ABSTRACT
Human epithelial growth factor receptor-2 (HER2) plays an oncogenic role in numerous tumors, including breast, gastric, and various other solid tumors. While anti-HER2 therapies are approved for the treatment of HER2-positive tumors, a necessity persists for creating novel HER2-targeted agents to resolve therapeutic resistance. Utilizing a synthetic nanobody library and affinity maturation, our study identified four anti-HER2 nanobodies that exhibited high affinity and specificity. These nanobodies recognized three distinct epitopes of HER2-ECD. Additionally, we constructed VHH-Fc and discovered that they facilitated superior internalization and showed moderate growth inhibition. Compared to the combination of trastuzumab and pertuzumab, the VHH-Fc combos or their combination with trastuzumab demonstrated greater or comparable antitumor activity in both ligand-independent and ligand-driven tumors. Most remarkably, A9B5-Fc, which targeted domain I of HER2-ECD, displayed significantly enhanced trastuzumab-synergistic antitumor efficacy compared to pertuzumab under trastuzumab-resistant conditions. Our findings offer anti-HER2 nanobodies with high affinity and non-overlapping epitope recognition. The novel nanobody-based HER2-targeted antibody, A9B5-Fc, binding to HER2-ECD I, mediates promising receptor internalization. It possesses the potential to serve as a potent synergistic partner with trastuzumab, contributing to overcoming acquired resistance.
Subject(s)
Neoplasms , Single-Domain Antibodies , Humans , Trastuzumab/pharmacology , Trastuzumab/therapeutic use , Receptor, ErbB-2 , Single-Domain Antibodies/pharmacology , Single-Domain Antibodies/therapeutic use , Ligands , Neoplasms/pathology , EpitopesABSTRACT
The recent evolution of molecular targeted therapy has improved clinical outcomes in several human malignancies. The translocation of anaplastic lymphoma kinase (ALK) was originally identified in anaplastic large-cell lymphoma (ALCL) and subsequently in non-small cell lung carcinoma (NSCLC). Since ALK fusion gene products act as a driver of carcinogenesis in both ALCL and NSCLC, several ALK tyrosine kinase inhibitors (TKIs) have been developed. Crizotinib and alectinib are first- and second-generation ALK TKIs, respectively, approved for the treatment of ALK-positive ALCL (ALK+ ALCL) and ALK+ NSCLC. Although most ALK+ NSCLC patients respond to crizotinib and alectinib, they generally relapse after several years of treatment. We previously found that DNA-demethylating agents enhanced the efficacy of ABL TKIs in chronic myeloid leukemia cells. Moreover, aberrant DNA methylation has also been observed in ALCL cells. Thus, to improve the clinical outcomes of ALK+ ALCL therapy, we investigated the synergistic efficacy of the combination of alectinib and the DNA-demethylating agent azacytidine, decitabine, or OR-2100 (an orally bioavailable decitabine derivative). As expected, the combination of alectinib and DNA-demethylating agents synergistically suppressed ALK+ ALCL cell proliferation, concomitant with DNA hypomethylation and a reduction in STAT3 (a downstream target of ALK fusion proteins) phosphorylation. The combination of alectinib and OR-2100 markedly altered gene expression in ALCL cells, including that of genes implicated in apoptotic signaling, which possibly contributed to the synergistic anti-ALCL effects of this drug combination. Therefore, alectinib and OR-2100 combination therapy has the potential to improve the outcomes of patients with ALK+ ALCL.
ABSTRACT
Introduction: The home learning environment is the earliest contact learning environment in early childhood development, which plays an important role in the development of children's social-emotional competence. However, previous studies have not clarified the precise mechanisms by which the home learning environment influences children's social-emotional competence. Therefore, the purpose of the study is to explore the relationship between the home learning environment and its intrinsic structure (i.e. structural family characteristics, parental beliefs and interests, and the educational processes) and children's social-emotional competence, and whether gender plays a moderating role in the relationship. Method: The study randomly selected a sample of 443 children from 14 kindergartens in western China. The Home Learning Environment Questionnaire and the Chinese Inventory of Children's Social-emotional competence scale were used to investigate the home learning environment and social-emotional competence of these children. Results: (1) Structural family characteristics and parental beliefs and interests both had a significant positive predictive effect on children's social-emotional competence. (2) The educational processes fully mediate between structural family characteristics, parental beliefs and interests, and children's social-emotional competence. (3) Gender moderated the effect of the home learning environment on children's social-emotional competence. Gender moderates not only the indirect effects between parental beliefs and interests and children's social-emotional competence, but also the indirect effects between structural family characteristics and children's social-emotional competence. At the same time, gender also moderated the direct effects between parental beliefs and interests and children's social-emotional competence. Discussion: The results emphasize the crucial role of the home learning environment in the development of children's early social-emotional competence. Therefore, parents should pay attention to the home learning environment and improve their ability to create a home learning environment that promotes the positive development of children's social-emotional competence.
