RESUMO
Personalized cancer vaccines based on tumor cell lysates offer promise for cancer immunotherapy yet fail to elicit a robust therapeutic effect due to the weak immunogenicity of tumor antigens. Autophagosomes, obtained from pleural effusions and ascites of cancer patients, have been identified as abundant reservoirs of tumor neoantigens that exhibit heightened immunogenicity. However, their potential as personalized cancer vaccines have been constrained by suboptimal lymphatic-targeting performances and challenges in antigen-presenting cell endocytosis. Here,a reinforced biomimetic autophagosome-based (BAPs) nanovaccine generated by precisely amalgamating autophagosome-derived neoantigens and two types of adjuvants capable of targeting lymph nodes is developed to potently elicit antitumor immunity. The redox-responsive BAPs facilitate cytosolic vaccine opening within antigen-presenting cells, thereby exposing adjuvants and antigens to stimulate a strong immune response. BAPs evoke broad-spectrum T-cell responses, culminating in the effective eradication of 71.4% of established tumors. Notably, BAPs vaccination triggers enduring T-cell responses that confer robust protection, with 100% of mice shielded against tumor rechallenge and a significant reduction in tumor incidence by 87.5%. Furthermore, BAPs synergize with checkpoint blockade therapy to inhibit tumor growth in the poorly immunogenic breast cancer model. The biomimetic approach presents a powerful nanovaccine formula with high versatility for personalized cancer immunotherapy.
RESUMO
Cancer vaccines provide a potential strategy to cure patients. Their clinical utilization and efficacy is, however, limited by incomplete coverage of tumor neoantigens and unspecific and restricted activation of dendritic cells (DCs). Tumor cell lysates (TCLs) containing a broad spectrum of neoantigens, while are considered ideal in formulating personalized vaccines, induce generally poor antigen presentation and transient antitumor immune response. Here, intelligent polymersomal nanovaccines (PNVs) that quantitatively coload, efficiently codeliver, and responsively corelease TCL and CpG adjuvant to lymph node (LN) DCs are developed to boost antigen presentation and to induce specific and robust antitumor immunity. PNVs carrying CpG and ovalbumin (OVA) markedly enhance the maturation, antigen presentation, and downstream T cell activation ability of bone-marrow-derived dendritic cells and induce strong systemic immune response after tail base injection. Remarkably, PNVs carrying CpG and TCL cure 85% of B16-F10 melanoma-bearing mice and generate long-lasting anticancer immune memory at a low dose, protecting all cured mice from tumor rechallenge. These LN-directed PNVs being highly versatile and straightforward opens a new door for personalized cancer vaccines.
Assuntos
Vacinas Anticâncer , Células Dendríticas , Imunoterapia , Linfonodos , Camundongos Endogâmicos C57BL , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Células Dendríticas/imunologia , Linfonodos/imunologia , Camundongos , Adjuvantes Imunológicos/administração & dosagem , Melanoma Experimental/terapia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Ovalbumina/química , Linhagem Celular Tumoral , Feminino , Nanopartículas/químicaRESUMO
Triple-negative breast cancer (TNBC) due to lack of clear target and notorious "cold" tumor microenvironment (TME) is one of the most intractable and lethal malignancies. Tuning "cold" TME into "hot" becomes an emerging therapeutic strategy to TNBC. Herewith, we report that integrin-targeting micellar gemcitabine and paclitaxel (ATN-mG/P, ATN sequence: Ac-PhScNK-NH2) cooperating with polymersomal CpG (NanoCpG) effectively "heated up" and treated TNBC. ATN-mG/P exhibited greatly boosted apoptotic activity in 4T1 cells, induced potent immunogenic cell death (ICD), and efficiently stimulated maturation of bone marrow-derived dendritic cells (BMDCs). Remarkably, in a postoperative TNBC model, ATN-mG/P combining with NanoCpG promoted strong anti-cancer immune responses, showing a greatly augmented proportion of mature DCs and CD8+ T cells while reduced immune-suppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg), which led to complete inhibition of lung metastasis and 60% mice tumor-free. The co-delivery of gemcitabine and paclitaxel at desired ratio in combination with NanoCpG provides a unique platform for potent chemoimmunotherapy of "cold" tumors like TNBC.
