxyl radical (·OH) via a Fenton-like reaction. The Mn2+ ions and ZGGOs also exhibit excellent T1-weighted magnetic resonance (MR) imaging and ultrasensitive XEPL imaging in tumors. Conclusion: Both the responsive dual-mode imaging and simultaneous self-supplied O2 for the production of 1O2 and oxygen-independent ·OH in tumors allow for more accurate diagnosis of deep tumors and more efficient inhibition of tumor growth without external activation energy.
Light-mediated therapy has many unique merits but monotherapy strategies rarely completely inhibit tumor growth because resistance often develops. Combination therapy is a promising strategy in oncology and has demonstrated superior safety and efficacy over monotherapy. Here, we conjugated a scintillator complex and gold nanorod nanosensitizer for dual-modal image-guided photothermal and X-ray-induced photodynamic therapy (PDT). Lanthanide complexes were successfully conjugated and offer excellent X-ray-excited optical luminescence for PDT effects. The strong near-infrared (NIR) light and X-ray absorption abilities of gold nanorods make the nanosensitizer function as both a photothermal agent for photothermal therapy and a radiosensitizer for enhanced radiotherapy. The studies in vitro and in vivo demonstrated that the nanosensitizer offers good dual-modal imaging capability and significantly suppresses tumor progression under NIR light and X-ray irradiation. This work shows the great potential of conjugating scintillator lanthanide complexes and gold nanosensitizers for multimodal image-guided therapy of deep-seated tumors.
An important objective of cancer nanomedicine is to improve the delivery efficacy of functional agents to solid tumors for effective cancer imaging and therapy. Stimulus-responsive nanoplatforms can target and regulate the tumor microenvironment (TME) for the optimization of cancer theranostics. Here, we developed magnetic manganese oxide sweetgum-ball nanospheres (MMOSs) with large mesopores as tools for improved cancer theranostics. MMOSs contain magnetic iron oxide nanoparticles and mesoporous manganese oxide (MnO2) nanosheets, which are assembled into gumball-like structures on magnetic iron oxides. The large mesopores of MMOSs are suited for cargo loading with chlorin e6 (Ce6) and doxorubicin (DOX), thus producing so-called CD@MMOSs. The core of magnetic iron oxides could achieve magnetic targeting of tumors under a magnetic field (0.25 mT), and the targeted CD@MMOSs may decompose under TME conditions, thereby releasing loaded cargo molecules and reacting with endogenous hydrogen peroxide (H2O2) to generate oxygen (O2) and manganese (II) ions (Mn2+). Investigation in vivo in tumor-bearing mice models showed that the CD@MMOS nanoplatforms achieved TME-responsive cargo release, which might be applied in chemotherapy and photodynamic therapy. A remarkable in vivo synergy of diagnostic and therapeutic functionalities was achieved by the decomposition of CD@MMOSs and coadministration with chemo-photodynamic therapy of tumors using the magnetic targeting mechanism. Thus, the result of this study demonstrates the feasibility of smart nanotheranostics to achieve tumor-specific enhanced combination therapy.
Carbon-based light-activated materials can absorb optical energy to generate photoacoustic (PA) signals for imaging or transduce optical photons to thermal energy, which holds great promise for biomedical applications. Herein, we synthesize hollow and mesoporous carbon nanospheres (HMCNs) with uniform size on a large scale. The properties of hollow cavity and mesoporous structures make the HMCNs achieve high drug loading (480 mg DOX per g HMCNs). The present intense near infrared (NIR) absorbance achieves excellent photoacoustic imaging ability and photothermal conversion efficacy (32.0%). More interestingly, the encapsulated drugs can have a triggered release under NIR irradiation. The investigations in vitro and in vivo demonstrate that HMCNs have excellent biocompatibility, and accumulate in tumors by the enhanced permeability and retention (EPR) effect. Moreover, under NIR irradiation, in vivo evaluation shows that HMCNs can perform strong PA imaging, and induce great tumor inhibition by the combination of chemotherapy and PTT under the guidance of photoacoustic imaging. The present study provides new insight for design of novel biocompatible light-activated carbons for cancer nanotheranostics.
