Multifaceted p21 in carcinogenesis,stemness of tumor and tumor therapy

Cancer cells possess metabolic properties that are different from those of benign cells.p21,encoded by CDKN1A gene,also named p21Cip1/WAF1,was first identified as a cyclin-dependent kinase regulator that suppresses cell cycle G1/S phase and retinoblastoma protein phosphorylation.CDKN1A(p21)acts as the downstream target gene of TP53(p53),and its expression is induced by wild-type p53 and it is not associated with mutant p53.p21 has been characterized as a vital regulator that involves multiple cell functions,including G1/S cell cycle progression,cell growth,DNA damage,and cell stemness.In 1994,p21 was found as a tumor suppressor in brain,lung and colon cancer by targeting p53 and was associated with tumorigenesis and metastasis.Notably,p21 plays a significant role in tumor development through p53-dependent and p53-independent pathways.In addition,expression of p21 is closely related to the resting state or terminal differentiation of cells.p21 is also associated with cancer stem cells and acts as a biomarker for such cells.In cancer therapy,given the importance of p21 in regulating the G1/S and G2 check points,it is not surprising that p21 is implicated in response to many cancer treatments and p21 promotes the effect of oncolytic virotherapy.

Clinical application of multidisciplinary teams in tumor therapy

Multidisciplinary team （MDT） model is a diagnostic and treatment model characterized by interdisciplinarity, integration, centralism, individualization, and precision and is becoming more common in the management of complex malignancies. MDT emphasizes team spirit and a personalized treatment strategy according to the actual condition of each patient. A cooperative and effective multidisciplinary team is an important guarantee for delivering high-quality services to patients. Under the guidance of a medical humanistic concept, MDT provides reasonable, effective, convenient, and a full range of excellent quality medical service to patients. The MDT maximizes patient benefits, and it is the developmental direction for large-scale general hospitals. At the same time, the MDT is also an important measure to strengthen the core competitiveness of hospitals. Here, we introduce the clinical application of the model in tumor therapy as well as the current state and development in our hospital.

Indocyanine green loaded graphene oxide for high-e±cient photoacoustic tumor therapy

Photoacoustic therapy,using the photoacoustic efect of agents for selectively kling tumor cells,has shown pronising for treat ing tumor.Utilization of high optical absorption probes can help to effectively improve the photoacoustic ther apy efficiency.Herein,we report a novel high-absorpt:ion photoacoustic probe that is composed of indocyanine green(ICG)and gr aphene oxide(GO),entitled GO-ICG,for photoacoustic ther apy.The attached ICG with narrow absorption spectral profile has strong optical absorption in the infrared region.The absorption spectrum of the GO-ICG solution reveals that the GO-ICG particles exhibited a 10-fold higher absorbance at 780 nm(its peak absorbance)as compared with GO.Importantly,ICG's fluorescence is quenched by GO via fuorescence resonance energy transfer.As a result,GO-ICG can high efficiently convert the absorbed light energy to acoustic wave under pulsed laser irradiation.We further demonstrate that GO-ICG can produce stronger photoacoustic wave than the GO and ICG alone.Moreover,we conjugate this contrast agent with integrin 0。As mono dlonal antibody to molecularly target the U87-MG human glioblastoma cells for selective tumor cell killing.Finally,our results testify that the photoacoustic therapy eficiency of GO-ICG is higher than the existing photoacoustic therapy agent.Our work demonstrates that GO-ICG is a high efficiency photo-acoustic therapy agent.This novel photoacoustic probe is likely to be an available candidate for tumor therapy.

ANALYSIS FOR A FREE BOUNDARY PROBLEM MODELING TUMOR THERAPY

This paper is devoted to studying a free boundary problem modeling the effects of drug resistance and vasculature on the response of solid tumors to therapy.The model consists of a system of partial differential equations governing intra-tumoral drug concentration and cancer cell density.By applying the Lp theory of parabolic equations and the Banach fixed point theorem,it is proved that this problem has a unique global classical solution.

Construction of Multi-Specific Antibody by Genetic Engineering and Its Progress in Tumor Therapy

Targeted treatment of cancer with monoclonal antibodies increases the benefit for patients. In order to improve the anti-tumor activity of monoclonal antibodies, multi-specific antibodies have entered the research field. The emergence of various techniques to produce multi-specific recombinant antibody molecules has led to the selection of target combinations in various forms. To date, only a few multi-specific constructs have entered phase III clinical trials, in contrast to classical monoclonal antibodies. Some of the format options are outlined from a technical point of view. We focus on the achievements and prospects of the underlying technologies for generating biand multispecific antibodies.

