Establishment of NaLuF_(4):15%Tb-based low dose X-PDT agent and its application on efficient antitumor therapy

X-ray excited photodynamic therapy(X-PDT)is the bravo answer of photodynamic therapy(PDT)for deep-seated tumors,as it employs X-ray as the irradiation source to overcome the limitation of light penetration depth.However,high X-ray irradiation dose caused organ lesions and side effects became the major barrier to X-PDT application.To address this issue,this work employed a classic-al co-precipitation reaction to synthesize NaLuF_(4):15%Tb^(3+)(NLF)with an average particle size of(23.48±0.91)nm,which was then coupled with the photosensitizer merocyanine 540(MC540)to form the X-PDT system NLF-MC540 with high production of singlet oxygen.The system could induce antitumor efficacy to about 24%in relative low dose X-ray irradiation range(0.1-0.3 Gy).In vivo,when NLF-MC540 irradiated by 0.1 Gy X-ray,the tumor inhibition percentage reached 89.5%±5.7%.The therapeutic mechanism of low dose X-PDT was found.A significant increase of neutrophils in serum was found on the third day after X-PDT.By immunohistochemical staining of tumor sections,the Ly6G^(+),CD8^(+),and CD11c^(+)cells infiltrated in the tumor microenvironment were studied.Utilizing the bilat-eral tumor model,the NLF-MC540 with 0.1 Gy X-ray irradiation could inhibit both the primary tumor and the distant tumor growth.De-tected by enzyme linked immunosorbent assay(ELISA),two cytokines IFN-γand TNF-αin serum were upregulated 7 and 6 times than negative control,respectively.Detected by enzyme linked immune spot assay(ELISPOT),the number of immune cells attributable to the IFN-γand TNF-αlevels in the group of low dose X-PDT were 14 and 6 times greater than that in the negative control group,respectively.Thus,it conclude that low dose X-PDT system could successfully upregulate the levels of immune cells,stimulate the secretion of cy-tokines(especially IFN-γand TNF-α),activate antitumor immunity,and finally inhibit colon tumor growth.

Chinese Medicine Single-Walled Carbon Nanotube Targeting Compound for Antitumor Therapy:A Feasible Way?

Malignant cancer is the leading cause of death in man,exceeding cerebrovascular disease and heart disease.More than half of the total mortality due to malignant cancer is from lung,liver,intestinal and gastric cancer.Chemotherapy is one of the effective treatments for cancer.However,the great majority of Western anticancer medicines have considerable side effects.Herbal medicines offer many more advantages than synthesized compounds because they are made from purely natural compounds and have less adverse effects.However,the single administration methods used as standard in herbal medicine,and deficient drug targeting,severely limit their anticancer activity.Single-walled carbon nanotubes（SWNTs）can be used as drug carriers.They have been modified to form Chinese anticancer medicine-SWNT compounds which can specifically target tumors,thereby significantly increasing the therapeutic effectiveness of these medicines.Water-soluble SWNTs have high stability.As a drug carrier,SWNTs functional modification of the anticancer medicine may improve the targeting and killing of tumor cells.SWNTs have been attached to the Chinese antitumor medicines paclitaxel and plumbagin and have achieved excellent therapeutic effects.Furthermore,choosing the best administration methods such as internal iliac arterial infusion,intravesical infusion and embedment of a hypodermic chemotherapeutic pump,may also improve the anticancer effects of Chinese medicine.

Acid-sensitive PEGylated cabazitaxel prodrugs for antitumor therapy

Although the antitumor drug cabazitaxel shows great therapeutic potential,its high toxicity and poor water solubility limit its utility.However,the use of stimuli-responsive prodrugs is a promising strategy for overcoming these limitations.Herein,we report the synthesis of two highly water soluble,acidsensitive PEGylated acyclic-ketal-linked cabazitaxel prodrugs(PKCs)with improved antitumor efficacy.In an acidic tumor microenvironment,the PKCs hydrolyzed rapidly to release the native drug,whereas they were stable in the normal physiological environment.Compared with cabazitaxel injection,the PKCs had much higher maximum tolerated doses:and in an MDA-MB-231 subcutaneous xenograft nude mouse model,the PKCs showed better antitumor efficacy and safety than cabazitaxel injection.The prodrug strategy reported herein could be useful for the development of other water soluble,acidsensitive prodrugs with improved efficacy.