ABSTRACT
Background: Synergistic anti-tumor effects were observed in vivo and in vitro when immune checkpoint inhibitors (ICIs) were combined with denosumab. However, the clinical benefit and safety of this synergy have not been adequately evaluated in non-small cell lung cancer (NSCLC). Methods: Consecutive charts of NSCLC patients with bone metastases between December 2020 and December 2021 in the Chinese National Cancer Center were reviewed. The entire cohort was divided into one experimental group (denosumab + ICIs [DI]) and three control groups (denosumab + non-ICIs [DnI], phosphates + ICIs [PI], phosphates + non-ICIs [PnI]). Real-world objective response rates (ORRs), median progression-free survival (mPFS), skeletal-related events (SREs), and adverse events (AEs) were compared between groups. Results: A total of 171/410 (41.7%) patients with advanced or recurrent NSCLC carrying bone metastases who received bone-targeted therapy were eligible for analysis. Although the DI group showed a better benefit trend, differences were not statistically significant concerning the therapeutic efficacy among the DI group (n = 40), PI group (n = 74), DnI group (n = 15), and PnI group (n = 42) (ORRs: 47.5%, 43.2%, 33.3%, and 40.5%, respectively, p = 0.799; and mPFS: 378, 190, 170, and 172 days, respectively, p = 0.115; SREs: 5%, 10.8%, 13.3%, and 11.9%, respectively, p = 0.733). Nevertheless, further analysis in the NON-DRIVER cohort revealed a greater benefit for the DI group (p = 0.045). Additionally, the AEs of the DI group were not significantly different from those of the PI, DnI, and PnI groups (AEs: 27.5%, 39.2%, 26.7%, and 28.6%, respectively, p = 0.742). Furthermore, the multivariate analysis revealed the independent prognostic role of DI treatment for PFS in the overall cohort. Within the DI group, we did not observe differences in benefit among different mutational subgroups (p = 0.814), but patients with single-site bone metastasis (p = 0.319) and high PD-L1 expression (p = 0.100) appeared to benefit more, though no significant differences were observed. Conclusions: Denosumab exhibited synergistic antitumor efficacy without increasing toxicity when used concomitantly with ICIs in patients with advanced non-small cell lung cancer carrying bone metastases.
Subject(s)
Bone Neoplasms , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Bone Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Denosumab/adverse effects , Humans , Immunologic Factors/therapeutic use , Immunotherapy , Lung Neoplasms/pathology , Neoplasm Recurrence, Local , Phosphates , Retrospective StudiesABSTRACT
BACKGROUND: Osteosarcoma (OS) is a tumour with a high malignancy level and a poor prognosis. First-line chemotherapy for OS has not been improved for many decades. Bromodomain and extraterminal domain (BET) and histone deacetylases (HDACs) regulate histone acetylation in tandem, and BET and HDACs have emerged as potential cancer therapeutic targets. METHODS: Cell proliferation, migration, invasion, colony formation, and sphere-forming assays were performed with the two inhibitors alone or in combination to evaluate their suppressive effect on the malignant properties of OS cells. Apoptosis and the cell cycle profile were measured by flow cytometry. The synergistic inhibitory effect of OTX015/WT-161 on tumours was also examined in a nude mouse xenograft model. RESULTS: The combined therapy of OTX015/WT-161 synergistically inhibited growth, migration, and invasion and induced apoptosis, resulting in G1/S arrest of OS cells. Additionally, OTX015/WT-161 inhibited the self-renewal ability of OS stem cells (OSCs) in a synergistic manner. Further mechanistic exploration revealed that the synergistic downregulation of ß-catenin by OTX015-mediated suppression of FZD2 and WT-161-mediated upregulation of PTEN may be critical for the synergistic effect. Finally, the results of an in vivo assay showed that tumour xenografts were significantly decreased after treatment with the OTX015/WT-161 combination compared with OTX015 or WT-161 alone. CONCLUSIONS: Our findings in this study demonstrated that OTX015 and WT-161 had synergistic anticancer efficacy against OS, and their combination might be a promising therapeutic strategy for OS.
