Construction of developmentally inspired periosteum-like tissue for bone regeneration

The periosteum, a highly vascularized thin tissue, has excellent osteogenic and bone regenerative abilities. The generation of periosteum-mimicking tissue has become a novel strategy for bone defect repair and regeneration, especially in critical-sized bone defects caused by trauma and bone tumor resection. Here, we utilized a bone morphogenetic protein-2(BMP-2)-loaded scaffold to create periosteum-like tissue(PT) in vivo, mimicking the mesenchymal condensation during native long bone development. We found that BMP-2-induced endochondral ossification plays an indispensable role in the construction of PTs. Moreover, we confirmed that BMP-2-induced PTs exhibit a similar architecture to the periosteum and harbor abundant functional periosteum-like tissue-derived cells(PTDCs), blood vessels, and osteochondral progenitor cells. Interestingly, we found that the addition of chondroitin sulfate(CS), an essential component of the extracellular matrix(ECM), could further increase the abundance and enhance the function of recruited PTDCs from the PTs and finally increase the regenerative capacity of the PTs in autologous transplantation assays, even in old mice. This novel biomimetic strategy for generating PT through in vivo endochondral ossification deserves further clinical translation.

Dynamic crosslinked polymeric nano-prodrugs for highly selective synergistic chemotherapy

To achieve highly selective synergistic chemotherapy attractive for clinical translation,the precise polymeric nano-prodrugs(PPD-NPs)were successfully constructed via the facile crosslinking reaction between p H-sensitive poly(ortho ester)s and reduction-sensitive small molecule synergistic prodrug(Pt(IV)-1).PPD-NPs endowed the defined structure and high drug loading of cisplatin and demethylcantharidin(DMC).Moreover,PPD-NPs exhibited steady long-term storage and circulation via the crosslinked structure,suitable negative potentials and low critical micelle concentration(CMC),improved selective tumour accumulation and cellular internalization via dynamic size transition and surficial amino protonation at tumoural extracellular p H,promoted efficient disintegration and drug release at tumoural intracellular p H/glutathione,and enhanced cytotoxicity via the synergistic effect between cisplatin and DMC with the feed ratio of 1:2,achieving significant tumour suppression while decreasing the side effects.Thus,the dynamic crosslinked polymeric nano-prodrugs exhibit tremendous potential for clinically targeted synergistic cancer therapy.

Carrier-free prodrug nanoparticles based on dasatinib and cisplatin for efficient antitumor in vivo

Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate(ADDC)with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery.Herein,we report a simple and effective strategy to prepare ADDC using derivatives of cisplatin(CP)and dasatinib(DAS),which further selfassembled to form reduction-responsive nanoparticles(CP-DDA NPs).DAS was modified with succinic anhydride and then connected with CP derivative by ester bonds.The size,micromorphology and in vitro drug release of CP-DDA NPs were characterized.The biocompatibility and bioactivity of these carrier-free nanoparticles were then investigated by HepG2 cells and H22-tumor bearing mice.In vitro and in vivo experiments proved that CPDDA NPs had excellent anti-tumor activity and significantly reduced toxicities.This study provides a new strategy to design the carrier-free nanomedicine composed of CP and DAS for synergistic tumor treatment.

pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages for enhanced MDR reversal and chemotherapy

TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.

pH-triggered dynamic erosive small molecule chlorambucil nano-prodrugs mediate robust oral chemotherapy

Currently,the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy,owing to its precise structure,high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract,blood circulation and tumor tissues compared to other oral nanomedicines.Herein,this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes,which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters.The precise nano-prodrugs exhibit extraordinarily high drug loading(68.16%),electric neutrality,strong hydrophobicity,and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH.These favorable physicochemical properties can effectively facilitate gastrointestinal absorption,blood circulation stability,tumor accumulation,cellular uptake,and cytotoxicity,therefore achieving high oral relative bioavailability(358.72%)and significant tumor growth inhibition while decreasing side effects.Thus,this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.

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.

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.

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.

Fluorescent Labeling of Nanometer Hydroxyapatite

A novel surface treatment method using 3-aminopropyltriethoxysilane （AMPTES）, was developed to immobilize the fluorescein molecule on nano-HAP （nanometer hydroxyapatite） powders. By pretreating the nano-HAP powders surface with AMPTES, fluorescein, chosen on the basis of the chemical structure of the nano- HAP powders, could be bound to the nano-HAP powders surface. The chemical compositions of nano-HAP before and after being labeled were characterized by Fourier transform infrared spectroscopy （FTIR） and X-ray photoelectron spectroscopy （XPS）. The morphology, phase composition, and the fluorescence characteristics of the nano-HAP powders with and without staining were also investigated. The FTIR and XPS results revealed that fluorescein had been successfully immobilized on the surface of AMPTES-bound nano-HAP powders via the acylamide bond formation between the -COOH of fluorescein and the -NH2 of AMPTES. The labeled nano-HAP powders possessed strong fluorescent intensity with a little deviation from the maximum emission wavelength of fluorescein. But the morphology and phase composition had no obvious alteration. Under fluorescence microscopy, the labeled nano-HAP powders, even after 24 h cell incubation, exhibited strong fluorescence.