Three positive charge nonapoptotic-induced photosensitizer with excellent water solubility for tumor therapy

Photodynamic therapy(PDT)has emerged as a significant cancer therapy option.Currently,cation-based organic small molecule aggregation-induced emission(AIE)photosensitizers(PSs)attract the wide atten-tion of many scientists,due to improved reactive oxygen species(ROS)production after cationization.However,such PSs tend to localize only the mitochondria,limiting the death way of tumor cells(usu-ally apoptosis)during PDT process,which may affect the therapeutic effect under some circumstances.Herein,we designed a novel water-soluble three positive charge PS,TPAN-18F,which could be distributed uniformly in cell cytoplasm and had distribution in different sub-organelles(mitochondria,endoplasmic reticulum,lysosome).The experimental results showed that TPAN-18F-based PDT process can not only disrupt mitochondrial functions(reducing ATP production and destroying mitochondrial membrane po-tential),but also elevate the intracellular lipid peroxides(LPOs)level,which evoke the non-apoptotic death manner of tumor cells.Further,in vivo studies showed that TPAN-18F-based PDT could effectively inhibit tumor growth.Accordingly,we believe that the construction of TPAN-18F is suggestive for tumor non-apoptotic therapy.

CA IX-targeted Ag_(2)S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy

Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the tumors.Therefore,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely concerned.As carbonic anhydrase IX(CA IX)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfonamide(ABS)as a CA IX inhibitor has inherent inhibitory activity and good targeting effect.In this study,Ag_(2)S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe(Ag_(2)S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation reaction.Ag_(2)S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II(NIR-II)fluorescence characteristics of Ag_(2)S QDs.PEG modification of Ag_(2)S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal stability and high photothermal conversion efficiency(PCE)of 45.17%.Under laser irradiation,Ag_(2)S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in vitro.It also has been proved that Ag_(2)S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good biocompatibility.Therefore,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

Effect of endothelial progenitor cells in neovascularization and their application in tumor therapy

Objective To review the effect of endothelial progenitor cells in neovascularization as well as their application to the therapy of tumors.Data sources The data used in this review were mainly from PubMed for relevant English language articles published from 1997 to 2009. The search term was ＂endothelial progenitor cells＂.Study selection Articles regarding the role of endothelial progenitor cells in neovascularization and their application to the therapy of tumors were selected.Results Endothelial progenitor cells isolated from bone marrow, umbilical cord blood and peripheral blood can proliferate, mobilize and differentiate into mature endothelial cells. Experiments suggest endothelial progenitor cells take part in forming the tumor vascular through a variety of mechanisms related to vascular endothelial growth factor, matrix metalloproteinases, chemokine stromal cell-derived factor 1 and its receptor C-X-C receptor-4, erythropoietin, Notchsignal pathway and so on. Evidence demonstrates that the number and function change of endothelial progenitor cells in peripheral blood can be used as a biomarker of the response of cancer patients to anti-tumor therapy and predict the prognosis and recurrence. In addition, irradiation temporarily increased endothelial cells number and decreased the endothelial progenitor cell counts in animal models. Meanwhile, in preclinical experiments, therapeutic gene-modified endothelial progenitor cells have been approved to attenuate tumor growth and offer a novel strategy for cell therapy and gene therapy of cancer.Conclusions Endothelial progenitor cells play a particular role in neovascularization and have attractively potential prognostic and therapeutic applications to malignant tumors. However, a series of problems, such as the definitive biomarkers of endothelial progenitor cells, their interrelationship with radiotherapy and their application in cell therapy and gene therapy of tumors, need further investigation.

Real-time in vivo visualization of tumor therapy by a near-infrared-II Ag2S quantum dot-based theranostic nanoplatform

Real-time and objective feedback of therapeutic efficacies would be of great value for tumor treatment. Here, we report a smart Ag2S QD-based theranostic nanoplatform （DOX@PEG-Ag2S） obtained by loading the anti-cancer drug doxorubicin （DOX） into polyethylene glycol-coated silver sulfide quantum dots （PEG-Ag2S QDs） through hydrophobic-hydrophobic interactions, which exhibited high drug loading capability （93 wt.% of DOX to Ag2S QDs）, long circulation in blood （t1/2 = 10.3 h）, and high passive tumor-targeting efficiency （8.9% ID/gram） in living mice where % ID/gram reflects the probe concentration in terms of the percentage of the injected dose （ID） per gram of tissue. After targeting the tumor tissue, DOX from PEG-AgRS cargoes was selectively and rapidly released into cancer cells, giving rise to a significant tumor inhibition. Owing to the deep tissue penetration and high spatio-temporal resolution of Ag2S QDs fluorescence in the second near-infrared window （NIR-II）, the DOX@PEG-Ag2S enabled real-time in vivo reading of the drug targeting process and therapeutic efficacy. We expect that such a novel theranostic nanoplatform, DOX@PEG-Ag2S, with integrated drug delivery, therapy and assessment functionalities, will be highly useful for personalized treatments of tumors.