ABSTRACT
Tumor vasculature-targeting therapy either using angiogenesis inhibitors or vascular disrupting agents offers an important new avenue for cancer therapy. In this work, a tumor-specific catalytic nanomedicine for enhanced tumor ablation accompanied with tumor vasculature disruption and angiogenesis inhibition was developed through a cascade reaction with enzyme glucose oxidase (GOD) modified on Fe-based metal organic framework (Fe-MOF) coupled with anti-VEGFR2.The GOD enzyme could catalyze the intratumoral glucose decomposition to trigger tumor starvation and yet provide abundant hydrogen peroxide as the substrate for Fenton-like reaction catalyzed by Fe-MOF to produce sufficient highly toxic hydroxyl radicals for enhanced chemodynamic therapy and instantly attacked tumor vascular endothelial cells to destroy the existing vasculature, while the anti-VEGFR2 antibody guided the nanohybrids to target blood vessels and block the VEGF-VEGFR2 connection to prevent angiogenesis. Both in vitro and in vivo results demonstrated the smart nanohybrids could cause the tumor cell apoptosis and vasculature disruption, and exhibited enhanced tumor regression in A549 xenograft tumor-bearing mice model. This study suggested that synergistic targeting tumor growth and its vasculature network would be more promising for curing solid tumors. STATEMENT OF SIGNIFICANCE: Cooperative destruction of tumor cells and tumor vasculature offers a potential avenue for cancer therapy. Under this premise, a tumor-specific catalytic nanomedicine for enhanced tumor ablation accompanied with tumor vasculature disruption and new angiogenesis inhibition was developed through a cascade reaction with glucose oxidase modified on the surface of iron-based metal organic framework coupled with VEGFR2 antibody. The resulting data demonstrated that a therapeutic regimen targeting tumor growth as well as its vasculature with both existing vasculature disruption and neovasculature inhibition would be more potential for complete eradication of tumors.
Subject(s)
Metal-Organic Frameworks , Neoplasms , Animals , Catalysis , Cell Line, Tumor , Endothelial Cells/metabolism , Glucose Oxidase/chemistry , Humans , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Mice , Neoplasms/drug therapy , Neoplasms/metabolismABSTRACT
The current study has been designed to appraise the efficacy of developed combinatorial lipid-nanosystem-based gel (linogel) of 5-fluorouracil and resveratrol for skin cancer treatment. Initially, linogel was prepared and characterized for different parameters, namely pH, texture, drug content uniformity, occlusiveness, etc. Then in vivo efficacy studies (tumor number, area, and volume, histopathology, ultrastructural and immunohistochemical analysis) of linogel were determined over-developed skin tumors. Developed linogel possessed significantly (p < 0.05) better texture and occlusiveness than conventional gel formulation. Decreased tumor number, area, and volume showed significant results (p < 0.05) in favor of linogel. Histopathological and ultrastructural analysis confirmed superior efficacy of linogel in terms of marked improvement in the nucleus and subcellular structures in photomicrographs. The antioxidants and anti-inflammatory analysis findings showed a significantly (p < 0.05) potent effectiveness of linogel. The apoptotic and anti-proliferation activity of linogel was confirmed by analysis of caspase-3 and ki-67, which showed significant (p < 0.05) elevation in the level of cleaved caspase-3 and reduction in the level of ki-67 than untreated and conventional gel formulation treated tumors, indicating antitumor effect due to cancerous cell death. Thus, developed linogel fulfilled all the criteria of dermal application and exhibited efficacious therapeutic results, which could be a beneficial therapeutic approach against skin cancer.
Subject(s)
Fluorouracil , Skin Neoplasms , Humans , Lipids , Resveratrol , Skin , Skin Neoplasms/drug therapy , VirtuesABSTRACT
BACKGROUND: 1,8 cineole-rich supercritical CO2 extract of small cardamom seeds of Alleppey green variety exhibiting prominent antioxidant property was microencapsulated and utilized in formulating an antioxidant-rich custard. However, the antioxidant potency of the prepared custard was not appreciable. To redress the phytochemical loss during custard preparation, custard using nanoliposomes was formulated. Patents related to 1,8 cineole-rich food products have been revised thoroughly. OBJECTIVE: The objective of the current study is to examine whether nanoencapsulationmediated entrapment of antioxidants is more effective in fortifying a dessert, namely custard, vis-à-vis microencapsulated (spray dried)-mediated enhancement of antioxidative potency in the same. METHODS: Our previous investigations have established that nanoliposome of 1,8 cineole- rich supercritical CO2 extract of small cardamom seeds effectively redresses type 2 diabetes and hypercholesterolemia. In the current investigation, this pre-characterized nanoliposome which exhibited appreciable in vitro and in vivo antioxidant efficacy has been utilized at varying concentrations for fortification of a custard. The designer custard samples have been characterized for their sensory and physicochemical properties, identification of the cardamom antioxidants therein and determination of the synergistic efficacy value of the identified antioxidants. RESULTS: The custard formulated with 0.3% nanoliposomes exhibited appreciable antioxidant potency in terms of DPPH radical scavenging activity (304.58±1.09 mg/ml) and reducing power (0.020±0.001 mg BHT/g custard), conferred by its total phenolic content (0.049±0.004 mg GAE/g custard). It also had relatively more stable textural attributes vis-à-vis the control sample (formulated with the non-encapsulated native extract). GCMS analysis of the nanoliposome-fortified custard confirmed retention of the spice antioxidants, namely1,8- cineole, α-terpinyl acetate, α-terpineol and linalool and its synergistic efficacy value being greater than unity, attested to the synergistic presence of the said antioxidants therein. The newly formulated custard retained more than 4.5 times of 1,8-cineole (5.05 mg/g custard) vis-à-vis the custard sample (1.12 mg/g custard) prepared with a microencapsulated (spray-dried) formulation of the extract. Additionally, the absence of heavy metals in the formulated custard confirmed it to be safe for human consumption. CONCLUSION: This is the first study on the application of nanoliposomes of spiceuticals in the formulation of a dessert, and more emphatically on use of a 'green' supercritical CO2 extract of spice antioxidants in fortification of a dessert to achieve antioxidant synergy.
