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1.
Adv Mater ; : e1904958, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961987

RESUMO

Although biomimetic virus-like strategies have been widely used in antitumor applications, construction of uniquely shaped virus-like agents and optimization of their specific morphological features to achieve diverse antitumor functions are worthwhile pursuits. Here, a novel strategy to construct an artificial tobacco mosaic virus (ATMV) that closely mimics the structure of the rod-like tobacco mosaic virus (TMV) is developed. The supramolecular array is self-assembled from small, repeated subunits of tailor-made capsid-mimicking dendrons onto RGD-modified single-walled carbon nanotube to construct the ATMVs with high structural stability. The ATMVs are tactfully designed with shielding, targeting, and arming approaches, including shielding the viruses against premature elimination, selectively targeting tumor tissue, and arming the viruses with oncolytic abilities. The elongated particles are concealed in blood until they arrived at a tumor site, then they induce robust composite oncolytic processes including cytomembrane penetration, endoplasmic reticulum disruption to cause Ca2+ release, chemotherapeutic delivery, and photothermal therapy. Excitingly, the ATMVs not only lyse primary infected cells, but permeate adjacent cells for secondary infection, spreading cell-to-cell and continuing to induce lysis even deep in solid tumors. This work inspires a uniquely shaped virus-like agent with tactically optimized oncolytic functions that completely defeated large drug-resistant colon tumor (LoVo/Adr, ≈500 mm3 ).

2.
Fish Shellfish Immunol ; 98: 218-223, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31935552

RESUMO

Quantification real-time PCR (qRT-PCR) is a common method in analysis of gene expression, but the stable reference genes for the normalization analysis have not been appreciated before identifying expression pattern of genes in teleost fishes. In this study, we selected eight candidate reference genes (18S, Actin, EF-1α, 40S, B2M, TUBA, UBCE and GAPDH) basing on transcriptome analysis and the traditional housekeeping genes, and analyzed the stability of the reference genes in spleen, head kidney and head kidney leukocytes (HKL) after pathogen challenge in Schizothorax prenanti (S. prenanti). Three common programs (geNorm, NormFinder and Bestkeeper) were used to evaluate the stability of the candidate reference genes. Two reference genes, Actin and EF-1α presented higher stability, while 18S and GAPDH were the lower stable genes, both in in vitro and in vivo. An important immune gene, toll-like receptor 22a (TLR22a), was selected to validate the stability of the proposed reference genes (Actin and EF-1α) across different experiment treatments. The results reveal that Actin and EF-1α are quite suitable reference genes for the normalization analysis. Otherwise, using the most stable gene Actin to validate the reliable of transcriptome data showed the high correlation between the fold change of transcriptome data and qRT-PCR data. In conclusion, our study not only acquired the suitable reference gene for the qRT-PCR assay under specific experiment condition, but also provided a comprehensive method to evaluate and validate the reference gene based on transcriptome analysis in teleost fishes.

3.
Fish Shellfish Immunol ; 97: 235-247, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31863902

RESUMO

Lipopolysaccharide (LPS) is a classical pathogen-associated molecular pattern that can trigger strong inflammatory response mainly by TLR4-mediated signaling pathway in mammals, but the molecular mechanism of anti-LPS immunity is unclear in teleost fishes. In this study, we analyzed the gene expression features based on transcriptome analysis in Schizothorax prenanti (S. prenanti), after stimulation with two sources of LPS from Aeromonas hydrophila and Escherichia coli (Ah. LPS and Ecoli. LPS). 921 different expression genes (DEGs) after Ah. LPS stimulation and 975 DEGs after Ecoli.LPS stimulation were acquired, but only 706 and 750 DEGs were successfully annotated into the databases, respectively. Both of two groups of DGEs were significantly enriched into immune-related pathways by KEGG enrichment analysis, such as "Toll-like receptor signaling pathway", "Cytokine-cytokine receptor interaction" and "JAK-STAT signaling pathway". The annotated DEGs from Ah. LPS and Ecoli. LPS stimulation shared 470 DEGs, including 88 immune-related DEGs (IRGs) identified mainly by KEGG enrichment to immune-related signaling pathways. Among the shared IRGs, four pattern-recognition genes (TLR5, TLR25, PTX3 and C1q) were induced with high expression foldchange, and IFN-γ and relative genes also showed higher expression levels than control. Meanwhile, inflammatory signals were highlighted by upregulating the expression of inflammatory cytokines (IL-1ß, IL-10 and IL-8). Moreover, some non-shared IRGs (including TLR2 and TLR4) were identified, suggesting that different sources of LPS own different potentials for the induction of immune gene expression. In conclusion, TLR5, TLR25, PTX3 and C1q may function as the sensing molecules to catch the invasion signal of LPS. The anti-LPS immune response may be involved into TLR25/TLR5-mediated inflammatory signals that regulate subsequently the activation of PTX3/C1q-modulated complement pathway upon the induction of PTX3 expression, and the crosstalk between IFN-γ and TLR signaling pathways in teleost fishes. This study will contribute to further explore the molecular mechanism of LPS-induced immunity in teleost fishes.