One-step nanoarchitectonics of a multiple functional hydrogel based on cellulose nanocrystals for effective tumor therapy

Hypoxia is a huge barrier for the development of photodynamic therapy(PDT).Chemodynamic therapy(CDT)could provide a possible solution to this dilemma.In this work,a controlled Schiff-base reaction was conducted between amido groups on the surface of carbon dots(CDs)and aldehyde groups on aldehyde-modified cellulose nanocrystals(mCNCs)as well as aldehydemCNCs decorated with Fe_(3)O_(4)nanoparticles.In this process,the mCNCs not only prevent the agglomeration of Fe_(3)O_(4)but also form hydrogels with CDs.The CDs act as both photothermal agent and photosensitizer.The hypoxia could be effectively relieved through the Fenton reaction due to the addition of Fe_(3)O_(4),and the·OH produced in the reaction further induces CDT and enhances tumor therapy efficiency.The therapy performance was further verified through in vitro cell experiments and in vivo animal experiments.This convenient method provides inspirations for the design and preparation of advanced biomaterials with multiple functions for cancer therapy.

Biomimetic copper single-atom nanozyme system for self-enhanced nanocatalytic tumor therapy

Single-atom nanozymes(SAZs)with peroxidase(POD)-like activity have good nanocatalytic tumor therapy(NCT)capabilities.However,insufficient hydrogen peroxide(H2O2)and hydrogen ions in the cells limit their therapeutic effects.Herein,to overcome these limitations,a biomimetic single-atom nanozyme system was developed for self-enhanced NCT.We used a previously described approach to produce platelet membrane vesicles.Using a high-temperature carbonization approach,copper SAZs with excellent POD-like activity were successfully synthesized.Finally,through physical extrusion,a proton pump inhibitor(PPI;pantoprazole sodium)and the SAZs were combined with platelet membrane vesicles to create PPS.Both in vivo and in vitro,PPS displayed good tumor-targeting and accumulation abilities.PPIs were able to simultaneously regulate the hydrogen ion,glutathione(GSH),and H2O2 content in tumor cells,significantly improve the catalytic ability of SAZs,and achieve self-enhanced NCT.Our in vivo studies showed that PPS had a tumor suppression rate of>90%.PPS also limited the synthesis of GSH in cells at the source;thus,glutamine metabolism therapy and NCT were integrated into an innovative method,which provides a novel strategy for multimodal tumor therapy.

Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS

Human cancers typically express a high level of tumor-promoting mutant p53 protein(Mutp53)with a minimal level of tumor-suppressing wild-type p53 protein(WTp53).In this regard,inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy.Herein,a new carrier-free nanoprodrug(i.e.,Mn-ZnO_(2)nanoparticles)was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species(ROS)within tumor to regulate the p53 protein for high anti-tumor efficacy.In response to the mild tumor acidic environment,the released Zn^(2+)and H_(2)O_(2)from Mn-ZnO_(2)NPs induced ubiquitination-mediated proteasomal degradation of Mutp53,while the liberative Mn^(2+)and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level.Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical(·OH)through the Fenton-like reaction.With the integration of multiple functions(i.e.,carrier-free ion and ROS delivery,tumor accumulation,p53 protein modulation,toxic·OH generation,and pH-activated MRI contrast)in a single nanosystem,Mn-ZnO_(2)NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy.

Fabrication of microwave-sensitized nanospheres of covalent organic framework with apatinib for tumor therapy

A new nanocomposite of hollow covalent organic framework(COF)conjugated with the apatinib(AP)and loading microwave-sensitizer(ionic liquid,IL)was prepared by layer by layer(LBL)method and hyaluronic acid(HA)coating,named as COF-AP-IL@HA.AP loading rate in COF hollow-spheres(~30 nm shell thickness)was~40.3%,due to the interactions of hydrogen andπ-πbonds between AP and COF shell,and acidic environment destroyed COF structure,promoting AP release.Microwave sensitization of loaded IL in COF hollow-spheres could enhance the microwave heat-effect,and combined AP therapeutic ability,leading to their higher inhibitation on tumor,due to targeting ability of HA and the local release of apatinib.88.9%of inhibition rate of COF-AP-IL@HA under microwave on the in vivo tumor was significantly higher than those without microwave(12.3%)and COF-IL@HA with microwave(37.5%),indicating a synergism of sensitized microwave hyperthermia and AP therapy on the reduced expression of VEGF via the downregulation pathway of hypoxia inducible factor.These results indicated that COF-AP-IL@HA was potential to the application in the combination therapy of tumor of the sensitized microwave hyperthermia and apatinib.

