Manganese-Zeolitic Imidazolate Frameworks-90 with High Blood Circulation Stability for MRI-Guided Tumor Therapy

Zeolitic imidazolate frameworks(ZIFs)as smart drug delivery systems with microenvironment-triggered release have attracted much attention for tumor therapy.However,the exploration of ZIFs in biomedicine still encounters many issues,such as inconvenient surface modification,fast drug release during blood circulation,undesired damage to major organs,and severe in vivo toxicity.To address the above issues,we developed an Mn-ZIF-90 nanosystem functionalized with an originally designed active-targeting and pH-responsive magnetic resonance imaging(MRI)Y1 receptor ligand[Asn28,Pro30,Trp32]-NPY(25-36)for imaging-guided tumor therapy.After Y1 receptor ligand modification,the Mn-ZIF-90 nanosystem exhibited high drug loading,better blood circulation stability,and dual breast cancer cell membrane and mitochondria targetability,further favoring specific microenvironment-triggered tumor therapy.Meanwhile,this nanosystem showed promising T1-weighted magnetic resonance imaging contrast in vivo in the tumor sites.Especially,this nanosystem with fast clean-up had almost no obvious toxicity and no damage occurred to the major organs in mice.Therefore,this nanosystem shows potential for use in imaging-guided tumor therapy.

Characterizing the luminescent properties of upconversion nanoparticles in single and densely packed state

Luminescent properties of Er^(3+)-and Yb^(3+)-co-doped CaF_(2)upconversion nanoparticles(UCNPs)were investigated in single particle and densely-packed states with a custom-built microscope.The single UCNPs exhibit linear dependency of luminescent intensity on excitation power while the densely-packed UCNPs exhibit a 2-order power law-dependency indicating a two-photon absorption process.Time-domain luminescence intensity measurements were performed and the curves were fitted to excitationnemission rate functions based on a simplified three-state model.The results indicate that the intermediates in single particles are much less and saturated in a short time,and there are strong couplings of the ground states and intermediate states between neighboring UCNPs in densely packed UCNPs.

Robust fault detection in linear systemsbased on full-order state observers

A parametric approach to robust fault detection in linear systems with unknown disturbances is presented. The residual is generated using full-order state observers （FSO）. Based on an analytical solution to a type of Sylvester matrix equations, the parameterization of the observer gain matrix is given. In terms of the design degrees of freedom provided by the parametric observer design and a group of introduced parameter vectors, a sufficient and necessary condition for fullorder state observer design with disturbance decoupling is then established. By properly constraining the design parameters according to this proposed condition, the effect of the disturbance on the residual signal is also decoupled, and a simple algorithm is developed. The presented approach offers all the degrees of design freedom. Finally, a numerical example illustrates the effect of the proposed approach.

Extended parameter-dependent H∞ filtering for uncertain continuous-time state-delayed systems

The design of robust H∞ filtering problem of polytopic uncertain linear time-delay systems is addressed. The uncertain parameters are supposed to reside in a polytope. A parameter-dependent Lyapunov function approach is proposed for the design of filters that ensure a prescribed H∞performance level for al ad-missible uncertain parameters, which is different from the quadratic framework that entails fixed matrices for the entire uncertainty do-main. This idea is realized by careful y selecting the structure of the matrices involved in the products with system matrices. An extended H∞ sufficient condition for the existence of robust esti-mators is formulated in terms of linear matrix inequalities, which can be solved via efficient interior-point algorithms.

Solving the generalized Sylvester matrix equation AV+BW=VF via Kronecker map

This note considers the solution to the generalized Sylvester matrix equation AV ＋ BW = VF with F being an arbitrary matrix, where V and W are the matrices to be determined. With the help of the Kronecker map, an explicit parametric solution to this matrix equation is established. The proposed solution possesses a very simple and neat form, and allows the matrix F to be undetermined.