4.
J Sci Food Agric ; 100(1): 92-101, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31435952

RESUMO

BACKGROUND: Oyster polypeptides have various biofunctions, such as anti-cancer and anti-oxidative stress, but whether it has the protective effects to primary ovarian failure (POF) remains poorly understand. To address this issue, daily gavage of oyster polypeptides was performed to investigate their protective effect, basing on d-galactose-induced POF model in C57BL/6 female mice. RESULTS: Oyster polypeptides restored the irregular estrous cycles and the abnormal serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and progesterone (P) levels as well as the decreased mRNA expression level of Amh that were induced by d-galactose. The follicle development of POF mice was improved by increasing the primordial follicle ratio and decreasing the atretic follicle number after oral administration of oyster polypeptides. Moreover, in the oyster polypeptides treated mice, the total superoxide dismutase (T-SOD) activity was significantly increased, while the malondialdehyde levels were significantly decreased. The mRNA expression levels of stress-related genes (SOD2, SIRT1 and FOXO3a) were remarkably up-regulated after d-galactose induction, but the up-regulation was weakened or disappeared by the gavage of oyster polypeptides. In addition, oyster polypeptides treatment also reduced the apoptosis of the ovarian granulosa cells and down-regulated the mRNA expression levels of apoptosis-related genes (p53 and Bad but not Bcl-2). CONCLUSION: This study reveals that oyster polypeptides may protect ovary against d-galactose-induced POF by their anti-oxidative stress activity to rescue d-galactose-induced ovarian oxidative damage and therefore to prevent ovarian cells apoptosis, thereby tipping the abnormality trigged by POF to get close to the normal levels. © 2019 Society of Chemical Industry.


Assuntos
Ostreidae/química , Peptídeos/administração & dosagem , Insuficiência Ovariana Primária/tratamento farmacológico , Substâncias Protetoras/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Feminino , Galactose/efeitos adversos , Humanos , Hormônio Luteinizante/metabolismo , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/metabolismo , Progesterona/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
5.
Fish Shellfish Immunol ; 95: 81-92, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31610291

RESUMO

Mammal Toll-like receptor 5 (TLR5) can directly recognize bacterial flagellin, initiate the inflammatory signaling cascades and trigger body immune system to clear the "non-self" substances. In teleosts, TLR5 has presented more complexes not only in increasing the molecular types, but also in elevating the functional diversity. In this study, we identified two TLR5 family members in Schizothorax prenanti, named as spTLR5-1 and spTLR5-2. The complete coding sequence (CDS) of spTLR5-1 is 2622 bp, encoding 873 amino acids, while the complete CDS of spTLR5-2 is 2640 bp, encoding 879 amino acids. Phylogenetic analysis showed that spTLR5-1 and spTLR5-2 were clustered to the TLR5 of schizothorax richardsonii and Cyprinus carpio respectively. The 3D structure analysis exhibited that the α-helix, ß-sheet, and the ligand binding site of spTLR5-1, spTLR5-2 and human TLR5 have large differences. The spTLR5-1 and spTLR5-2 had extensively expressed in various tissues, including the higher expression in liver, spleen and head kidney. Both the expression levels of spTLR5-1 and spTLR5-2 were significantly up-regulated after Aeromonas hydrophila (A. hydrophila) challenge. And, the downstream genes, such as AP-1, IKK-α, NF-kB, IL-1ß, IL-8 and TNF-α, were also significantly up-regulated after A. hydrophila challenge. Apart from that, the luciferase reporter assay demonstrated that the co-transfection of spTLR5-1 or spTLR5-2 into HEK293T cells showed the significantly increased NF-kB luciferase activity after flagellin stimulation. In conclusion, our results reveal that both two molecular types of fish TLR5 may commonly mediate the recognition of flagellin and the activation of the downstream inflammatory signaling molecules.