Subject(s)
Diabetes Mellitus, Type 2 , Elettaria , Antioxidants/pharmacology , Carbon Dioxide , Dietary Supplements , Humans , Patents as Topic , Plant Extracts/pharmacologyABSTRACT
The incidence of zoonotic Staphylococcus pseudintermedius and Microsporum canis infections is rapidly growing worldwide in the context of an increasing frequency of close contact between animals and humans, presenting challenges in both human and veterinary medicine. Moreover, the development of microbial resistance and emergence of recalcitrant biofilms, accompanied by the insufficiency of new antimicrobial agents, have become major obstacles in treating superficial skin infections caused by various microbes including S. pseudintermedius and M. canis. Over recent years, the prospects of antimicrobial peptides as emerging antimicrobials to combat microbial infections have been demonstrated. In our study, two novel short-chain peptides, namely, allomyrinasin and andricin B, produced by Allomyrina dichotoma and Andrias davidianus, were revealed to exhibit potent antimicrobial efficacy against clinical isolates of S. pseudintermedius and M. canis with remarkable and rapid fungicidal and bactericidal effects, while allomyrinasin exhibited inhibition of biofilm formation and eradication of mature biofilm. These peptides displayed synergistic activity when combined with amoxicillin and terbinafine against S. pseudintermedius and M. canis. Cytoplasmic leakage via cytomembrane permeabilization serves as a mechanism of action. Extremely low hemolytic activity and serum stability in vitro, as well as superior anti-infective efficacy in reducing bacterial counts and relieving the inflammatory response in vivo, were detected. The potent antibacterial, antifungal, and anti-inflammatory activities of allomyrinasin and andricin B might indicate promising anti-infective alternatives for the treatment of S. pseudintermedius and M. canis infections in the context of human and veterinary medicine.
ABSTRACT
Cancer chemotherapy is confronted with challenges regarding the effective delivery of chemotherapeutics into tumor cells after systemic administration. Herein, we propose a strategy to load drugs into probiotic E. coli Nissle 1917 (EcN) for self-guided navigation to tumor tissues and subsequently release the drugs with in situ transformation into bacterial ghosts (BGs). Chemotherapeutic agent 5-fluorouracil (FU) and macrophage phenotype regulator zoledronic acid (ZOL) are loaded into EcN through electroporation, followed by decoration of Au nanorods on the ECN surface to construct EcNZ/F@Au. High loading levels of 5FU (8.8%) and ZOL (10.5%) are achieved as well as high retention rates of bacterial viability (87%) and motion velocity (88%). Under near infrared (NIR) illumination the photothermal effect of Au nanorods elevates the local temperature to induce the transformation of live EcN into BGs. The created transmembrane channels initiate the gradual drug release from BGs, thus representing the first attempt to control the drug release via a biological evolution. An intermittent NIR illumination causes stepwise increases in the BG formation and drug release, which could implement an external on-off control and spatiotemporal drug release. Self-guided motion of EcN promotes efficient extravasation across blood vessels and preferential accumulation of drugs in tumors. In addition to the chemotherapeutic effect of FU, the local release of ZOL from EcNZ/F@Au enhances valid polarization of tumor-associated macrophages toward the M1 phenotype and an effective production of proinflammatory cytokines, leading to a synergistic efficacy on tumor growth inhibition. Thus, this study demonstrates a feasible strategy to integrate chemotherapy, immunotherapy, and photothermal effects in a concise manner for effective cancer treatment with few side effects. STATEMENT OF SIGNIFICANCE: Bacteria are capable to trace and colonize in hypoxic tumor tissues. Bacterial drug carriers indicate limitations in efficient drug loading and effective release modulation. Herein, we propose a strategy to load drugs into bacteria for self-guided delivery and subsequently release the drugs in tumors with in situ transformation into bacterial ghost (BGs). Drugs are loaded into live bacteria through electroporation and Au nanorods are decorated on the bacterial surface, wherein the photothermal effect, chemotherapy, and immunotherapy are integrated in a concise manner. NIR illmumination of Au nanorods elevates the local temparature, induces the BG tranformation, and activates the spatiotemporal drug release, representing the first attempt of release modulation via a biological evolution.