Tumor microenvironment-activatable neuropeptide-drug conjugates enhanced tumor penetration and inhibition via multiple delivery pathways and calcium deposition

Peptide-drug conjugates have achieved considerable development and application as a novel strategy for targeted delivery of anticancer drugs. Bioactive peptides induced calcium deposition can irreversibly assist inhibition of tumors. However, active regulation of calcium level through signal transduction of bioactive substances has not been reported yet. In this study, novel neuropeptide-doxorubicin conjugates(NP-DOX) with lysosome-specific acid response were described for neuropeptide Y_1 receptor(Y_1R)-overexpressed triple-negative breast cancer. The delivery mechanism of NP-DOX was clarified that diverse pathways were involved, including intracellular and intercellular transport. Importantly, up-regulation of Y_1 R-mediated intracellular calcium level via second messenger inositol triphosphate was presented in NP-DOX treated MDA-MB-231 cells. In vivo antitumor efficacy demonstrated that NP-DOX showed less organ toxicity and enhanced tumor inhibition benefited from its controlled release and Y_1R-mediated calcium deposition, compared with free DOX. This bioconjugate is a proof-of-concept confirming that neuropeptide-mediated control of signaling responses in neuropeptide-drug conjugates enables great potential for further applications in tumor chemotherapy.

D-type neuropeptide decorated AIEgen/RENP hybrid nanoprobes with light-driven ROS generation ability for NIR-Ⅱ fluorescence imaging-guided through-skull photodynamic therapy of gliomas

Glioma is one of the most common malignant tumors of the central nervous system,leading high mortality rates in human.Aggregation-induced emission(AIE)photosensitizers-based photodynamic therapy(PDT)has emerged as a promising therapeutic strategy for least-invasive treatment of glioma,which involves local irradiation of the tumor using an external near-infrared(NIR)laser.Unfortunately,most AIE photosensitizers suffered from poorly penetration of the visible light excitation,bad spatiotemporal resolution in deep tissues and low efficient blood-brain barrier(BBB)crossing ability,which greatly limited the clinical practice of AIE photosensitizers for especially deep-seated brain tumor treatment.In this work,we developed a multifunctional NIR-driven theranostic agent through hybrid of AIE photosensitizers TIND with rare-earth doping nanoparticles(RENPs)NaGdF4:Nd/Yb/Tm with up/down dual-mode conversion luminescence.The theranostic agent was further decorated with D-type neuropeptide DNPY for crossing BBB and targeting glioma.Under the 808-nm light irradiation,the down-conversion NIR-II luminescence could indicate the position glioma and the upconversion NIR-I luminescence could trigger the AIE photosensitizers producing reactive oxygen species to inhibit orthotopic glioma tumor growth in situ.These results demonstrate that the integration of Dtype neuropeptide,AIE photosensitizers and RENPs could be promising candidates for in vivo NIR-II fluorescence image-guided through-skull PDT treatments of brain tumors.

HPDA/Zn as a CREB Inhibitor for Ultrasound imaging and Stabilization of Atherosclerosis Plaque+

Thrombosis,secondary to rupture of unstable plaque,is a fatal risk factor for myocardial infarction and ischemic stroke.At present,more novel methods are needed for the diagnosis and treatment of vulnerable plaque.Here,we report a hollow polydopamine/Zn(HPDA/Zn)ultrasound contrast agent.Through western-blot,Elisa,and other experiments,we found that in addition to having a good contrast-enhancement capability in ultrasound imaging in vitro and in vivo,HPDA/Zn also has the effect of reducing the expres-sion of CREB.CREB protein and its downstream-regulated proteins and factors are closely related to the stability of plaque.HPDA/Zn has the effect of reducing the expression of CREB protein,which leads to the decrease of expression of MMP-9,the regulatory pro-tein downstream of the CREB protein.In addition,it also reduces the secretion of inflammatory factors hs-CRP and IL-17A.Thus,HPDA/Zn can stabilize plaque by inhibiting CREB and reducing plaque vulnerable markers and inflammatory factors.In a word,HPDA/Zn is a kind of ultrasound contrast agent,which can stabilize plaques by inhibiting CREB protein.

