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1.
Anim Sci J ; 95(1): e13937, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38500367

RESUMO

This experiment aimed to study the degradation characteristics of bagasse after three fermentation treatments in beef cattle. Bagasse 1 was treated with 0.3% lactic acid bacteria (w/w). Bagasse 2 was treated with 0.3% mixed strains (Saccharomyces cerevisiae, Aspergillus niger, Aspergillus oryzae, and lactic acid bacteria at 2:1:1:1). Bagasse 3 was treated with 0.1% cellulase and 0.1% xylanase in addition to 0.3% mixed strains of bagasse 2. The dry matter (DM), crude ash (ASH), crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF) in the bagasses were determined. Compared to the control bagasse (without the strain and enzyme treatments), three fermented bagasses showed higher DM after 4 h fermentation. The CP and ASH contents in fermented bagasse 3 were the highest, while the contents of NDF and ADF in fermented bagasse 3 were the lowest among all the groups. The effective degradability of DM, CP, NDF, and ADF was highest in fermented bagasse 3 among the evaluated bagasse feed, followed by fermented bagasse 2 > fermented bagasse 1 > bagasse. Overall, fermented bagasse 3 was better than the control and other treated bagasses, thus fermented bagasse 3 is a hopeful source for ruminant diet of beef cattle.


Assuntos
Celulose , Detergentes , Rúmen , Bovinos , Animais , Rúmen/metabolismo , Fermentação , Detergentes/metabolismo , Digestão , Dieta/veterinária , Ruminantes/metabolismo , Saccharomyces cerevisiae , Ração Animal/análise , Fibras na Dieta/metabolismo
2.
Front Microbiol ; 14: 1236955, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38045032

RESUMO

This study investigated the effects of replacing hybrid giant napiers with sugarcane bagasse and fermented sugarcane bagasse on the growth performance, apparent nutrient digestibility, rumen fermentation characteristics, and rumen microorganisms of Simmental crossbred cattle. Twenty-one Simmental crossbred cattle with similar initial body weight (363.42 ± 8.67 kg) were randomly divided into three groups: Group CON (20% hybrid giant napier +45% distillers grains +35% concentrate mixture), Group SB (20% sugarcane bagasse +45% distillers grains +35% concentrate mixture), and Group FSB (20% fermented sugarcane bagasse +45% distillers grains +35% concentrate mixture). The average daily weight gain in the SB group was lower than in the CON group, no significant difference was found between the CON and FSB groups. The feed conversion ratio of the CON and FSB groups was lower compared to the SB group. The apparent digestibility of neutral detergent fiber and acid detergent fiber in the SB group was lower than in the CON group, no significant difference was found between the CON and FSB groups. The levels of NH3-N, microbial protein, acetate, propionate, butyrate, isobutyrate, and total volatile fatty acids were higher in the CON and FSB groups than in the SB group, no significant difference was found between the CON and FSB groups. The relative abundances of Christensenellaceae_R-7_group, Rikenellaceae_RC9_gut_group, Prevotellaceae_UCG-003, Saccharofermentans, and Eubacteriumcoprostanoligenes_group were lower in the CON and FSB groups compared to the SB group. The relative abundance of Succiniclasticum was highest in the FSB group, followed by the CON group and then the SB group. Correlation analysis showed that the relative abundance of Succiniclasticum was positively correlated with propionate and NH3-N content, while the relative abundance of Rikenellaceae_RC9_gut_group was inversely correlated with NH3-N content. Gene function prediction indicated that fermented sugarcane bagasse promoted rumen microbial amino acid metabolism. In conclusion, replacing hybrid giant napiers with 20% sugarcane bagasse negatively affected the growth performance of Simmental crossbred cattle, while the addition of 20% fermented sugarcane bagasse had no adverse effects on growth performance and rumen fermentation characteristics, and did not alter the abundance of the rumen core flora in Simmental crossbred cattle.