Multifunctional theranostic nanoplatforms greatly improve the accuracy and effectiveness in tumor treatments. Much effort has been made in developing advanced optical imaging-based tumor theranostic nanoplatforms. However, autofluorescence and irradiation damage of the conventional fluorescence imaging technologies as well as unsatisfied curative effects of the nanoplatforms remain great challenges against their wide applications. Herein, we constructed a novel core-shell multifunctional nanoplatform, that is, chromium-doped zinc gallogermanate (ZGGO) near-infrared (NIR) persistent luminescent nanoparticles (PLNPs) as a core and zeolitic imidazolate framework-8 (ZIF-8) as a shell (namely ZGGO@ZIF-8). The ZGGO@ZIF-8 nanoplatform possessed dual functionalities of the autofluorescence-free NIR PersL imaging as well as the pH-responsive drug delivery, thus it has high potential in tumor theranostics. Notably, the loading content of doxorubicin (DOX) in ZGGO@ZIF-8 (LC = 93.2%) was quite high, and the drug release of DOX-loaded ZGGO@ZIF-8 was accelerated in an acidic microenvironment such as tumor cells. The ZGGO@ZIF-8 opens up a new material system in the combination of PLNPs with metal-organic frameworks and may offer new opportunities for the development of advanced multifunctional nanoplatforms for tumor theranostics, chemical sensing, and optical information storage.
Photosensitizers (PS) are an essential component of photodynamic therapy (PDT). Conventional PSs are often porphyrin derivatives, which are associated with high hydrophobicity, low quantum yield in aqueous solutions, and suboptimal tumor‐to‐normal‐tissue (T/N) selectivity. There have been extensive efforts to load PSs into nanoparticle carriers to improve pharmacokinetics. The approach, however, is often limited by PS self‐quenching, pre‐mature release, and nanoparticle accumulation in the reticuloendothelial system organs. Herein, a novel, nanoparticle‐based PS made of gadolinium‐encapsulated graphene carbon nanoparticles (Gd@GCNs), which feature a high 1O2 quantum yield, is reported. Meanwhile, Gd@GCNs afford strong fluorescence and high T1 relaxivity (16.0 × 10−3m−1 s−1, 7 T), making them an intrinsically dual‐modal imaging probe. Having a size of approximately 5 nm, Gd@GCNs can accumulate in tumors through the enhanced permeability and retention effect. The unbound Gd@GCNs cause little toxicity because Gd is safely encapsulated within an inert carbon shell and because the particles are efficiently excreted from the host through renal clearance. Studies with rodent tumor models demonstrate the potential of the Gd@GCNs to mediate image‐guided PDT for cancer treatment. Overall, the present study shows that Gd@GCNs possess unique physical, pharmaceutical, and toxicological properties and are an all‐in‐one nanotheranostic tool with substantial clinical translation potential.
Theranostics that combines the disease diagnosis with treatment is of promising application in the foreground of personalized medicine to achieve a precise treatment with minimum side effects. In this work, we strategically designed a "four-in-one'' theranostic nanoplatform for realizing the desired imaging-guided phototherapy, in which functions of fluorescent imaging, photoacoustic imaging tomography (PAT), photothermal therapy (PTT) and photodynamic therapy (PDT) were implemented by bioconjugated MoS2 nanosheets. The protagonist of MoS2 is a light-harvesting material in the near-infrared (NIR) region, which would produce localized hyperthermia at the tumor site to trigger the photothermal therapy effect for the tumor ablation as well as a PAT signal to depict the tumor concurrently upon NIR excitation. To our surprise, MoS2 has been found to be a photosensitizer for the cancer PDT treatment as well. Moreover, bovine serum albumin (BSA) decoration on MoS2 has been made to improve biocompatibility, which also allowed further conjugation with a fluorescent molecule of Cy5.5 to endow the overall nanoplatform with fluorescence imaging and monitoring features. On the basis of the above characters, great successes in cancer imaging and tumor photoablation were achieved in both in vitro and in vivo experiments. Innovatively, B-ultrasonography and MRI imaging were employed to monitor the elimination process of solid tumor after treatment, which clearly revealed a liquefaction necrosis process for rehabilitation. In short, MoS2 represents a nanoplatform of this work and manifested huge advantages in the cancer theranostics.