Subject(s)
Antineoplastic Agents , Neoplasms , Drug Delivery Systems , Drug Liberation , Escherichia coli , Humans , Neoplasms/drug therapyABSTRACT
The over-use of antibiotics has promoted multidrug resistance and decreased the efficacy of antibiotic therapy. Thus, it is still in great need to develop efficient treatment strategies to combat the bacteria infection. The antimicrobial photodynamic therapy (aPDT) and silver nanoparticles have been emerged as effective antibacterial methods. However, the silver therapy may induce serious damages to human cells at high concentrations and, the bare silver nanoparticles may rapidly aggregate, which would reduce the antibacterial efficacy. The encapsulation of sliver by nano-carrier is a promising way to avoid its aggregation and facilitates the co-delivery of drugs for combination therapy, which does not require high concentration of sliver to exert antibacterial efficacy. This work constructed a self-assembled supermolecular nano-carrier consisting of the photosensitizers (PSs), the anti-inflammatory agent and silver. The synthesized supermolecular nano-carrier produced reactive oxygen species (ROS) under the exposure of 620-nm laser. It exhibited satisfying biocompatibility in L02 cells. And, this nano-carrier showed excellent antibacterial efficacy in Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as indicated by bacterial growth and colony formation. Its antibacterial performance is further validated by the bacteria morphology through the scanning electron microscope (SEM), showing severely damaged structures of bacteria. To summary, the supermolecular nano-carrier TCPP-MTX-Ag-NP combining the therapeutic effects of ROS and silver may serve as a novel strategy of treatment for bacterial infection.
ABSTRACT
Obesity is a primary risk factor for type 2 diabetes, cardiovascular diseases, cancer, and other chronic diseases. Current antiobesity medications need frequent administration and show limited efficacy with severe side effects. Herein, browning agent rosiglitazone (Rsg) and antioxidant manganese tetroxide nanoparticles (MnNPs, around 250 nm) are integrated into electrospun short fibers (SF@Rsg-Mn) with a 1.5 µm width and a 20 µm length. Upon injection into inguinal adipose tissues, SF@Rsg-Mn are well retained in the local depots to sustainably release Rsg in 30 days for adipose tissue browning, while MnNPs on the fiber surface continuously scavenge adipose reactive oxygen species (ROS) for an extended period of time. Synergistic inhibition of fat accumulation through ROS scavenging and white adipocyte browning has been demonstrated for the first time, and the optimal synergistic ratio of Rsg and MnNPs is determined to be 1/14 via combination index examination. SF@Rsg-Mn inhibit lipid accumulation through downregulation of adipogenic gene PPARγ while promoting energy expenditure through upregulation of brown-specific gene UCP1 and mitochondrial function gene COX7A1. In a diet-induced obesity mouse model, a single injection of SF@Rsg-Mn into inguinal adipose tissues has accomplished a synergistic effect on body weight loss, fat reduction, glucose, and lipid metabolic improvement while minimizing adverse effects on other tissues, thereby paving the way to efficacious, safe, and practical treatment of obesity.
Subject(s)
Adipogenesis , Diabetes Mellitus, Type 2 , Adipose Tissue, Brown , Animals , Antioxidants , Diet, High-Fat/adverse effects , Mice , Obesity/drug therapyABSTRACT
Overuse or abuse of antibiotics has undoubtedly accelerated the increasing prevalence of global antibiotic resistance crisis, and thus, people have been trying to explore approaches to decrease dosage of antibiotics or find new antibacterial agents for many years. Antimicrobial peptides (AMPs) are the ideal candidates that could kill pathogens and multidrug-resistant bacteria either alone or in combination with conventional antibiotics. In the study, the antimicrobial efficacy of mud crab Scylla paramamosain AMPs Sphistin and Sph12-38 in combination with eight selected antibiotics was evaluated using a clinical pathogen, Pseudomonas aeruginosa. It was interesting to note that the in vitro combination of rifampicin and azithromycin with Sphistin and Sph12-38 showed significant synergistic activity against P. aeruginosa. Moreover, an in vivo study was carried out using a mouse model challenged with P. aeruginosa, and the result showed that the combination of Sph12-38 with either rifampicin or azithromycin could significantly promote the healing of wounds and had the healing time shortened to 4-5 days compared with 7-8 days in control. The underlying mechanism might be due to the binding of Sphistin and Sph12-38 with P. aeruginosa lipopolysaccharides (LPS) and subsequent promotion of the intracellular uptake of rifampicin and azithromycin. Taken together, the significant synergistic antibacterial effect on P. aeruginosa in vitro and in vivo conferred by the combination of low dose of Sphistin and Sph12-38 with low dose of rifampicin and azithromycin would be beneficial for the control of antibiotic resistance and effective treatment of P. aeruginosa-infected diseases in the future.