RESUMO
The development of carrier systems that are able to transport and release therapeutics to target cells is an emergent strategy to treat cancer; however, they following endocytosis are usually trapped in the endo/lysosomal compartments. The efficacy of drug conjugates and nanotherapeutics relies critically on their intracellular drug release ability, for which advanced systems responding to the unique lysosomal environment such as acidic pH and abundant enzymes (e.g. cathepsin B, sulfatase and ß-glucuronidase) or equipped with photochemical internalization property have been energetically pursued. In this review, we highlight the recent designs of smart systems that promote efficient lysosomal release and/or escape of anticancer agents including chemotherapeutics (e.g. doxorubicin, platinum, chloroquine and hydrochloroquine) and biotherapeutics (e.g. proteins, siRNA, miRNA, mRNA and pDNA) to cancer cells or immunotherapeutic agents (e.g. antigens, mRNA and immunoadjuvants) to antigen-presenting cells (APCs), thereby boosting cancer therapy and immunotherapy. Lysosomal-mediated drug release presents an appealing approach to develop innovative cancer therapeutics and immunotherapeutics.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Liberação Controlada de Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Imunoterapia , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Lisossomos/metabolismo , Concentração de Íons de HidrogênioRESUMO
Introduction: Helicobacter pylori (H.pylori, Hp) affects billions of people worldwide. However, the emerging resistance of Hp to antibiotics challenges the effectiveness of current treatments. Investigating the genotype-phenotype connection for Hp using next-generation sequencing could enhance our understanding of this resistance. Methods: In this study, we analyzed 52 Hp strains collected from various hospitals. The susceptibility of these strains to five antibiotics was assessed using the agar dilution assay. Whole-genome sequencing was then performed to screen the antimicrobial resistance (AMR) genotypes of these Hp strains. To model the relationship between drug resistance and genotype, we employed univariate statistical tests, unsupervised machine learning, and supervised machine learning techniques, including the development of support vector machine models. Results: Our models for predicting Amoxicillin resistance demonstrated 66% sensitivity and 100% specificity, while those for Clarithromycin resistance showed 100% sensitivity and 100% specificity. These results outperformed the known resistance sites for Amoxicillin (A1834G) and Clarithromycin (A2147), which had sensitivities of 22.2% and 87%, and specificities of 100% and 96%, respectively. Discussion: Our study demonstrates that predictive modeling using supervised learning algorithms with feature selection can yield diagnostic models with higher predictive power compared to models relying on single single-nucleotide polymorphism (SNP) sites. This approach significantly contributes to enhancing the precision and effectiveness of antibiotic treatment strategies for Hp infections. The application of whole-genome sequencing for Hp presents a promising pathway for advancing personalized medicine in this context.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Humanos , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Amoxicilina/farmacologia , Amoxicilina/uso terapêutico , Resistência Microbiana a Medicamentos , Aprendizado de Máquina , Sequenciamento Completo do Genoma , Farmacorresistência Bacteriana/genética , Testes de Sensibilidade MicrobianaRESUMO