3.
Adv Drug Deliv Rev ; 203: 115137, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37949414

RESUMO

The rapid development of nanomedicines is revolutionizing the landscape of cancer treatment, while effectively delivering them into solid tumors remains a formidable challenge. Currently, there is a huge disconnect on therapeutic response between regulatory approved nanomedicines and laboratory reported nanoparticles. The discrepancy is mainly resulted from the failure of using the classic overall pharmacokinetics behaviors of nanomedicines in tumors to predict the antitumor efficacy. Increasing evidence has revealed that the therapeutic efficacy predominantly relies on the intratumoral spatiotemporal distribution of nanomedicines. This review focuses on the spatiotemporal distribution of systemically administered chemotherapeutic nanomedicines in solid tumor. Firstly, the intratumoral biological barriers that regulate the spatiotemporal distribution of nanomedicines are described in detail. Next, the influences on antitumor efficacy caused by the spatial distribution and temporal drug release of nanomedicines are emphatically analyzed. Then, current methodologies for evaluating the spatiotemporal distribution of nanomedicines are summarized. Finally, the advanced strategies to positively modulate the spatiotemporal distribution of nanomedicines for an optimal tumor therapy are comprehensively reviewed.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos
4.
Nat Commun ; 14(1): 5888, 2023 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-37735462

RESUMO

Tumour-associated macrophages (TAMs), as one of the most abundant tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, limiting an effective antigen cross-presentation. How to selectively reprogram M2-like TAMs to reinvigorate anti-tumour immune responses is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to a M1-like phenotype with attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus eliciting adaptive immune response and sustained tumour regression in tumour-bearing female mice. Our findings provide insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.


Assuntos
Nanopartículas , Neoplasias , Feminino , Animais , Camundongos , Macrófagos Associados a Tumor , Lisossomos , Imunoterapia , Concentração de Íons de Hidrogênio , Neoplasias/terapia
5.
Animals (Basel) ; 13(13)2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37443996

RESUMO

The purpose of this study was to investigate the effects of dried blueberry pomace (BP) and pineapple pomace (PP) on the growth performance and meat quality of broiler chickens. A total of 240 1-day-old Ross 308 broiler chickens were randomly divided into 3 groups, with 10 replicates per treatment group and 8 birds per replicate (4 males and 4 females). The three groups were the control (CON) group, the 3% BP group, and 3% PP group. The entire trial period lasted 42 days. The results show that the average daily feed intake, average daily gain, and feed-to-gain ratio of the BP group and the PP group were not significantly different from those in the CON group (p > 0.05). Adding BP to the diet significantly reduced the proportion of liver and giblets (p < 0.05). Adding PP to the diet significantly reduced the proportion of liver, while the proportion of gizzard significantly increased (p < 0.05). The pH24h and L* of breast muscles were significantly lower in the PP group than in the CON group (p < 0.05). The water-holding capacity of the leg muscles in the BP group and the PP group was significantly lower than that in the CON group (p < 0.05). The crude protein content of breast muscle and the ether extract content of leg muscle in the BP group were significantly lower than those in the CON group (p < 0.05). In conclusion, the addition of 3% BP and PP to broiler chickens' diets had no adverse effects on growth performance or meat quality.

6.
Genes (Basel) ; 14(3)2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-36981030

RESUMO

(1) Background: MicroRNAs (miRNAs) are involved in a variety of biological processes, such as cell proliferation, cell differentiation, and organ development. Recent studies have shown that plant miRNAs may enter the diet and play physiological and/or pathophysiological roles in human health and disease; however, little is known about plant miRNAs in chickens. (2) Methods: Here, we analyzed miRNA sequencing data, with the use of five Chinese native chicken breeds and six different tissues (heart, liver, spleen, lung, kidney, and leg muscle), and used Illumina sequencing to detect the expression of plant miRNAs in the pectoralis muscles at fourteen developmental stages of Tibetan chickens. (3) Results: The results showed that plant miRNAs are detectable in multiple tissues and organs in different chicken breeds. Surprisingly, we found that plant miRNAs, such as tae-miR2018, were detectable in free-range Tibetan chicken embryos at different stages. The results of gavage feeding experiments also showed that synthetic tae-miR2018 was detectable in caged Tibetan chickens after ingestion. The analysis of tae-miR2018 showed that its target genes were related to skeletal muscle organ development, regulation of mesodermal cell fate specification, growth factor activity, negative regulation of the cell cycle, and regulation of growth, indicating that exogenous miRNA may regulate the development of chicken embryos. Further cell cultures and exogenous miRNA uptake assay experiments showed that synthetic wheat miR2018 can be absorbed by chicken myoblasts. (4) Conclusions: Our study found that chickens can absorb and deposit plant miRNAs in various tissues and organs. The plant miRNAs detected in embryos may be involved in the development of chicken embryos.