Subject(s)
Azithromycin , Brachyura , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azithromycin/pharmacology , Microbial Sensitivity Tests , Pore Forming Cytotoxic Proteins , Pseudomonas aeruginosa , Rifampin/pharmacologyABSTRACT
The incorporation of new modalities into chemotherapy greatly enhances the anticancer efficacy combining the merits of each treatment, showing promising potentials in clinical translations. Herein, a hybrid nanomedicine (Au/FeMOF@CPT NPs) is fabricated using metal-organic framework (MOF) nanoparticles and gold nanoparticles (Au NPs) as building blocks for cancer chemo/chemodynamic therapy. MOF NPs are used as vehicles to encapsulate camptothecin (CPT), and the hybridization by Au NPs greatly improves the stability of the nanomedicine in a physiological environment. Triggered by the high concentration of phosphate inside the cancer cells, Au/FeMOF@CPT NPs effectively collapse after internalization, resulting in the complete drug release and activation of the cascade catalytic reactions. The intracellular glucose can be oxidized by Au NPs to produce hydrogen dioxide, which is further utilized as chemical fuel for the Fenton reaction, thus realizing the synergistic anticancer efficacy. Benefitting from the enhanced permeability and retention effect and sophisticated fabrications, the blood circulation time and tumor accumulation of Au/FeMOF@CPT NPs are significantly increased. In vivo results demonstrate that the combination of chemotherapy and chemodynamic therapy effectively suppresses the tumor growth, meantime the systemic toxicity of this nanomedicine is greatly avoided.
ABSTRACT
BACKGROUND: Pertuzumab is currently used in combination with trastuzumab as the first-line treatment for HER2-positive metastatic breast cancer. However, pertuzumab was originally developed independently from trastuzumab and was later incidentally found to have synergistic efficacy when combined with trastuzumab, it remains to be seen whether a more potent synergistic efficacy partner exists for trastuzumab. METHODS: A trastuzumab-based functional assay was used to screen anti-HER2 antibodies harboring trastuzumab-synergistic antitumor activity. The lead candidate 5G9, in combination with trastuzumab, was further characterized for its bioactivities in cell proliferation, cell apoptosis, antigen-antibody endocytosis and HER2-mediated cell signaling pathway blocking. Finally, animal models were used to evaluate the in vivo synergistic antitumor efficacy of 5G9 in combination with trastuzumab. FINDINGS: Compared to pertuzumab, 5G9 demonstrated more potent synergistic cell growth inhibitory activity when combined with trastuzumab (85% vs. 55%, P<0.001). In addition, 5G9 exhibited a higher internalization rate than pertuzumab (20% vs. 9%, P<0.05), and was able to further synergize with trastuzumab to promote antigen-antibody endocytosis. The internalization rate of the combination of 5G9 and trastuzumab was higher than that of pertuzumab and trastuzumab (35% vs. 14%, P<0.001). In vivo animal studies demonstrated that 5G9 in combination with trastuzumab showed more potent synergistic antitumor efficacy than the combination of pertuzumab and trastuzumab. INTERPRETATION: 5G9, together with trastuzumab, may provide a potential opportunity for more efficacious treatment of HER2-positive cancers. FUNDING: National Natural Science Foundation of China; State Key Laboratory of Analytical Chemistry for Life Science.
Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Drug Screening Assays, Antitumor , Receptor, ErbB-2/antagonists & inhibitors , Animals , Antibody-Dependent Cell Cytotoxicity , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Drug Screening Assays, Antitumor/methods , Drug Synergism , Epitopes/immunology , Humans , Mice , Protein Binding/immunology , Receptor, ErbB-2/immunology , Receptor, ErbB-2/metabolism , Signal Transduction/drug effects , Trastuzumab/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Both ceritinib (CER) and programmed cell death (PD)-1/PD ligand-1 (PD-L1) have brought significant breakthroughs for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, the overall clinical efficacy of either CER or PD-1/PD-L1 inhibitor monotherapy has been limited to a large extent. In addition, the antitumor effect of combined CER and PD-L1 inhibitor in ALK-rearranged NSCLC is not fully understood. In H2228 cells, we examined the tumor killing effect of CER plus PD-L1 inhibitor in vitro by quantitative RT-PCR, flow cytometry, ELISA, western blot analysis, PBMC coculture system, and plasmid and transfection experiments. A Ba/F3 (EML4-ALK-WT) xenograft mouse model was also utilized to further evaluate the synergistic anticancer effects of CER and PD-L1 inhibitor in vivo. The coculture system of PBMCs with H2228 cells promotes the expression of PD-L1 and phospho-ERK, and combined treatments facilitate lymphocyte proliferation and activation, inhibit PD-L1 expression, and enhance lymphocyte cytotoxicity and cell death. In the in vivo NSCLC xenograft model, the volumes of tumors treated with CER and PD-L1 inhibitor in combination were significantly smaller than those treated with CER or PD-L1 alone. The relative tumor growth inhibitions were 84.9%, 20.0%, and 91.9% for CER, PD-L1 inhibitor, and CER plus PD-L1 groups, respectively. Ceritinib could synergize with PD-1/PD-L1 blockade to yield enhanced antitumor responses along with favorable tolerability of adverse effects. Ceritinib and PD-L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provides a key insight and proof of principle for evaluating CER plus PD-L1 blockade as combination therapy in clinical therapeutic practice.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Pyrimidines/administration & dosage , Sulfones/administration & dosage , Anaplastic Lymphoma Kinase/genetics , Animals , Antibodies, Monoclonal/pharmacology , Cell Line, Tumor , Drug Synergism , Humans , Mice , Xenograft Model Antitumor AssaysABSTRACT
Albumin has been regarded as the ideal drug carrier for delivering hydrophobic agents into cancer cells over decades. Combination therapy of paclitaxel (PTX) with resveratrol (RES) could enhance the sensitivity of multidrug resistance (MDR) cancer cell lines to PTX. In this study, novel paclitaxel/resveratrol co-loaded albumin nanoparticles (PTX/RES NPs) were developed to achieve synergistic anticancer efficacy and conquer paclitaxel resistance. The hybrid NPs had an average diameter of about 150 nm and an apparent negative surface charge of about -33 mV. PTX/RES NPs could be efficiently internalized by cells and exert synergistic combination efficacy of the two drugs, thus resulting in dramatically in vitro cytotoxicity even against MDR cancer cells. In vivo antitumor assay demonstrated that the antitumor effect of the hybrid NPs was superior to that of single drug-loaded NPs or free drug combination. Molecular docking analysis disclosed that the binding of PTX and RES to bovine serum albumin (BSA) was noncompetitive but the binding free energy of BSA/PTX dockings was significantly lower than BSA/RES dockings, which resulted in high encapsulation efficiency and sustained drug release profiles of PTX. In summary, the PTX/RES co-delivery system might be a promising strategy for combined anticancer therapy to overcome tumor drug resistance.
Subject(s)
Drug Carriers/chemistry , Nanoparticles/chemistry , Paclitaxel/administration & dosage , Paclitaxel/metabolism , Resveratrol/administration & dosage , Resveratrol/metabolism , Serum Albumin, Bovine/metabolism , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Cattle , Cell Line, Tumor , Drug Liberation , Humans , Molecular Docking Simulation , Paclitaxel/chemistry , Paclitaxel/pharmacology , Particle Size , Protein Binding , Protein Conformation , Resveratrol/chemistry , Resveratrol/pharmacology , Serum Albumin, Bovine/chemistry , Xenograft Model Antitumor AssaysABSTRACT
The clinical application of chemotherapy is impeded by the unsatisfactory efficacy and severe side effects. Chemodynamic therapy (CDT) has emerged as an efficient strategy for cancer treatment utilizing Fenton chemistry to destroy cancer cells by converting endogenous H2 O2 into highly toxic reactive oxygen species. Apart from the chemotherapeutic effect, cisplatin is able to act as an artificial enzyme to produce H2 O2 for CDT through cascade reactions, thus remarkably improving the anti-tumor outcomes. Herein, an organic theranostic nanomedicine (PTCG NPs) is constructed with high loading capability using epigallocatechin-3-gallate (EGCG), phenolic platinum(IV) prodrug (Pt-OH), and polyphenol modified block copolymer (PEG-b-PPOH) as the building blocks. The high stability of PTCG NPs during circulation stems from their strong metal-polyphenol coordination interactions, and efficient drug release is realized after cellular internalization. The activated cisplatin elevates the intracellular H2 O2 level through cascade reactions. This is further utilized to produce highly toxic reactive oxygen species catalyzed by an iron-based Fenton reaction. In vitro and in vivo investigations