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.

Injectable nanofiber-reinforced bone cement with controlled biodegradability for minimally-invasive bone regeneration

Injectable materials show their special merits in regeneration of damaged/degenerated bones in minimally-invasive approach.Injectable calcium phosphate bone cement(CPC)has attracted broad attention for its bioactivity,as compared to non-degradable polymethyl methacrylate cement.However,its brittleness,poor anti-washout property and uncontrollable biodegradability are the main challenges to limit its further clinical application mainly because of its stone-like dense structure and fragile inorganic-salt weakness.Herein,we developed a kind of injectable CPC bone cement with porous structure and improved robustness by incorporating poly(lactide-co-glycolic acid)(PLGA)nanofiber into CPC,with carboxymethyl cellulose(CMC)to offer good injectability as well as anti-wash-out capacity.Furthermore,the introduction of PLGA and CMC also enabled a formation of initial porous structure in the cements,where PLGA nanofiber endowed the cement with a dynamically controllable biodegradability which provided room for cell movement and bone ingrowth.Inter-estingly,the reinforced biodegradable cement afforded a sustainable provision of Ca^(2+)bioactive components,together with its porous structure,to improve synergistically new bone formation and osteo-integration in vivo by using a rat model of femur condyle defect.Further study on regenerative mechanisms indicated that the good minimally-invasive bone regeneration may come from the synergistic enhanced osteogenic effect of calcium ion enrichment and the improved revascularization capacity contributed from the porosity as well as the lactic acid released from PLGA nanofiber.These results indicate the injectable bone cement with high strength,anti-washout property and controllable biodegradability is a promising candidate for bone regeneration in a minimally-invasive approach.

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.

Rotational manipulation of massive particles in a 2D acoustofluidic chamber constituted by multiple nonlinear vibration sources

Rotational manipulation of massive particles and biolo gical samples is essential for the development of miniaturized lab-on-a-chip platforms in the fields of chemical,medical,and biological applications.In this paper,a device concept of a two-dimensional acoustofluidic chamber actuated by multiple nonlinear vibration sources is proposed.The functional chamber enables the generation of acoustic streaming vortices for potential applications that include strong mixing of multiphase flows and rotational manipulation of micro-/nano-scale objects without any rotating component.Using numerical simulations,we find that diversified acoustofluidic fields can be generated in the chamber under various actuations,and massive polystyrene beads inside can experience different acoustophoretic motions under the combined effect of an acoustic radiation force and acoustic streaming.Moreover,we investigate and clarify the effects of structural design on modulation of the acoustofluidic fields in the chamber.We believe the presented study could not only provide a promising potential tool for rotational acoustofluidic manipulation,but could also bring this community some useful design insights into the achievement of desired acoustofluidic fields for assorted microfluidic applications.

Effect of Oxygen on Surface Properties and Drug Release Behavior of Plasma Polymer of n-Butyl Methacrylate

The effects of oxygen on the chemical structure, morphology, hydrophilicity and drug release behavior of radio-frequency plasma poly n- butyl methacrylate （PPBMA） thin film were carded out for the first time. ATR-FTIR and XPS showed that oxygen had little influence on the chemical structure and composition of PPBMAs, which did not agree with the thought that the presence of oxygen gas would increase the oxidized carbon functionalities in the plasma polymer. SEM and static contact angle measurement indicated that in case of deposition with oxygen, the smoothness and hydrophilicity of PPBMA were dramatically improved. The drug release behavior showed that drug release from the PPBMA coating without oxygen was biphasic patterns, while from PPBMA coating with oxygen was Higuchi release. These results were helpful for the design and tailoring of the PPBMA polymer film and other of plasma polymers film, but could provide a new idea for the drug release controlled form.

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.

用于常见疾病成像的纳米材料造影剂

生物医学精准诊断对于疾病的有效治疗十分重要.纳米基成像造影剂具有灵敏度高、特异性强、生物相容性好等特点,在生物医学成像诊断中具有巨大的临床转化潜力.目前,尽管研究者们构筑了大量的纳米基探针材料作为疾病诊断造影剂,但纳米材料造影剂在临床转化方面仍然面临极大的挑战.这里我们主要概述了不同生物医学成像类型的纳米基造影剂所面临的问题,并针对这些难题提出了应对方案和未来的研究重点,最后对纳米基造影剂的临床转化前景进行了展望.