Preparation of NIR-II-excited Drug-loaded Liposomes and Their Antitumor Activity and in Vitro Imaging Studies

In recent years,with the rapid development of nano-technology,the combination of diagnosis and treatment by nanotechnologyhas brought new hope for mankind to overcome cancer.The Near-infrared two-region(NIR-II)imaging technology hasdeveloped rapidly in recent years because of its non-invasive nature,strong tissue penetration and overall imaging of small animals.In this study,a novel nano-drug delivery system(DOX-IR1061 cationic liposomes)was prepared,loaded with doxorubicin(DOX)as a chemotherapeutic drug and NIR-II-excited fluorescent probe IR1061 as an imaging agent,and the uptake ability of tumor cellswas enhanced by octadecylamine.DOX-IR1061 cationic liposomes have good NIR-II imaging ability,clear imaging and obvioussignal.Cell uptake indicated that palamine could enhance the uptake efficiency of cationic liposomes by tumor cells,while in vitroanti-tumor experiments revealed that the enhancement of uptake efficiency would enhance the anti-tumor effect of DOX.Therefore,DOX-IR1061 cationic liposomes we prepared have the potential to realize both tumor imaging and therapy,and to realize theintegration of rapid diagnosis and treatment,and provide new ideas for cancer cure and the development of the field of diagnosis andtreatment integration.

Biomedical overview of melanin.1.Updating melanin biology and chemistry,physico-chemical properties,melanoma tumors,and photothermal therapy

Melanins(eumelanin,pheomelanin,and allomelanin)represent a very,if not themost,important group of biological pigments.Their biological roles are multiple,from photoprotection to antioxidant activity,heavy metal disposal or the myriad uses of color in organisms across all Phyla.In the first part of this review,eumelanin biology and some chemical aspects will be presented,as well as key physico-chemical features that make this biological pigment so interesting.The principal characteristics of the melanocyte,the melanin-synthesizing cell in mammals,will also be introduced.Transformed melanocytes are the cause of one of the most devastating known cancers:the malignant melanoma.Epidemiology and molecular signaling aspects will be presented next,as well as the principal advances in promising oncotherapies designed and applied for the treatment of melanoma.In particular,on account of the photo-physical properties of melanin,special details will be provided regarding the use of photothermal therapy for melanoma treatment.

Construction of curcumin-loaded micelles and evaluation of the anti-tumor effect based on angiogenesis

Objective:Inhibition of tumor angiogenesis has become a new targeted tumor therapy.In this study,we established a micellar carrier with a tumor neovascularization-targeting effect modified by the neovascularization-targeting peptide NGR.Methods:The targeted polymer poly(ethylene glycol)-b-poly(lactide-co-glycolide)(PEG-PLGA)modified with Asn–Gly–Arg(NGR)peptide was prepared and characterized by 1H nuclear magnetic resonance and Fourier-transform infrared spectrometry.NGR-PEG-PLGA was used to construct curcumin(Cur)-loaded micelles by the solvent evaporation method.The physicochemical properties of the micelles were also investigated.Additionally,we evaluated the antitumor efficacy of the polymer micelles(PM)using in vitro cytology experiments and in vivo animal studies.Results:The particle size of Cur-NGR-PM was 139.70±2.51 nm,and the drug-loading capacity was 14.37±0.06%.In vitro cytological evaluation showed that NGR-modified micelles showed higher cellular uptake through receptor-mediated endocytosis pathways than did unmodified micelles,leading to the apoptosis of tumor cells.Then,in vivo antitumor experiments showed that the modified micelles significantly inhibited tumor growth and were safe.Conclusions:NGR-modified micelles significantly optimized the therapeutic efficacy of Cur.This strategy offers a viable avenue for cancer treatment.

Chinese expert consensus on prevention and treatment of delayed nausea and vomiting(2022 Edition)

Nausea and vomiting are common adverse reactions of antitumor therapy,among which chemotherapy-induced nausea and vomiting(CINV)has been studied most intensively.Because of insufficient prevention or insufficient attention,CINV brings a series of harms to can-cer patients and even lead to the delay or termination of antitumor therapy.Delayed CINV is often underestimated because it mostly occurs outside the hospital,and patients cannot report it immediately.In recent years,the proportion of outpatient chemotherapy and day-time chemotherapy patients in China has increased year by year.Therefore,the prevention of delayed CINV is particularly important.Currently,the challenges faced by delayed CINV include the need to deeply explore its physiological and pathological mechanisms,improve its risk assessment standards,and optimize its prevention programs.However,there is still lack of practice guidelines or consensus on delayed CINV.Therefore,the Committee of Neoplastic Supportive-Care of China Anti-Cancer Association organized multidisciplinary experts in this field to formulate this consensus based on the analysis and discussion of current evidence-based medical research in combination with clinical problems that need to be solved urgently.