Mn-doped Ti-based MOFs for magnetic resonance imaging-guided synergistic microwave thermal and microwave dynamic therapy of liver cancer

Currently,precise ablation of tumors without damaging the surrounding normal tissue is still an urgent problem for clinical microwave therapy of liver cancer.Herein,we synthesized Mn-doped Ti MOFs(Mn-Ti MOFs)nanosheets by in-situ doping method and applied them for microwave therapy.Infrared thermal imaging results indicate Mn-Ti MOFs can rapidly increase the temperature of normal saline,attributing to the porous structure improving microwave-induced ion collision frequency.Moreover,Mn-Ti MOFs show higher 1O2 output than Ti MOFs under 2 W of low-power microwave irradiation due to the narrower band-gap after Mn doping.At the same time,Mn endows the MOFs with a desirable T1 contrast of magnetic resonance imaging(r2/r1=2.315).Further,results on HepG2 tumor-bearing mice prove that microwave-triggered Mn-Ti MOFs nearly eradicate the tumors after 14 days of treatment.Our study offers a promising sensitizer for synergistic microwave thermal and microwave dynamic therapy of liver cancer.

Ultrasound-visualized nanocarriers with siRNA for targeted inhibition of M2-like TAM polarization to enhance photothermal therapy in NSCLC

Photothermal therapy(PTT)has received a lot of attention as a promising strategy for eliminating tumors quickly.However,the unavoidable inflammatory response during the treatment might result in a high concentration of M2-like tumor-associated macrophages(TAMs),increasing the risk of tumor recurrence and metastasis.To address this problem,gold-based nanocarriers(PGMP-small interfering RNA(siRNA)nanoparticles(NPs))containing STAT6siRNA,that inhibited M2-like TAM polarization,were designed and investigated for PTT and gene therapy of non-small cell lung cancer(NSCLC).In an NSCLC model,the nanocarriers demonstrated excellent siRNA delivery ability and a high gene transfection rate of up to 90%in macrophages,thus inhibiting the polarization of about 87%of M2-like TAMs and effectively suppressing the invasion and metastasis of NSCLC.Meanwhile,the unique gold nanosphere structure offered improved PTT and contrast-enhanced ultrasound imaging,thus contributing to the efficient elimination and real-time monitoring of the tumor tissues.These nanocarriers with combined gene and photothermal therapeutic capabilities improved the efficacy of single-modality treatment,and showed the potential to inhibit cancer cell recurrence and metastasis to ultimately cure NSCLC.

GSH responsive traditional clinical drugs probe for cancer cell fluorescence imaging and therapy

Despite the rapid development of fluorescence detection modalities for disease diagnosis,novel fluorescent molecules and probes still face with tremendous pressure to transform before employing such fluorescent tools in the clinic.Impressively,the fluorescent probes based on the traditional fluorescent dye are expected to accelerate the transformation process.Herein,methylene blue is requisitioned to design the GSH responsive probe MB-SS-CPT elaborately.The as-synthesized MB-SS-CPT provides a dramatic optical advantage for GSH detection in vitro,cell fluorescence imaging,in vivo imaging,and antitumor therapy.

Black phosphorus nanosheets-based tumor microenvironment responsive multifunctional nanosystem for highly efficient photo-/sono-synergistic therapy of non-Hodgkin lymphoma

Finding improved therapeutic protocols against non-Hodgkin’s lymphoma(NHL) remains an unmet clinical demand. Phototherapy is a promising alternative treatment for traditional clinical therapeutic methods, but the limited tissue penetration blocks the therapeutics. Inspired by the excellent physical and chemical properties of black phosphorus nanosheets(BPNSs), a fluorescence and thermal imaging guided photo-/sono-synergistic treatment platform BPNSs@PEG-SS-IR780/RGD is developed. This ingenious multifunctional theranostic platform not only exhibits outstanding photothermal conversion efficiency and highly efficient reactive oxygen species generation, but also has good biocompatibility, tumor-targeting and tumor microenvironment responsiveness. In addition, BPNSs@PEG-SS-IR780/RGD could actively target the tumor sites and generate excellent photothermal, photodynamic and sonodynamic therapeutic efficacy. Both in vitro and in vivo experiments indicate that BPNSs@PEG-SS-IR780/RGD can be a promising nanomaterial for NHL imaging and therapy. Taken together, this study not only expands the application field of black phosphorus materials, but also provides a possibility to design a new generation of NHL treatment regimens with clinical application potential.