Assuntos
Galinhas , MicroRNAs , Humanos , Embrião de Galinha , Animais , Galinhas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Melhoramento Vegetal , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Músculo Esquelético/metabolismo
7.
Animals (Basel) ; 13(4)2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36830399

RESUMO

The present study investigated the effects of methionine (Met) on growth, immune function, and antioxidant capacity in partridge shank broilers, which were treated with either an anticoccidial drug or a coccidia vaccine. Chickens were fed five graded levels of Met (0.33%, 0.39%, 0.45%, 0.51%, or 0.57%) for 21 days in combination with the drug or vaccine. The results revealed that an optimal level of Met supplementation (1) increased ADFI (average daily feed intake), ADG (average daily gain), and F/G values (feed-to-gain ratio), indicating improved production; (2) increased OPG levels (oocysts per gram feces), intestinal lesion scores, bursa of Fabricius and thymus indexes, and sIgA content; (3) improved GSH-Px activities, and increased content levels of T-protein, albumin, and urea nitrogen. In addition, birds in the anticoccidial drug group had higher final weights, higher ADFI and ADG values, as well as lower F/G values, compared with birds in the vaccine group, indicating that coccidia vaccine reduces the performance of broilers. In conclusion, we found that an optimal level of dietary Met improved the production of partridge shank broilers, and this result might be related to immune function and antioxidant capacity. Optimal levels of digestible Met in terms of production performance (ADG and F/G) and immune function (sIgA in ileum mucosa) in partridge shank broilers (1-21 days) were found to be 0.418, 0.451, and 0.451 of diet, respectively, when birds were given anticoccidial drug treatment, with corresponding figures of 0.444, 0.455, and 0.452% when the coccidia vaccine was administered.

8.
Artigo em Inglês | MEDLINE | ID: mdl-35734967

RESUMO

Polymer-drug conjugates (PDCs) fabricated as nanoparticles have hogged the limelight in cancer theranostics in the past decade. Many researchers have devoted to developing novel and efficient polymeric drug delivery system since the first generation of poly(N-[2-hydroxypropyl]methacrylamide) copolymer-drug conjugates. However, none of them has been approved for chemotherapy in clinic. An ideal PDC nanoparticle for cancer theranostics should possess several properties, including prolonged circulation in blood, sufficient accumulation and internalization in tumors, and efficient drug release in target sites. To achieve these goals, it is important to rationally design the nanoparticulate PDCs based on circulation, accumulation, penetration, internalization, and drug release (CAPIR) cascade. Specifically, CAPIR cascades are divided into five steps: (1) circulation in the vascular compartment without burst release, (2) accumulation in tumors via enhanced permeability and retention effect, (3) subsequent penetration into the deep regions of tumors, (4) internalization into tumor cells, and (5) release of drugs as free molecules to exert their pharmacological effects. In this review, we focus on the development and novel approaches of nanoparticulate PDCs based on CAPIR cascade, and provide an outlook on future clinical application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Preparações Farmacêuticas , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Polímeros/uso terapêutico , Medicina de Precisão , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Sistemas de Liberação de Medicamentos
9.
Front Microbiol ; 13: 951726, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081790

RESUMO

Sustainable meat production is important to providing safe and quality protein sources for humans worldwide. Intensive artificial selection and high energy input into the diet of many commercial animals for the last decade has significantly increased the daily gain of body weight and shortened the raising period, but unexpectedly decreased the meat quality. The gastrointestinal tract of animals harbors a diverse and complex microbial community that plays a vital role in the digestion and absorption of nutrients, immune system development, pathogen exclusion, and meat quality. Fatty acid composition and oxidative stress in adipose and muscle tissue influences meat quality in livestock and poultry. Recent studies showed that nutraceuticals are receiving increased attention, which could alter the intestinal microbiota and regulate the fat deposition and immunity of hosts to improve their meat quality. Understanding the microbiota composition, the functions of key bacteria, and the host-microbiota interaction is crucial for the development of knowledge-based strategies to improve both animal meat quality and host health. This paper reviews the microorganisms that affect the meat quality of livestock and poultry. A greater understanding of microbial changes that accompany beneficial dietary changes will lead to novel strategies to improve livestock and poultry meat product quality.