Image-guided phototherapy is considered to be a prospective technique for cancer treatment because it can provide both oncotherapy and bioimaging, thus achieving an optimized therapeutic efficacy and higher treatment accuracy. Compared to complicated systems with multiple components, using a single material for this multifunctional purpose is preferable. In this work, we strategically fabricated poly(acrylic acid)- (PAA-) coated Cu2(OH)PO4 quantum dots [denoted as Cu2(OH)PO4@PAA QDs], which exhibit a strong near-infrared photoabsorption ability. As a result, an excellent photothermal conversion ability and the photoactivated formation of reactive oxygen species could be realized upon NIR irradiation, concurrently meeting the basic requirements for photothermal and photodynamic therapies. Moreover, phototherapeutic investigations on both cervical cancer cells in vitro and solid tumors of an in vivo mice model illustrated the effective antitumor effects of Cu2(OH)PO4@PAA upon 1064-nm laser irradiation, with no detectable lesions in major organs during treatment. Meanwhile, Cu2(OH)PO4@PAA is also an exogenous contrast for photoacoustic tomography (PAT) imaging to depict tumors under NIR irradiation. In brief, the Cu2(OH)PO4@PAA QDs prepared in this work are expected to serve as a multifunctional theranostic platform.
A theranostic system of image-guided phototherapy is considered as a potential technique for cancer treatment because of the ability to integrate diagnostics and therapies together, thus enhancing accuracy and visualization during the treatment. In this work, we realized photoacoustic (PA) imaging-guided photothermal (PT)/photodynamic (PD) combined cancer treatment just via a single material, MoO3-x quantum dots (QDs). Due to their strong NIR harvesting ability, MoO3-x QDs can convert incident light into hyperthermia and sensitize the formation of singlet oxygen synchronously as evidenced by in vitro assay, hence, they can behave as both PT and PD agents effectively and act as a "dual-punch" to cancer cells. In a further study, elimination of solid tumors from HeLa-tumor bearing mice could be achieved in a MoO3-x QD mediated phototherapeutic group without obvious lesions to the major organs. In addition, the desired PT effect also makes MoO3-x QDs an exogenous PA contrast agent for in vivo live-imaging to depict tumors. Compared with previously reported theranostic systems that put several components into one system, our multifunctional agent of MoO3-x QDs is exempt from unpredictable mutual interference between components and ease of leakage of virtual components from the composited system.
Being an encouraging approach with high selectivity and minor side-effects, imaging-guided phototherapy for cancer treatment has attracted lots of research interest. Wherein particularly important is the development of a novel agent that favors cancer imaging and phototherapy in one. In this study, urchin-like tungsten suboxide nanomaterials (WOs) were synthesized for photothermal (PT) and photodynamic (PD) combined cancer treatment, as well as photoacoustic (PA) imaging to depict tumors. On the basis of strong photoabsorption in the near-infrared (NIR) region, the WOs exhibit high photothermal conversion and singlet-oxygen generation efficiency, and thus can achieve dual effects of PT and PD therapies, resulting in severe cancer cell death and apoptosis as proved by in vitro assays. Further in vivo experiments with HeLa tumor-bearing nude mice reveal that WOs have an effective photoablation outcome for malignant tumors under 1064 nm NIR light irradiation, whereas there is no obvious systematical toxicity for major organs and no hematological disorders. Finally, WOs could also function as excellent PA agents in consideration of their rapid and significant PA signal enhancement in the tumor region. Altogether, our research work demonstrates the potential of WOs as a multifunctional nanoagent for PA imaging-guided PT and PD cancer therapy.
We herein present oxygen-deficient molybdenum oxide quantum dots (MoO3-x QDs), which possess matching-absorption-spectrum to solar light in both visible and near infrared regions, for proof-of-concept of interfacial water evaporation. Theoretical modeling suggests that the unique optical property of MoO3-x QDs results from oxygen defect level, instead of localized surface plasmon resonance.