Research progress on O-GlcNAcylation in the occurrence,development,and treatment of colorectal cancer

For a long time,colorectal cancer(CRC)has been ranked among the top cancerrelated mortality rates,threatening human health.As a significant posttranslational modification,O-GlcNAcylation plays an essential role in complex life activities.Related studies have found that the occurrence,development,and metastasis of CRC are all related to abnormal O-GlcNAcylation and participate in many critical biological processes,such as gene transcription,signal transduction,cell growth,and differentiation.Recently,nucleotide sugar analogs,tumorspecific carbohydrate vaccine,SIRT1 longevity gene,dendritic cells as targets,and NOTCH gene have become effective methods to induce antitumor therapy.Not long ago,checkpoint kinase 1 and checkpoint kinase 2 were used as therapeutic targets for CRC,but there are still many problems to be solved.With an in-depth study of protein chip,mass spectrometry,chromatography,and other technologies,O-GlcNAcylation research will accelerate rapidly,which may provide new ideas for the research and development of antitumor drugs and the discovery of new CRC diagnostic markers.

Integrins in human hepatocellular carcinoma tumorigenesis and therapy

Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.

PDA-BPs integrated mussel-inspired multifunctional hydrogel coating on PPENK implants for anti-tumor therapy,antibacterial infection and bone regeneration

Currently,many cancer patients with bone defects are still threatened by tumor recurrence,postoperative bacterial infection,and massive bone loss.Many methods have been studied to endow bone implants with biocompatibility,but it is difficult to find an implant material that can simultaneously solve the problems of anticancer,antibacterial and bone promotion.Here,a multifunctional gelatin methacrylate/dopamine methacrylate adhesive hydrogel coating containing 2D black phosphorus(BP)nanoparticle protected by polydopamine(pBP)is prepared by photocrosslinking to modify the surface of poly(aryl ether nitrile ketone)containing phthalazinone(PPENK)implant.The multifunctional hydrogel coating works in conjunction with pBP,which can deliver drug through photothermal mediation and kill bacteria through photodynamic therapy at the initial phase followed by promotion of osteointegration.In this design,photothermal effect of pBP control the release of doxorubicin hydrochloride loaded via electrostatic attraction.Meanwhile,pBP can generate reactive oxygen species(ROS)to eliminate bacterial infection under 808 nm laser.In the slow degradation process,pBP not only effectively consumes excess ROS and avoid apoptosis induced by ROS in normal cells,but also degrade into PO43to promote osteogenesis.In summary,nanocomposite hydrogel coatings provide a promising strategy for treatment of cancer patients with bone defects.

Research Article Dynamically crosslinked nanocapsules for the efficient and serumresistant cytosolic protein delivery

Intracellular protein delivery is critical to the development of protein-based biopharmaceuticals and therapies.However,current delivery vectors often suffer from complicated syntheses,low generality among various proteins,and insufficient serum stability.Herein,we developed an enlightened cytosolic protein delivery strategy by dynamically crosslinking epigallocatechin gallate(EGCG),low-molecular-weight polyethylenimine(PEI 1.8k),and 2-acetylphenylboric acid(2-APBA)on the protein surface,hence forming the EPP-protein nanocapsules(NCs).EGCG enhanced protein encapsulation via hydrogen bonding,and reduced the positive charge density of PEI to endow the NCs with high serum tolerance,thereby enabling effective cellular internalization in serum.The formation of reversible imine and boronate ester among 2-APBA,EGCG,and PEI 1.8k allowed acid-triggered dissociation of EPP-protein NCs in the endolysosomes,which triggered efficient intracellular release of the native proteins.Such strategy therefore showed high efficiency and universality for diversities of proteins with different molecular weights and isoelectric points,including enzyme,toxin,antibody,and CRISPR(clustered regularly interspaced short palindromic repeats)-Cas9 ribonucleoprotein(RNP),outperforming the commercial protein transduction reagent PULSin and RNP transfection reagent lipofectamine CMAX.Moreover,intravenously(i.v.)injected EPP-saporin NCs efficiently delivered saporin into 4T1 tumor cells to provoke robust antitumor effect.This simple,versatile,and robust cytosolic protein delivery system holds translational potentials for the development of protein-based therapeutics.