10.
Front Vet Sci ; 9: 911685, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909692

RESUMO

Tibetan chickens living at high altitudes show specific physiological adaptations to the extreme environmental conditions. However, the regulated base of how chickens adapt to high-altitude habitats remains largely unknown. In this study, we sequenced 96 transcriptomes (including 48 miRNA and 48 mRNA transcriptomes of heart, liver, lung, and brain) and resequenced 12 whole genomes of Tibetan chickens and Peng'xian yellow chickens. We found that several miRNAs show the locally optimal plastic changes that occurred in miRNAs of chickens, such as miR-10c-5p, miR-144-3p, miR-3536, and miR-499-5p. These miRNAs could have effects on early adaption to the high-altitude environment of chickens. In addition, the genes under selection between Tibetan chickens and Peng'xian yellow chickens were mainly related to oxygen transport and oxidative stress. The I-kappa B kinase/NF-kappa B signaling pathway is widely found for high-altitude adaptation in Tibetan chickens. The candidate differentially expressed miRNAs and selected genes identified in this study may be useful in current breeding efforts to develop improved breeds for the highlands.

11.
Nat Nanotechnol ; 17(7): 788-798, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35606443

RESUMO

Pyroptosis is a gasdermin-mediated programmed necrosis that occurs via membrane perforation and that can be exploited for biomedical applications in cancer therapy. However, inducing specific pyroptotic cancer cell death while sparing normal cells is challenging. Here, we report an acid-activatable nanophotosensitizer library that can be used to spatiotemporally target distinct stages of endosomal maturation, enabling tunable cellular pyroptosis. Specific activation of phospholipase C signalling transduction in early endosomes triggers gasdermin-E-mediated pyroptosis, which is dramatically reduced when acid-activatable nanophotosensitizers are transported into late endosomes/lysosomes. This nanotuner platform induces pyroptotic cell death with up to 40-fold tunability in various gasdermin-E-positive human cancers, resulting in enhanced anti-tumour efficacy and minimized systemic side effects. This study offers new insights into how to engineer nanomedicines with tunable pyroptosis activity through specific targeting of distinct endocytic signalling for biomedical applications.


Assuntos
Neoplasias , Piroptose , Apoptose , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Proteínas de Ligação a Fosfato
12.
Nat Commun ; 13(1): 2004, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35422063

RESUMO

Efficient delivery of payload to intracellular targets has been identified as the central principle for nanomedicine development, while the extracellular targets are equally important for cancer treatment. Notably, the contribution of extracellularly distributed nanoparticles to therapeutic outcome is far from being understood. Herein, we develop a pH/light dual-responsive monochromatic ratiometric imaging nanoparticle (MRIN), which functions through sequentially lighting up the intracellular and extracellular fluorescence signals by acidic endocytic pH and near-infrared light. Enabled by MRIN nanotechnology, we accurately quantify the extracellular and intracellular distribution of nanoparticles in several tumor models, which account for 65-80% and 20-35% of total tumor exposure, respectively. Given that the majority of nanoparticles are trapped in extracellular regions, we successfully dissect the contribution of extracellularly distributed nanophotosensitizer to therapeutic efficacy, thereby maximize the treatment outcome. Our study provides key strategies to precisely quantify nanocarrier microdistribtion and engineer multifunctional nanomedicines for efficient theranostics.


Assuntos
Nanopartículas , Neoplasias , Diagnóstico por Imagem , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Nanomedicina/métodos , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Nanomedicina Teranóstica/métodos
13.
Nano Lett ; 22(7): 2978-2987, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35302770

RESUMO

Toll-like receptor (TLR) agonists are potent immune-stimulators that hold great potential in vaccine adjuvants as well as cancer immunotherapy. However, TLR agonists in free form are prone to be eliminated quickly by the circulatory system and cause systemic inflammation side effects. It remains a challenge to achieve precise release of TLR7/8 agonist in the native form at the receptor site in the endosomal compartments while keeping stable encapsulation and inactive in nontarget environment. Here, we report a pH-/enzyme-responsive TLR7/8 agonist-conjugated nanovaccine (TNV), which responds intelligently to the acidic environment and cathepsin B in the endosome, precisely releases TLR7/8 agonist to activate its receptor signaling at the endosomal membrane, stimulates DCs maturation, and provokes specific cellular immunity. In vivo experiments demonstrate outstanding prophylactic and therapeutic efficacy of TNV in mouse melanoma and colon cancer. The endosome-targeted responsive nanoparticle strategy provides a potential delivery toolbox of adjuvants to advance the development of tumor nanovaccines.


Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Vacinas Anticâncer/uso terapêutico , Células Dendríticas , Endossomos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Receptores Toll-Like , Vacinação
14.
Asian J Pharm Sci ; 17(1): 120-128, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35261648

RESUMO

Photothermal (PTT) and photodynamic (PDT) combined therapy has been hindered to clinical translation, due to the lack of available biomaterials, difficult designs of functions, and complex chemical synthetic or preparation procedures. To actualize a high-efficiency combination therapy for cancer via a feasible approach, three readily available materials are simply associated together in one-pot, namely the single-walled carbon nanohorns (SWCNH), zinc phthalocyanine (ZnPc), and surfactant TPGS. The established nanodispersion is recorded as PCT. The association of SWCNH/ZnPc/TPGS was confirmed by energy dispersive spectrum, Raman spectrum and thermogravimetric analysis. Under lighting, PCT induced a temperature rising up to about 60 °C due to the presence of SWCNH, production a 7-folds of singlet oxygen level elevation because of ZnPc, which destroyed almost all 4T1 tumor cells in vitro. The photothermal effect of PCT depended on both laser intensity and nanodispersion concentration in a linear and nonlinear manner, respectively. After a single peritumoral injection in mice and laser treatment, PCT exhibited the highest tumor temperature rise (to 65 °C) among all test groups, completely destroyed primary tumor without obvious toxicity, and inhibited distant site tumor. Generally, this study demonstrated the high potential of PCT nanodispersion in tumor combined therapy.

15.
J Anim Sci Biotechnol ; 13(1): 3, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35139922

RESUMO

BACKGROUND: The emergence of antimicrobial resistance has necessitated the development of effective alternatives to antibiotics for livestock and poultry production. This study investigated a possible synergy between butyrate and forskolin (a natural labdane diterpene) in enhancing innate host defense, barrier function, disease resistance, growth performance, and meat quality of broilers. METHODS: The expressions of representative genes involved in host defense (AvBD9 and AvBD10), barrier function (MUC2, CLDN1, and TJP1), and inflammation (IL-1ß) were measured in chicken HD11 macrophages in response to butyrate and forskolin in the presence or absence of bacterial lipopolysaccharides (LPS). Intestinal lesions and the Clostridium perfringens titers were also assessed in C. perfringens-challenged chickens fed butyrate and forskolin-containing Coleus forskohlii (CF) extract individually or in combination. Furthermore, growth performance and carcass characteristics were evaluated in broilers supplemented with butyrate and the CF extract for 42 d. RESULTS: Butyrate and forskolin synergistically induced the expressions of AvBD9, AvBD10, and MUC2 in chicken HD11 cells (P < 0.05) and the synergy was maintained in the presence of LPS. Butyrate and forskolin also suppressed LPS-induced IL-1ß gene expression in HD11 cells in a synergistic manner (P < 0.05). The two compounds significantly reduced the intestinal lesions of C. perfringens-challenged chickens when combined (P < 0.05), but not individually. Furthermore, butyrate in combination with forskolin-containing CF extract had no influence on weight gain, but significantly reduced feed intake (P < 0.05) with a strong tendency to improve feed efficiency (P = 0.07) in a 42-d feeding trial. Desirably, the butyrate/forskolin combination significantly decreased abdominal fat deposition (P = 0.01) with no impact on the carcass yield, breast meat color, drip loss, or pH of d-42 broilers. CONCLUSIONS: Butyrate and forskolin has potential to be developed as novel antibiotic alternatives to improve disease resistance, feed efficiency, and carcass composition of broilers.

16.
Angew Chem Int Ed Engl ; 61(19): e202200152, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35218123

RESUMO

Precise monitoring of the subtle pH fluctuation during biological events remains a big challenge. Previously, we reported an ultra-pH-sensitive (UPS) nanoprobe library with a sharp pH response using co-polymerization of two tertiary amine-containing monomers with distinct pKa . Currently, we have generalized the UPS nanoparticle library with tunable pH transitions (pHt ) by copolymerization of a tertiary amine-containing monomer with a series of non-ionizable monomers. The pHt of nanoparticles is fine-tuned by the non-ionizable monomers with different hydrophobicity. Each non-ionizable monomer presents a constant contribution to pH tunability regardless of tertiary amine-containing monomers. Based on this strategy, we produced two libraries of nanoprobes with continuous pHt covering the entire physiological pH range (5.0-7.4) for fluorescent imaging of endosome maturation and cancers. This generalized strategy provides a powerful toolkit for biological studies and cancer theranostics.