有向图中含弹性关节多机械臂系统的分布式一致性

本文主要研究有向图中含弹性关节多机械臂系统的一致性问题,利用模型参考自适应一致性方法,将含弹性关节多机械臂系统的一致性问题转化成参考模型的一致性和单个机械臂系统的轨迹跟踪问题两个子问题.考虑到机械臂的相对角速度信息难以获取的情况,提出了无需相对角速度信息的线性参考模型.在轨迹跟踪算法设计上,利用反步法对单个机械臂系统设计了跟踪控制算法,使得系统达到关节角度趋于一致的结果.

Two-dimensional layered nanomaterials fortumor diagnosis and treatment

With the evolution of nanomedicine,the past decades witnessed diversified nanomaterials as marvelous antitumor tools ushering in a new era of tumor diagnosis and treatment.Among them,two-dimensional layered nano-material as an emerging class of nanomaterials has one dimension less than 100 nm,showing a high specific area and the thinnest sheet-like structure(Liu S,Pan X,Liu H.Twodimensional nanomaterials for photothermal therapy.Angew Chem Int Ed 2020;59:5890–900).The discovery of graphene drove the exploration of various new two-dimensional layered nanomaterials for tumor diagnosis and treatment including graphene-based nanomaterials,black phosphorus(BP),transition metal dichalcogenides(TMDs),layered double hydroxides(LDHs),and bismuth oxyhalides(BiOX,X=F,Cl,Br,I)(Ma H,Xue MQ.Recent advances in the photothermal applications of two-dimensional nanomaterial:photothermal therapy and beyond.J Mater Chem 2021;9:17569).On the one hand,they exhibit strong near-infrared(NIR)absorption and the capacity of optimizing corresponding properties by adjusting the crystal structure.On the other hand,they own unique strengths such as fantastic physicochemical properties(graphene-based nanomaterials),high loading capacity(BP),distinct phase-dependent optical properties(TMDs),a specific chemical response to the tumor microenvironment(LDHs),and large X-ray attenuation coefficient(BiOX).Herein,we briefly introduce three typical two-dimensional layered nanomaterials,their prospects and future research priorities in tumor diagnosis and treatment are concluded.

Research progress and mechanism of nanomaterials-mediated in-situ remediation of cadmium-contaminated soil:A critical review

Cadmium contamination of soil is a global issue and in-situ remediation technology as a promising mitigation strategy has attracted more and more attention.Many nanomaterials have been applied for the in-situ remediation of cadmium-contaminated soil due to their excellent properties of the nano-scale size effect.In this work,recent research progress of various nanomaterials,including carbon nanomaterials,metal-based nanomaterials and nano mineral materials,in the removal of cadmium and in-situ remediation of cadmiumcontaminated soil were systematically discussed.Additional emphases were particularly laid on both laboratory and field restoration effects.Moreover,the factors which can affect the stability of cadmium,main interaction mechanisms between nanomaterials and cadmium in the soil,and potential future research direction were also provided.Therefore,it is believed that this work will ultimately contribute to the myriad of environmental cleanup advances,and further improve human health and sustainable development.