Regulating Signal Pathway Triggers Circular Reactive Oxygen Species Production to Augment Oxidative Stress with Enzyme-Activated Nanoparticles

Regulating antioxidative stress pathways to augment oxidative stress and enhance antitumor therapy is highly desirable but very challenging.Herein,we initiated a multifunctional nanoparticle to regulate the Keap1-Nrf2 antioxidative stress pathway to promote cancer cell apoptosis.The OPFV-SnMP@GE11 nanoparticles were assembled by enzyme-activated OPFV-TLQ,tin mesoporphyrin(SnMP),and DSPEPEG-GE11.OPFV-SnMP@GE11 accumulated at tumor sites through specific targeting with GE11.OPFV-TLQ was specifically reduced to a photosensitizer OPFVNH2 by endocellular NAD(P)H:quinone oxidoreductase 1(NQO1).Under irradiation,OPFV-NH2 greatly produced reactive oxygen species(ROS)through a type I mechanism,which activated the Keap1-Nrf2 signal pathway and enhanced the transcription of NQO1,resulting in a continuous and explosive generation of ROS.Additionally,SnMP inhibited the activity of heme oxygenase-1(HO-1),further depressing antioxidative stress.This strategy provides insight into the regulation of the signal pathway to amplify oxidative stress,paving the way to studying the molecular mechanisms of cellular activities to enhance cancer therapy.

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

Toll-like receptors(TLRs)are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses.TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response.The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer(NK)cells.However,the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear,and different TLR7/8 agonists have been found to induce different responses.In this study,we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes,stimulate the activation of splenic T,NK and natural killer T(NKT)cells,increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines,and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells(DCs).In a murine model,both agonists improved the antitumor effects of tumor lysate-loaded DCs,resulting in delayed growth of subcutaneous B16 melanoma tumors and suppression of pulmonary metastasis.Further,we found that gardiquimod demonstrated more potent antitumor activity than imiquimod.These results suggest that TLR7/8 agonists may serve as potent innate and adaptive immune response modifiers in tumor therapy.More importantly,they can be used as vaccine adjuvants to potentiate the efficiency of DC-based tumor immunotherapy.

In situ triggering antitumor efficacy of alcoholabuse drug disulfiram through Cu-based metalorganic framework nanoparticles

Although approved as an alcohol-abuse drug,disulfiram(DSF)exhibited potential anticancer activity when chelated with copper(Cu).However,the low level of intrinsic Cu,toxicity originated from exogenous Cu supplementation,and poor stability of DSF in vivo severely limited its application in cancer treatment.Herein,we proposed an in situ DSF antitumor efficacy triggered system,taking advantages of Cu-based metal-organic framework(MOF).In detail,DSF was encapsulated into Cu-MOF nanoparticles(NPs)during its formation,and the obtained NPs were coated with hyaluronic acid to enhance the tumor targetability and biocompatibility.Notably,DSF loaded Cu-MOF NPs maintained stability and integrity without Cu;leakage in blood circulation,thus showing excellent biosafety.Once accumulating at tumor site,NPs were internalized into tumor cells via receptor-mediated endocytosis and released DSF and Cu;simultaneously in the hyaluronidase-enriched and acidic intracellular tumor microenvironment.This profile lead to in situ chelation reaction between DSF and Cu;,generating toxic DSF/Cu complex against tumor cells.Both in vitro and in vivo results demonstrated the programmed degradation and recombination property of Cu-based MOF NPs,which facilitated the tumor-specific chemotherapeutic effects of DSF.This system provided a promising strategy for the application of DSF in tumor therapy.

Super-sensitive bifunctional nanoprobe: Self-assembly of peptide-driven nanoparticles demonstrating tumor fluorescence imaging and therapy

The development of nanomedicine has recently achieved several breakthroughs in the field of cancer treatment;however,biocompatibility and targeted penetration of these nanomaterials remain as limitations,which lead to serious side effects and significantly narrow the scope of their application.The self-assembly of intermediate filaments with arginine-glycine-aspartate(RGD)peptide(RGDIFP)was triggered by the hydrophobic cationic molecule 7-amino actinomycin D(7-AAD)to synthesize a bifunctional nanoparticle that could serve as a fluorescent imaging probe to visualize tumor treatment.The designed RGD-IFP peptide possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step method.This fluorescent nanoprobe with RGD peptide could be targeted for delivery into tumor cells and released in acidic environments such as endosomes/lysosomes,ultimately inducing cytotoxicity by arresting tumor cell cycling with inserted DNA.It is noteworthy that the RGD-IFP/7-AAD nanoprobe tail-vein injection approach demonstrated not only high tumor-targeted imaging potential,but also potent antitumor therapeutic effects in vivo.The proposed strategy may be used in peptide-driven bifunctional nanoparticles for precise imaging and cancer therapy.