Gemcitabine (GEM) is among the most used chemotherapies for advanced malignancies including non-small cell lung cancer. The clinical efficacy of GEM is, however, downplayed by its poor bioavailability, short half-life, drug resistance, and dose-limiting toxicities (e.g. myelosuppression). In spite of many approaches exploited to improve the efficacy and safety of GEM, limited success was achieved. The short A6 peptide (sequence: Ac-KPSSPPEE-NH2) is clinically validated for specific binding to CD44 on metastatic tumors. Here, we designed a robust and CD44-specific GEM nanotherapeutics by encapsulating hydrophobic phosphorylated gemcitabine prodrug (HPG) into the core of A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG), which exhibited reduction-triggered HPG release and specific targetability to CD44 overexpressing tumor cells. Interestingly, A6 greatly enhanced the internalization and inhibitory activity of micellar HPG (mHPG) in CD44 positive A549 cells, and increased its accumulation in A549 cancerous lung, leading to potent repression of orthotopic tumor growth, depleted toxicity, and marked survival benefits compared to free HPG and mHPG (median survival time: 59 days versus 30 and 45 days, respectively). The targeted delivery of gemcitabine prodrug with disulfide-crosslinked biodegradable micelles appears to be a highly appealing strategy to boost gemcitabine therapy for advance tumors. STATEMENT OF SIGNIFICANCE: Gemcitabine (GEM) though widely used in clinics for treating advanced tumors is associated with poor bioavailability, short half-life and dose-limiting toxicities. Development of clinically translatable GEM formulations to improve its anti-tumor efficacy and safety is of great interest. Here, we report on CD44-targeting GEM nanotherapeutics obtained by encapsulating hydrophobic phosphorylated GEM prodrug (HPG), a single isomer of NUC-1031, into A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG). A6-mHPG demonstrates stability against degradation, enhanced internalization and inhibition toward CD44+ cells, and increased accumulation in A549 lung tumor xenografts, leading to potent repression of orthotopic tumor growth, depleted toxicity and marked survival benefits. The targeted delivery of GEM prodrug using A6-mHPG is a highly appealing strategy to GEM cancer therapy.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pró-Fármacos , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Dissulfetos , Humanos , Receptores de Hialuronatos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Metoxi-Hidroxifenilglicol , Micelas , Pró-Fármacos/química , Pró-Fármacos/farmacologia , GencitabinaRESUMO
BACKGROUND: Recent studies have found that programmed death ligand 1 (PD-L1) might be involved in chemotherapy resistance in non-small cell lung cancer (NSCLC). Arsenic sulfide (As4 S4 ) has been recognized to have antitumor activities and enhance the cytotoxic effect of chemotherapy drugs. In this study, we aimed to verify the relationship between PD-L1 and cisplatin (DDP) resistance and identify whether As4 S4 could reverse DDP resistance through targeting PD-L1 in NSCLC. METHODS: The effect of As4 S4 and DDP on cell proliferation and apoptosis was investigated in NSCLC cell lines. The expression of p53 and PD-L1 proteins was measured by western blotting analysis. The levels of miR-34a-5p, miR-34a-3p and PD-L1 in cells were measured by real-time qPCR analysis. Mouse xenograft models were established by inoculation with A549/DDP (DDP-resistant) cells. RESULTS: Depletion of PD-L1 inhibited DDP resistance in A549/DDP and H1299/DDP cells. As4 S4 was capable of sensitizing A549/DDP cells to DDP by enhancing apoptosis. As4 S4 upregulated p53 expression and downregulated PD-L1 expression in A549/DDP cells. As4 S4 increased miR-34a-5p level in A549/DDP cells. Inhibition of p53 by PFT-α partially restored the levels of PD-L1 and miR-34a-5p. Pretreatment with PFT-α suppressed the apoptosis rate induced by cotreatment of As4 S4 and DDP in A549/DDP cells. Cotreatment of DDP and As4 S4 notably reduced the tumor size when compared with DDP treatment alone in vivo. CONCLUSIONS: Upregulation of PD-L1 was correlated with DDP resistance in NSCLC cells. Mechanistic analyses indicated that As4 S4 might sensitize NSCLC cells to DDP through targeting p53/miR-34a-5p/PD-L1 axis.