PCN-Fe(Ⅲ)-PTX nanoparticles for MRI guided high efficiency chemo-photodynamic therapy in pancreatic cancer through alleviating tumor hypoxia

As nanomedicine-based clinical strategies have continued to develop,the possibility of combining chemotherapy and singlet oxygen-dependent photodynamic therapy(PDT)to treat pancreatic cancer(PaC)has emerged as a viable therapeutic modality.The efficacy of such an approach,however,is likely to be constrained by the mechanisms of drug release and tumor oxygen levels.In the present study,we developed an Fe(Ⅲ)-complexed porous coordination network(PCN)which we then used to encapsulate PTX(PCN-Fe(Ⅲ)-PTX)nanoparticles(NPs)in order to treat PaC via a combination of chemotherapy and PDT.The resultant NPs were able to release drug in response to both laser irradiation and pH changes to promote drug accumulation within tumors.Furthermore,through a Fe(Ⅲ)-based Fenton-like reaction these NPs were able to convert H2O2 in the tumor site to O2,thereby regulating local hypoxic conditions and enhancing the efficacy of PDT approaches.Also these NPs were suitable for use as a T1-MRI weighted contrast agent,making them viable for monitoring therapeutic efficacy upon treatment.Our results in both cell line and animal models of PaC suggest that these NPs represent an ideal agent for mediating effective MRI-guided chemotherapy-PDT,giving them great promise for the clinical treatment of PaC.

IMPROVED ROBUST H-INFINITY ESTIMATION FOR UNCERTAIN CONTINUOUS-TIME SYSTEMS

完整顺序的柔韧的评估者的设计为连续时间的 polytopic 被调查不明确的系统。主要目的是获得一个稳定的线性评估者以便评价错误系统与规定 H ∞变细水平仍然保持要用体力地稳定。第一，一个简单其他的证明为性能最近建议了的 H ∞的一个改进 LMI 代表被给。基于阻止 Lyapunov 矩阵系统的产品的表演标准动态矩阵，为柔韧的评估者的存在的一个足够的条件以线性矩阵不平等被提供。建议设计策略允许参数依赖者 Lyapunov 功能的使用，这被显示出；因此它不比更早的结果保守。一个数字例子被采用说明可行性；建议设计的优点。

Chemotherapeutic nanomaterials in tumor boundary delineation:Prospects for effective tumor treatment

Accurately delineating tumor boundaries is key to predicting survival rates of cancer patients and assessing response of tumor microenvironment to various therapeutic techniques such as chemotherapy and radiotherapy.This review discusses various strategies that have been deployed to accurately delineate tumor boundaries with particular emphasis on the potential of chemotherapeutic nanomaterials in tumor boundary delineation.It also compiles the types of tumors that have been successfully delineated by currently available strategies.Finally,the challenges that still abound in accurate tumor boundary delineation are presented alongside possible perspective strategies to either ameliorate or solve the problems.It is expected that the information communicated herein will form the first compendious baseline information on tumor boundary delineation with chemotherapeutic nanomaterials and provide useful insights into future possible paths to advancing current available tumor boundary delineation approaches to achieve efficacious tumor therapy.

Pressure-induced amorphous zeolitic imidazole frameworks with reduced toxicity and increased tumor accumulation improves therapeutic efficacy In vivo

Zeolitic Imidazole Frameworks(ZIFs)are widely applied in nanomedicine for their high drug loading,suitable pore size,pH-responsive drug release,and so on.However,fast drug release during circulation,unexpected toxicity to mice major organs,undesirable long-term accumulation in the lung and even death currently hinder their in vivo biomedical applications.Herein,we report an amorphous ZIF-8(aZIF-8)with high loading of 5-Fu through pressure-induced amorphization.This nano-system avoids early drug release during circulation and provides tumor microenvironment-responsive drug release with improved in vitro cell viability,and survival rate in in vivo evaluations as compared to ZIF-8.Furthermore,aZIF-8 shows longer blood circulation and lower lung accumulation than ZIF-8 at same injected doses.Less drug release during circulation,longer blood circulation,and better biocompatibility of aZIF-8/5-Fu significantly improves its therapeutic efficacy in ECA-109 tumorbearing mouse,and result in 100%survival rate over 50 days after treatment.Therefore,aZIF-8 with favorable biocompatibility and long blood circulation is expected to be a promising nano-system for efficacious cancer therapy in vivo.