demonstrate that the combination of chemotherapy and chemodynamic therapy achieves excellent anticancer efficacy. Meanwhile, systemic toxicity faced by platinum-based drugs is avoided through this nanoformulation. This work provides a promising strategy to develop advanced nanomedicine for cascade cancer therapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Catechin/analogs & derivatives , Cisplatin/therapeutic use , Neoplasms/drug therapy , Polyphenols/therapeutic use , Prodrugs/therapeutic use , Animals , Antineoplastic Agents/chemistry , Catechin/chemistry , Catechin/therapeutic use , Cisplatin/chemistry , Hep G2 Cells , Humans , Mice , Nanomedicine , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Nanoparticles/ultrastructure , Neoplasms/metabolism , Polyphenols/chemistry , Prodrugs/chemistry , Reactive Oxygen Species/metabolismABSTRACT
The combination therapy strategy based on both chemotherapy and photodynamic therapy (PDT) exhibits great potential for advanced cancer treatment. Multimodal nanodrug delivery systems based on both chemotherapeutic drug and photodynamic agent have been proven to possess excellent synergistic efficacy. In this study, 7-ethyl-10-hydroxycamptothecin (SN38) and chlorin e6 (Ce6) were co-assembled into novel carrier-free nanoparticles (SN38/Ce6 NPs) via simple antisolvent precipitation method. As expected, SN38/Ce6 NPs exhibited uniform morphology with a particle size of around 150â¯nm and a zeta potential of about -30â¯mV, good stability in aqueous solution/at lyophilized state and high cellular uptake efficiency against murine mammary carcinoma (4T1) cell lines. Besides, enhanced singlet oxygen generation capacity of the nanoparticles was both observed in test-tube and in 4T1 cell lines in contrast with Ce6 injection. Moreover, a â¼85 % inhibition rate of SN38/Ce6 NPs with laser was detected, which was significantly higher (Pâ¯<â¯0.05) than those without laser (â¼65 %) and injections (less than 20 %), verified the excellent synergistic antitumor efficacy of the nanoparticles due to combined chemo-photodynamic therapy, enhanced tumor accumulation and higher cellular internalization. Notably, chemical thermodynamic method and molecular dynamics (MD) simulations supplied solid data and visual images to estimate the driving forces for the self-assembly process of the carrier-free nanoparticles as primary hydrophobic interactions (π-π stacking) and subordinate hydrogen bonds. Conclusively, the above self-assembled carrier-free nanoparticles represented a promising synergistic anticancer strategy capable of maximal therapeutic efficacy and minimal systemic toxicity. Moreover, the application of thermodynamic method together with MD simulations in the investigation of NPs self-assembly process also provided new ideas for the assembly mechanism exploration of more complicated nanodrug delivery system.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Irinotecan/pharmacology , Nanoparticles/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Chlorophyllides , Drug Screening Assays, Antitumor , Irinotecan/chemistry , Mice , Molecular Dynamics Simulation , Particle Size , Photochemotherapy , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Porphyrins/chemistry , Surface Properties , ThermodynamicsABSTRACT
In this work, we firstly tested five spatial repellent pyrethroids, meperfluthrin, dimefluthrin, heptafluthrin, metofluthrin and transfluthrin, to determine the susceptibility of pyrethroids to field strains of Culex quinquefasciatus using adult topical bioassay. The results showed that though field strains exhibited the highest resistance to dimefluthrin among the selected five pyrethroids, it still can be considered low resistance in the scale of Cui et al. (2006; 2007). Then, the aim of this study was to optimise the synergistic efficacy of essential oils combined with dimefluthrin and explore the major contribution composition of eucalyptus oil, basil oil and cinnamon oil as natural synergist of dimefluthrin against the field populations of C. quinquefasciatus. GC-MS analysis showed 1,8-cineole, eugenol and trans-cinnamaldehyde were the main chemical components of eucalyptus oil, basil oil and cinnamon oil, respectively. The results of bioactivity showed that eucalyptus oil and 1,8-cineole have highly fumigant knock-down activity to the adults, showing KT50 (the median knockdown time) of 5.76 and 4.27â¯min at the concentration of 24.2⯵L/L; basil oil and eugenol, cinnamon oil and trans-cinnamaldehyde have highly fumigant toxicity to the adults, showing LD50 of 1.00 and 0.79, 1.26 and 1.03⯵L/L, respectively. Three effective main essential oil components were selected to prepare binary mixtures, which combined with dimefluthrin against the field population of Culex quinquefasciatus. 1,8-cineole+eugenol (9:1, w/w), 1,8-cineole+trans-cinnamaldehyde (1:1, w/w) and trans-cinnamaldehyde+eugenol (9:1, w/w) combined with dimefluthrin (10:1, w/w) were the most synergistic interaction, showed SR (synergistic ratio) values of 1.2471, 1.5709 and 1.1969; KT50 of 11.68, 9.51 and 10.67â¯min respectively, by quadrate box method. In addition, to validate the stable synergistic interaction of 1,8-cineole+trans-cinnamaldehyde (1:1, w/w) combined with dimefluthrin (10:1, w/w), the SR values were about 1.3, and KT50 values were 38.72-50.26â¯min by simulated house method. Overall, our results pointed out the promising potential of these essential oils to increase the efficacy of dimefluthrin. It might be expected that these essential oils could be developed to a useful botanical synergist of dimefluthrin for the control of the field populations of C. quinquefasciatus.