Reductive damage induced autophagy inhibition for tumor therapy

Numerous therapeutic anti-tumor strategies have been developed in recent decades.However,their therapeutic efficacy is reduced by the intrinsic protective autophagy of tumors.Autophagy plays a key role in tumorigenesis and tumor treatment,in which the overproduction of reactive oxygen species(ROS)is recognized as the direct cause of protective autophagy.Only a few molecules have been employed as autophagy inhibitors in tumor therapy to reduce protective autophagy.Among them,hydroxychloroquine is the most commonly used autophagy inhibitor in clinics,but it is severely limited by its high therapeutic dose,significant toxicity,poor reversal efficacy,and nonspecific action.Herein,we demonstrate a reductive-damage strategy to enable tumor therapy by the inhibition of protective autophagy via the catalytic scavenging of ROS using porous nanorods of ceria(PN-CeO_(2))nanozymes as autophagy inhibitor.The antineoplastic effects of PN-CeO_(2)were mediated by its high reductive activity for intratumoral ROS degradation,thereby inhibiting protective autophagy and activating apoptosis by suppressing the activities of phosphatidylinositide 3-kinase/protein kinase B and p38 mitogen-activated protein kinase pathways in human cutaneous squamous cell carcinoma.Further investigation highlighted PN-CeO_(2)as a safe and efficient anti-tumor autophagy inhibitor.Overall,this study presents a reductive-damage strategy as a promising anti-tumor approach that catalytically inhibits autophagy and activates the intrinsic antioxidant pathways of tumor cells and also shows its potential for the therapy of other autophagy-related diseases.

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.Herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

Melt electrospinning of daunorubicin hydrochloride-loaded poly (ε-caprolactone) fibrous membrane for tumor therapy

Daunorubicin hydrochloride is a cell-cycle non-specific antitumor drug with a high therapeutic effect.The present study outlines the fabrication of daunorubicin hydrochloride-loaded poly (ε-caprolactone)(PCL) fibrous membranes by melt electrospinning for potential application in localized tumor therapy.The diameters of the drug-loaded fibers prepared with varying concentrations of daunorubicin hydrochloride(1, 5, and 10 wt%) were 2.48 ± 1.25, 2.51 ± 0.78, and 2.49 ± 1.58 μm, respectively. Fluorescenceimages indicated that the hydrophobic drug was dispersed in the hydrophilic PCL fibers in theiraggregated state. The drug release profiles of the drug-loaded PCL melt electrospun fibrous membraneswere approximately linear, with slow release rates and long-term release periods, and no observed burstrelease. The MTT assay was used to examine the cytotoxic effect of the released daunorubicin hydrochlorideon HeLa and glioma cells (U87) in vitro. The inhibition ratios of HeLa and glioma cells followingtreatment with membranes prepared with 1, 5, and 10 wt% daunorubicin hydrochloride were 62.69%,76.12%, and 85.07% and 62.50%, 77.27%, and 84.66%, respectively. Therefore, PCL melt electrospun fibrousmembranes loaded with daunorubicin hydrochloride may be used in the local administration ofoncotherapy.

Phenylboronic acid-modified hollow silica nanoparticles for dual-responsive delivery of doxorubicin for targeted tumor therapy

This work reports a multifunctional nanocarrier based on hollow mesoporous silica nanoparticles(HMSNs)for targeting tumor therapy.Doxorubicin(DOX)was loaded into HMSNs and blocked with cytochrome C conjugated lactobionic acid(CytC–LA)via redox-cleavable disulfide bonds and pH-disassociation boronate ester bonds as intermediate linkers.The CytC–LA was used both as sealing agent and targeting motif.A series of characterizations demonstrated the successful construction of the drug delivery system.The system demonstrated pH and redox dual-responsive drug release behavior in vitro.The DOX loading HMSNs system displayed a good biocompatibility,which could be specifically endocytosed by HepG2 cells and led to high cytotoxicity against tumor cells by inducing cell apoptosis.In vivo data(tumor volume,tumor weight,terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining)proved that the system could deliver DOX to tumor site with high efficiency and inhibit tumor growth with minimal toxic side effect.

Realize molecular surgical knife in tumor therapy by nanotechnology

In cancer therapy,the main challenge is how to attack the tumor and avoid injuring any normal organs in the meantime.In the last decades,scientists have made great efforts to try targeting the tumors,but little progress is achieved because all of the known therapeutic techniques could not latch the tumor cells down and always bring

Ferritin-based drug delivery system for tumor therapy

Ferritin has been widely used in drug delivery in recent years due to its unique spherical nanocage structure.In addition,the natural targeting and good biocompatibility of ferritin make it an excellent drug delivery system.Therefore,ferritin has shown a broad application prospect in the field of nanomedicine.In this perspective,we will describe ferritin-based drug delivery system,ferritin-based drug delivery system for tumor treatment,and future challenges in ferritin development.Hopefully,this perspective may inspire the future development of ferritin-based drug delivery systems for tumor treatment.