Assuntos
Nanopartículas , Aminas , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Polimerização
17.
Nano Lett ; 21(10): 4371-4380, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-33984236

RESUMO

Anticancer immunotherapy is hampered by poor immunogenicity and a profoundly immunosuppressive microenvironment in solid tumors and lymph nodes. Herein, sequential pH/redox-responsive nanoparticles (SRNs) are engineered to activate the immune microenvironment of tumor sites and lymph nodes. The two-modular SRNs could sequentially respond to the acidic tumor microenvironment and endosome compartments of dendritic cells (DCs) to precisely deliver doxorubicin (DOX) and imidazoquinolines (IMDQs). In the tumor microenvironment, released DOX triggers immunogenic cell death. In sentinel lymph nodes, the IMDQ nanoparticle module is dissociated in the acidic endosome compartment to specifically stimulate toll-like receptor 7/8 for DC maturation. Thus, the orchestrated nanoparticle system could enhance the infiltration of CD8α+ T cells in tumors and provoke a strong antitumor immune response toward primary and abscopal tumors in B16-OVA and CT26 tumor-bearing mice models. The cooperative self-assembled nanoparticle strategy provides a potential candidate of nanomedicine to advance the synergistic cancer chemo-immunotherapy.


Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Doxorrubicina , Morte Celular Imunogênica , Imunoterapia , Camundongos , Microambiente Tumoral
18.
Nat Commun ; 12(1): 2385, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888701

RESUMO

Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/análise , Imagem Molecular/métodos , Nanopartículas/análise , Neoplasias/tratamento farmacológico , Animais , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Corantes Fluorescentes/química , Humanos , Microscopia Intravital , Camundongos , Sondas Moleculares/administração & dosagem , Sondas Moleculares/análise , Sondas Moleculares/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Imagem Óptica/métodos , Paclitaxel/administração & dosagem , Seleção de Pacientes , Reprodutibilidade dos Testes , Nanomedicina Teranóstica/métodos , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos
19.
Angew Chem Int Ed Engl ; 60(26): 14512-14520, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-33860575

RESUMO

Noninvasive imaging strategies have been extensively investigated for in vivo mapping of sentinel lymph nodes (SLNs). However, the current imaging strategies fail to accurately assess tumor metastatic status in SLNs with high sensitivity. Here we report pH-amplified self-illuminating near-infrared nanoparticles, which integrate chemiluminescence resonance energy transfer (CRET) and signal amplification strategy, enabling accurate identification of metastatic SLNs. After draining into lymph nodes, the nanoparticles were phagocytosed and dissociated in acidic phagosomes of inflammatory macrophages to emit near-infrared luminescent light. Using these nanoparticles, we successfully differentiated tumor metastatic lymph nodes from benign ones. These nanoparticles also exhibited excellent imaging capability for early detection of metastatic SLNs in diverse animal tumor models with small tumor volume (100-200 mm3 ).


Assuntos
Transferência Ressonante de Energia de Fluorescência , Linfonodos/patologia , Linfoma/patologia , Nanopartículas/química , Humanos , Concentração de Íons de Hidrogênio
20.
ACS Appl Mater Interfaces ; 13(16): 18533-18544, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33856773

RESUMO

Singlet oxygen (1O2) plays a vital role in pathophysiological processes and is the dominant executor of photodynamic therapy (PDT). Several small molecular probes have been designed to detect singlet oxygen for the evaluation of PDT efficacy. However, little attention was paid to the precise visualization of the 1O2 signal at the subcellular organelle level in living biological systems. Herein, a super-pH-resolved (SPR) nanosensor was developed to specifically illuminate 1O2 in endocytic organelles through encoding the cell-impermeant singlet oxygen sensor green (SOSG) into pH-sensitive micelles. The acid-activatable SPR-SOSG achieved more than 10-fold amplification of the 1O2 signal, leading to extremely higher sensitivity of singlet oxygen detection in specific endocytic organelles of living cells and animals, as compared with the nonactivatable nanoprobe and the commercially available 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe. Hence, the SPR-SOSG nanoplatform provides a promising tool to evaluate the efficacy and mechanism of nanocarrier-based photodynamic therapy.


Assuntos
Endocitose , Nanotecnologia/instrumentação , Organelas/metabolismo , Oxigênio Singlete/metabolismo , Fluoresceínas/metabolismo , Concentração de Íons de Hidrogênio , Micelas
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