Multifunctional Reduced Graphene Oxide Hydrogel as Drug Carrier for Localized and Synergic Photothermal/Photodynamics/Chemo Therapy

To combine localized drug release with multimodal therapy for malignant tumor, a composite hydrogel as an integrative drug delivery system was facilely prepared. The system contains spinach extract （SE）, reduced graphene oxide （rGO） and gold nanocages （AuNCs）. SE conduces to the formation of hydrogel, and also serves as a green material for improving the biocompatibility of hydrogel, and a natural pho- tosensitizer for killing tumor cells under laser radiation （fi60 nm）. AuNts show obvious photothermy and can enhance the generation of cytotoxic singlet oxygen （102）. The composite hydrogel shell on tumor cells exhibits several competitive advantages including enhanced antitumor effect by retaining the high con- centration of drugs around cancer cell, excellent PDT/FFr compatibility as well as high loading and controllable release of fluorouracil （5-FU） for synergetic multimodal treatment. The survival rate of HeLa cells incubated with 5-FU loaded hydrogel under NIR radiation for 10 min sharply decreases to 1.2%, in- dicating remarkably improved antitumor effects. These results demonstrate that the hydrogel is an excellent delivery carrier for localizable, NIR-responsive and combined PTT/PDT/Chemo synergetic antitumor.

Recent advances for liquid metals:Synthesis,modification and bio-applications

Considering the application requirements for modern biomedicine,research into novel biomaterials with unusual functions is highly desired.As an alternative,liquid metals(LMs),a nontraditional family of metal materials,have piqued the interest of biomedical researchers and made significant advances in biomed-ical areas,owing to their shape transformability,self-healing capability,excellent electrical,and thermal conductivities.In particular,many functionalized strategies for the preparation and modification of LMs or LMs-based composites to achieve extended biomedical applications have been investigated in recent years.These findings provided inspiring while constructive reference for the fabrication and engineering of novel LMs-based composites.Herein,in this topic review,we elaborate on the recent advances of LMs-based functional materials,with particular focuses on the synthesis,modification,and bio-applications,especially in antitumor therapy,antibacterial,contrast agent for imaging,bone repair,electronic skin sen-sor,and nerve connection agent.Further on,the current challenges and future prospects of LMs-based composites are carefully discussed.

Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

Peroxidase-mimicking evodiamine/indocyanine green nanoliposomes for multimodal imaging-guided theranostics for oral squamous cell carcinoma

Here,evodiamine(EVO)and the photosensitizer indocyanine green(ICG)were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma(OSCC).EVO,as an active component extracted from traditional Chinese medicine,not only functioned as an antitumor chemotherapeutic agent but was also capable of 68Ga-chelation,thus working as a contrast agent for positron emission tomography/computed tomography(PET/CT)imaging.Moreover,EVO could exhibit peroxidase-like catalytic activity,converting endogenous tumor H2O2 into cytotoxic reactive oxygen species(ROS),enabling Chemo catalytic therapy beyond the well-known chemotherapy effect of EVO.As proven by in vitro and in vivo experiments,guided by optical imaging and PET/CT imaging,we show that the theragnostic liposomes have a significant inhibiting effect on in situ tongue tumor through photodynamic therapy combined with chemodynamic chemotherapy.

Amino acid derivatives of pyropheophorbide-a ethers as photosensitizer： Synthesis and photodynamic activity

Ten new water-soluble amino acid conjugates of pyropheophorbide-a ethers 4a-4J were synthesized and investigated for their in vitro photodynamic antitumor activity. The results showed that all compounds exhibited higher phototoxicity and lower dark toxicity against three kinds of tumor cell lines than BPD-MA. In particular, the most phototoxic compound 4d and 4j individually showed ICso values of 41 nmol/L and 33 nmol/L against HCT116 cell, which represented 7.8- and 9.7-fold increase of antitumor potency compared to BPD-MA, respectively, suggesting that they were promising photosensitizers for PDT applications because of their strong absorption at long wavelength （λmax 〉 650 nm）, high phototoxicitv, low dark cvtotoxicitv and ~ood water-solubility.