Assuntos
Arsenicais/farmacologia , Antígeno B7-H1/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Sulfetos/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Humanos , Camundongos , Regulação para CimaRESUMO
Brain metastases are a most disturbing situation for breast cancer patients as there is basically no adequate treatment available. Any potential drug formulation has to be able to cross the blood-brain barrier (BBB) and specific to metastatic brain tumors without causing unacceptable adverse effects. Here, we developed transferrin-functionalized chimeric polymersomes carrying siRNA against polo-like kinase 1 (Tf@TBP-CPs-siPLK1) for treating brain metastatic MDA-MB 231 triple negative breast cancer (TNBC) xenografts in mice. To facilitate the loading of siPLK1, chimaeric polymersomes (CPs) were designed with spermine in the watery core and transferrin-binding peptide (TBP) at the surface, enabling attachment of transferrin after the siRNA loading step and thereby circumventing interference of transferrin with siRNA loading. Tf@TBP-CPs-siPLK1 encapsulating 3.8 wt% siRNA had a mean size of about 50 nm and a neutral zeta potential in phosphate buffer (PB). By virtue of the presence of transferrin, Tf@TBP-CPs demonstrated greatly (ca. 5-fold) enhanced internalization in MDA-MB 231 cells and transcytosis in the endothelial (bEnd.3) monolayer model in vitro as well as markedly improved accumulation in the orthotopically xenografted MDA-MB 231 tumor in the brain in vivo compared with control CPs lacking transferrin, supporting that transferrin mediates efficient BBB penetration and high specificity towards MDA-MB 231 cells. As a result, Tf@TBP-CPs-siPLK1 effectively inhibited tumor progression and prolonged the lifespan of the mice significantly. Selective transferrin coating appears to be a particularly facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/terapia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Terapêutica com RNAi , Transferrina/metabolismoRESUMO
OBJECTIVE: The aim of this study was to compare the clinical efficacy of neoadjuvant chemoradiotherapy (NACRT) combined with postoperative adjuvant XELOX (Oxaliplatin +Capecitabine) chemotherapy and postoperative adjuvant chemotherapy (ACT) with XELOX for local advanced gastric cancer (LAGC). METHODS: In this prospectively randomized trial, we investigated the effect of NACRT combined with postoperative ACT for LAGC. 60 patients were randomly divided into NACRT group and ACT group, with 30 patients in each group. Patients in NACRT group were given three-dimensional conformal radiotherapy (45 Gy/1.8 Gy/f) accompanied by synchronous XELOX of two cycles, followed by surgery, and then postoperative adjuvant XELOX chemotherapy of four cycles was performed. Patients in ACT group received surgery in advance, and then XELOX chemotherapy of six cycles was given. RESULTS: The objective response rate of NACRT was 76.7%. The overall incidence of postoperative complications in NACRT group was not significantly different from that in ACT group (23.1% vs 30.0%, p = 0.560). The 1 year, 2 years, and 3 years progression-free survival (PFSï¼and overall survival (OS) in NACRT and ACT groups were 80.0% vs 56.7%, 73.3% vs 46.7%, 60.0% vs 33.3%, and 86.7% vs 80.0%, 76.7% vs 66.7%, 63.3% vs 50.0%, respectively. Patients in NACRT group showed a significantly higher R0 resection rate (84.6% vs 56.7%, p = 0.029),lower loco-regional recurrence rate (36.7% vs 11.5%, p = 0.039), longer PFS (p = 0.019) and freedom from locoregional progression(FFLP) (p = 0.004) than patients in ACT group, while there was no difference in OS (p = 0.215) and in toxicity incidence (p > 0.05). CONCLUSIONS: NACRT combined with postoperative adjuvant XELOX chemotherapy can improve R0 resection rate, reduce loco-regional recurrence, prolong PFS and FFLP without increasing the incidence of postoperative complications in patients with LAGC. ADVANCES IN KNOWLEDGE: Compared with postoperative adjuvant chemotherapy, locally advanced gastric cancer patients may benefit from neoadjuvant chemoradiotherapy, and toxicity associated with chemoradiotherapy was tolerant and manageable.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Oxaloacetatos/uso terapêutico , Radioterapia Conformacional , Neoplasias Gástricas/terapia , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Período Pós-Operatório , Estudos Prospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
Gallbladder carcinoma (GC) is an extremely malignant gastrointestinal tumor, but relevant mechanisms are still under investigation. MicroRNA (miR) is differentially expressed in a variety of tumors. Here we explored miR-204 in patients with GC and related mechanisms. A GSE104165 chip was downloaded from the gene expression omnibus (GEO) for analysis. The qRT-PCR assay was used for quantifying miR-204 and Notch2 in the serum and tissues of the patients, and the patients were followed up for 3 years to analyze independent factors of prognosis. The CCK8, transwell, and flow cytometry assays were applied for analyzing proliferation, invasion, as well as apoptosis of cells, and the dual luciferase reporter (DLR) assay was adopted for determining the association of miR-204 with Notch2. MiR-204 was low in patients with GC, and it might serve as a diagnostic indicator for GC. In addition, patients with low e MiR-204 usually faced high rates of III+IV stage, distant metastasis, and low differentiation, and also showed a poor prognosis. DLR assay verified the targeted binding of miR-204 to Notch2 mRNA.
Assuntos
Apoptose/genética , Proliferação de Células/genética , Neoplasias da Vesícula Biliar/metabolismo , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Receptor Notch2/metabolismo , Regulação para Cima , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , Receptor Notch2/genéticaRESUMO
Docetaxel (DTX) widely used for treating nonsmall cell lung cancer (NSCLC) patients is associated with dose-limiting side effects, especially neurotoxicity and myelosuppression. Here, we have developed cyclic cNGQGEQc peptide-directed polymersomal docetaxel (cNGQ-PS-DTX) as a targeted and multifunctional formulation for NSCLC. cNGQ-PS-DTX carrying 8.1 wt % DTX had a size of 93 nm, neutral surface charge, high stability, and glutathione-triggered DTX release behavior. Cytotoxicity studies demonstrated a clearly better antitumor activity of cNGQ-PS-DTX in α3ß1 integrin overexpressing A549 human lung cancer cells than free DTX and nontargeted PS-DTX. cNGQ-PS-DTX showed a remarkably high tolerability (over 8 times better than free DTX) and slow elimination in mice. Importantly, cNGQ-PS-DTX exhibited greatly improved tumor accumulation and higher suppression of subcutaneous and orthotopic A549 xenografts as compared to PS-DTX and free DTX controls. α3ß1 integrin-targeting polymersomal docetaxel emerges as an advanced nanotherapeutic for NSCLC treatment.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/química , Integrina alfa3beta1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Portadores de Fármacos/química , Meia-Vida , Humanos , Integrina alfa3beta1/antagonistas & inibidores , Integrina alfa3beta1/genética , Camundongos , Camundongos Nus , Nanopartículas/química , Peptídeos/química , Peptídeos/metabolismo , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Transferrin receptor (TfR) is a promising target validated in the clinical trials for managing various malignancies. Transferrin (Tf) and single chain antibody fragment can target TfR and are typically conjugated to nanomedicines via post-modification, which poses significant production challenges. Here, we report that the polymersomes functionalized with a Tf-binding peptide CGGGHKYLRW (TBP-Ps) can selectively and stably bind Tf and subsequently mediate targeted doxorubicin (Dox) delivery to TfR over-expressing HCT-116 colorectal cancer cells in vitro and in vivo. The Tf surface density of the polymersomes could be controlled by the surface content of TBP. Interestingly, modifying Dox-loaded TBP-Ps with Tf led to greatly increased cellular uptake and inhibitory effect of HCT-116 cells. Tf-bound TBP-Ps demonstrated rapid accumulation in the tumor xenografts in nude mice following i.v. injection. More importantly, Dox-loaded Ps with Tf binding significantly enhanced the antitumor efficacy in mice bearing HCT-116 tumors compared to polymersomes without Tf binding. Surface functionalization of the nanoparticles with Tf-binding peptide provides an appealing strategy in formulating Tf-targeted nanomedicines.
Assuntos
Neoplasias Colorretais , Transferrina , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina , Sistemas de Liberação de Medicamentos , Camundongos , Camundongos Nus , PeptídeosRESUMO
There is tremendous interest in integrating CT imaging with chemotherapy; however, reported iodine-based nanosystems such as nanogels and nano-emulsions display typically reduced contrast coefficient, low drug loading and stability, and poor targetability. Here, cRGD-functionalized disulfide-crosslinked iodine-rich polymersomes (cRGD-XIPs) were designed as a novel, robust and smart theranostic agent and investigated for targeted CT imaging and chemotherapy of malignant tumors. Methods: cRGD-XIPs were prepared from co-self-assembly of poly(ethylene glycol)-b-poly(dithiolane trimethylene carbonate-co-iodinated trimethylene carbonate) (PEG-P(DTC-IC)) and cRGD-PEG-P(DTC-IC) block copolymers. In vitro and in vivo CT contrast effect of cRGD-XIPs was studied using αvß3-overexpressing B16 melanoma as a tumor model in comparison with clinical agent iohexol. The therapeutic efficacy of doxorubicin-loaded cRGD-XIPs (cRGD-XIPs-Dox) to B16 melanoma was investigated and compared with XIPs-Dox (non-targeted), cRGD-IPs-Dox (non-crosslinked) and free Dox. Results: cRGD-XIPs were formed with 55.5 wt.% iodine and ca. 90 nm in diameter. cRGD-XIPs-Dox with a Dox loading of 15.3 wt.% bared superior colloidal stability and reduction-responsive drug release. Notably, blank cRGD-XIPs showed a maximum-tolerated dose (MTD) > 400 mg iodine equiv./kg while cRGD-XIPs-Dox had an MTD > 150 mg Dox equiv./kg, ca. 15-fold improvement over free Dox. cRGD-XIPs revealed superior CT contrast effect and achieved 46.5- and 24.0-fold better enhancement of CT imaging of B16 melanoma than iohexol at 4 h following intratumoral and intravenous injection, respectively. cRGD-XIPs-Dox displayed an elimination half-life of 6.5 h and an elevated accumulation of 6.68% ID/g in the tumors. Furthermore, cRGD-XIPs-Dox was significantly more effective than XIPs-Dox and cRGD-XPs-Dox in inhibiting growth of B16 melanoma model. Conclusion: This proof-of-concept study demonstrates that cRGD-XIPs are a robust, non-toxic and smart polymeric theranostic agent that can not only significantly enhance CT imaging of tumors but also mediate efficient tumor-targeted chemotherapy. XIPs offer a unique and safe platform for theranostic polymersomes that pre-select patients using CT imaging prior to targeted chemotherapy with the same system.
Assuntos
Dissulfetos/química , Iodo/química , Peptídeos Cíclicos/química , Polímeros/química , Animais , Doxorrubicina/química , Feminino , Masculino , Melanoma Experimental/diagnóstico por imagem , Camundongos Endogâmicos C57BL , Nanomedicina Teranóstica/métodosRESUMO
Semaphorin4A (Sema4A) is a family member of semaphorins expressed in immune cells and is also related with disease progression of tumor disease. In this study, we investigate the expression and pathological role of Sema4A in breast cancer (BCa). Our data showed that the expression of Sema4A increased in the tissues and serum of BCa patients when compared with normal controls. The expression of Sema4A in BCa cells could be induced by hypoxic treatment, whereas silencing hypoxia-inducible factor (HIF)-1α could attenuate the above induced. Furthermore, chromatin immunoprecipitation (ChIP) analysis demonstrated that HIF-1α could regulate the expression of Sema4A through directly binding to the promoter of Sema4A gene, whose enrichment could be further enhanced by hypoxic stimulation. In addition, silencing Sema4A could inhibit the proliferation, vascular endothelial growth factor (VEGF) production and the phosphorylation of Akt, extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) and signal transduction and activator of transcription (STAT)3, but induce apoptosis of BCa cells in the presence of hypoxia. In contrast, recombinant human Sema4A treatment showed the opposite effects. Taken together, these results suggest that Sema4A could promote progression of BCa in the presence of hypoxia and it may hold potential for treatment target for BCa.
Assuntos
Neoplasias da Mama/metabolismo , Progressão da Doença , Semaforinas/biossíntese , Hipóxia Tumoral/fisiologia , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Semaforinas/genética , Semaforinas/farmacologia , Hipóxia Tumoral/efeitos dos fármacosRESUMO
RATIONALE: Small intestinal diverticulum with bleeding is an important reason for obscure gastrointestinal bleeding (OGB) , in addition to tumor and vascular diseases. Small intestinal diverticulum with bleeding is difficult to detect by barium meal and angiographic methods and has been regarded as an important cause of obscure gastrointestinal tract bleeding in adolescents. Because of its complicated etiology and non-specific clinical manifestations, it is relatively difficult to detect small intestinal diverticulum with bleeding, especially in patients with a large amount of bleeding and hemodynamic instability. PATIENT CONCERNS: This retrospective study collects clinical statistics of 19 patients admitted to our hospital from January 2010 to December 2016. Patients who had small intestinal diverticulum patients with bleeding were included in this study. Patients who were taking anticoagulants were excluded DIAGNOSES:: Small intestinal diverticulum patients with bleeding. INTERVENTIONS: This retrospective study describes the clinical features of patients with small intestinal diverticulum whose main symptom was gastrointestinal bleeding and analyze the literature on this topic, with particular reference to the clinical characteristics, pathological features, and choice of examination methods. LESSONS: Small intestinal diverticulum with bleeding is a common cause of obscure gastrointestinal bleeding, but it is difficult to detect using normal examination methods. For patients with repeated gastrointestinal bleeding and no positive results found on gastroscopy and colonoscopy, endoscopy of the small intestine and CTE with contrast can be considered as a diagnostic modality.
Assuntos
Divertículo/patologia , Hemorragia Gastrointestinal/patologia , Intestino Delgado/patologia , Adolescente , Adulto , Divertículo/complicações , Divertículo/diagnóstico por imagem , Feminino , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/etiologia , Humanos , Intestino Delgado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Migraine is a prevalent, disabling type of primary headache disorder associated with a high socioeconomic burden. The clinical management of migraine is challenging. This study was to identify potential serum lipidomic biomarkers of migraine. METHODS: The serum lipidomic profile of migraine sufferers was compared with healthy individuals using Liquid Chromatography coupled to Mass Spectrometry (LC-MS). Volcano plot analysis by Student's t-test was performed to identify the differential metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under ROC curves (AUC) was calculated to evaluate whether the metabolites could be efficiently exploited for constructing a sensitive biomarker of migraine. RESULTS: A total of 29 serum metabolites from 4 classes of lipids including acylcarnitines, non-alpha-hydroxy-sphingosine ceramides (Cer_NSs), lysophosphatidylcholines (lysoPCs) and lysophosphatidylethanolamines (lysoPEs) were significantly different in migraine patients and controls. Of note, Cer_NSs were significantly elevated and lysoPEs were significantly decreased in migraine patients. LysoPE 18:1, lysoPE 18:2 and lysoPE 22:5 were found to be decreased in both positive and negative ion mode. Moreover, except for lysoPC 20:0, other lysoPCs were decreased in migraine patients. ROC curve analysis indicated that lysoPC 16:0 and lysoPC 20:0 are potential sensitive and specific biomarkers for migraine. CONCLUSION: LysoPC 16:0 and lysoPC 20:0 may be potential biomarkers for migraine. We suggest therapeutic management of these metabolites may be helpful in the prevention and treatment of migraine.
Assuntos
Biomarcadores/sangue , Carnitina/análogos & derivados , Lipídeos/sangue , Transtornos de Enxaqueca/sangue , Adulto , Carnitina/sangue , Ceramidas/sangue , Cromatografia Líquida , Feminino , Humanos , Lisofosfatidilcolinas/sangue , Lisofosfolipídeos/sangue , Masculino , Espectrometria de Massas , Transtornos de Enxaqueca/patologiaRESUMO
Migraine is a highly disabling primary headache associated with a high socioeconomic burden and a generally high prevalence. The clinical management of migraine remains a challenge. This study was undertaken to identify potential serum biomarkers of migraine. Using Liquid Chromatography coupled to Mass Spectrometry (LC-MS), the metabolomic profile of migraine was compared with healthy individuals. Principal component analysis (PCA) and Orthogonal partial least squares-discriminant analysis (orthoPLS-DA) showed the metabolomic profile of migraine is distinguishable from controls. Volcano plot analysis identified 10 serum metabolites significantly decreased during migraine. One of these was serotonin, and the other 9 were amino acids. Pathway analysis and enrichment analysis showed tryptophan metabolism (serotonin metabolism), arginine and proline metabolism, and aminoacyl-tRNA biosynthesis are the three most prominently altered pathways in migraine. ROC curve analysis indicated Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine are potential sensitive and specific biomarkers for migraine. Our results show Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine may be as specific or more specific for migraine than serotonin which is the traditional biomarker of migraine. We propose that therapeutic manipulation of these metabolites or metabolic pathways may be helpful in the prevention and treatment of migraine.
Assuntos
Alanina/análogos & derivados , Dipeptídeos/sangue , Metionina/sangue , Transtornos de Enxaqueca/diagnóstico , Serotonina/sangue , Adulto , Alanina/sangue , Arginina/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão/métodos , Análise Discriminante , Feminino , Humanos , Masculino , Metaboloma , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/fisiopatologia , Análise de Componente Principal , Prolina/sangue , Aminoacil-RNA de Transferência/sangue , Curva ROC , Triptofano/sangueRESUMO
Myocardial ischemia is a heart condition caused by reduction of blood flow to the heart, preventing heart from receiving enough oxygen. Myocardial ischemia is the most common cause of death globally. Heart ischemic preconditioning (IPC) has a protective effect against myocardial cell death induced by ischemia and ischemia-reperfusion injury. WDR26 has recently been identified as a protein that is increased following rat cardiac IPC. WDR26 can promote the proliferation of H9c2 cells and protect cardiomyocytes against oxidative stress through inhibiting apoptosis. However, its role in myocardial ischemia is unclear. The aim of this study was to explore the role of WDR26 in myocardial ischemia and H9c2 cell hypoxia. Our results showed that WDR26 is induced by myocardial ischemia and H9c2 cell hypoxia. WDR26 protects H9c2 cells against hypoxia injury through inhibiting LDH release and increasing cell viability. WDR26 promotes hypoxia-induced autophagy in hypoxia of H9c2 cells. We further demonstrated that in H9c2 cell hypoxia, WDR26 increases mitochondrial membrane potential, thereby increases Parkin translocation of mitochondria. After Parkin is translocated at mitochondria, WDR26 can increase mitochondrial protein ubiquitination in hypoxia of H9c2 cells. WDR26 is a mediator of response to hypoxia, and WDR26 plays an important role in hypoxia-mediated autophagy and mitophagy. This study provides novel insights into the protective role of WDR26 in cardiomyocyte injury during hypoxia. WDR26 may serve as a potential target for the treatment of myocardial ischemia.
Assuntos
Hipóxia Celular , Mitofagia/fisiologia , Miócitos Cardíacos/citologia , Proteínas/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular , Potencial da Membrana Mitocondrial , Miócitos Cardíacos/metabolismo , Transporte Proteico , Ratos , Ratos Sprague-DawleyRESUMO
Radioresistance represents a major obstacle in cancer treatment, the underlying mechanism of which is complex and not well understood. miR-148b has been reported to be implicated regulating radioresistance in lymphoma cells. However, this function has not been investigated in lung cancer cells. Microarray analysis was performed in A549 cells 48 h after exposure to 8 Gy of γ-irradiation or sham irradiation to identify differentially expressed miRNAs. miR-148b mimic and inhibitor were transfected, followed by clonogenic survival assay to examine response to irradiation in A549 cells. Western Blot and luciferase assay were performed to investigate the direct target of miR-148b Xenograft mouse models were used to examine in vivo function of miR-148b Our data showed that expression of miR-148b was significantly down-regulated in both serum and cancerous tissues of radioresistant lung cancer patients compared with radiosensitive patients. Overexpression of miR-148b reversed radioresistance in A549 cells. MutL homologue 1 (MLH1) is the direct target of miR-148b which is required for the regulatory role of miR-148b in radioresistance. miR-148b mimic sensitized A549 xenografts to irradiation in vivo Our study demonstrated that miR-148b regulates radioresistance of lung cancer cells by modulating MLH1 expression level. miR-148b may represent a new therapeutic target for the intervention of lung cancer.