6.
Nanoscale ; 11(32): 15091-15103, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31385582

RESUMO

Multi-responsive polymeric nanoparticles have shown great promise in the sufficient site-specific delivery of drugs in heterogeneous and complicated biological microenvironments, but without great success due to many problems such as sophisticated manufacture process, high cost and cytotoxicity. In this work, a novel triple responsive dendrimeric nanocage (TDN) is fabricated through co-assembling and cross-linking of lipoic acid modified low generation dendrimers with lipoic acid modified polyethylene glycols (PEGs). This nanocage exhibits improved drug loading capacity (about 2 times higher) at a lower temperature and stimuli-responsive drug release profile upon the stimulation of temperature, acid pH and reducing agent. More importantly, the nanocage promotes drug internalization, conduces endosomal escape, and realizes intracellular controlled drug release. Furthermore, the nanocage significantly improves the pharmacokinetics and biodistribution of antitumor drugs, confirming the potent in vivo therapeutic effect with reduced side effects. The rational design and facile fabrication of multi-responsive dendrimeric nanocages provide a "proof-of-concept" for precise targeted drug delivery, and may have great potential for clinical use in the future.


Assuntos
Antineoplásicos/química , Materiais Biocompatíveis/química , Dendrímeros/química , Portadores de Fármacos/química , Nanoestruturas/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Polietilenoglicóis/química , Temperatura Ambiente , Distribuição Tecidual , Transplante Homólogo
7.
Fish Shellfish Immunol ; 93: 986-996, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31422176

RESUMO

Evolutionary development has increased the diversity of genotypes and the complexity of gene functions in fish. TLR22 has been identified as a teleost-specific gene, but its functions are tremendously different among different fish species. Whether the functional diversity relates to the difference of genotypes remains poorly understand. In this study, we cloned and identified three TLR22 molecules from Schizothorax prenanti (S. prenanti), named as spTLR22-1, spTLR22-2 and spTLR22-3. The full-length coding regions of spTLR22s are 2841 bp, 2805 bp and 2868 bp and coding 946 aa, 934 aa and 955 aa, respectively. All spTLR22s are composed of multiple leucine-rich repeat (LRR) domains, a transmembrane structure and a Toll/IL-1 receptor (TIR) region. The phylogenetic analysis showed that three spTLR22s were close to Cyprinus carpio TLR22-1, TLR22-2 and TLR22-3, respectively. Among the spTLR22s, they presented not close relationship but remained to belong to TLR22 subfamily. All spTLR22s were ubiquitously expressed in all tested tissues, but the expression levels of spTLR22s were dominant in immune-related tissues, such as gill and spleen. The expression levels of spTLR22-1 and spTLR22-3 were significantly increased after treatment with bacteria, LPS and Poly(I:C). However, spTLR22-2 seems like no response to these treatments. The luciferase reporter assay demonstrated that all spTLR22s could activate NF-κB signaling pathway, but only spTLR22-1 and spTLR22-2 could activate IFN-ß signaling pathway. Interestingly, in the ligand recognition analysis, spTLR22-1 and spTLR22-3 but not spTLR22-2 had the recognized potential to Poly(I:C), and all spTLR22s could not recognize LPS. Both spTLR22-1 and spTLR22-3 significantly up-regulated the expression of anti-viral-related genes (Mx, IFN and ISG15) and down-regulated the expression of anti-inflammatory factor IL-10 after the overexpression in carp EPC cell line, but spTLR22-2 failed to impact the expression of these genes. Moreover, we found that all spTLR22s localized to the intracellular region. Taken together, our results reveal that spTLR22-1 and spTLR22-3 but not spTLR22-2 may be involved into the anti-viral immune response via IFN-ß signaling pathway, and all spTLR22s can activate NF-κB signaling pathway but only spTLR22-1 and spTLR22-3 response to the stimulation of bacteria and LPS.


Assuntos
Cyprinidae/genética , Cyprinidae/imunologia , Proteínas de Peixes/genética , Expressão Gênica/imunologia , Receptores Toll-Like/genética , Animais , Fenômenos Fisiológicos Bacterianos , Linhagem Celular , Cyprinidae/metabolismo , Citocinas/metabolismo , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Lipopolissacarídeos/farmacologia , Luciferases/metabolismo , Filogenia , Poli I-C/farmacologia , Análise de Sequência de Proteína/veterinária , Receptores Toll-Like/metabolismo
8.
Fish Shellfish Immunol ; 84: 816-824, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30393178

RESUMO

Schizothorax prenanti (S. prenanti), an important species of economical fish in Southwest China, is susceptible to Aeromonas hydrophila (Ah). To understand the immune response to Ah, the transcriptome profiling of spleen of S. prenanti was analyzed after Ah infection. A total of 6, 213 different expression genes (DEGs) were obtained, including 3, 066 up-regulated DEGs and 3, 147 down-regulated DEGs. These DEGs were annotated by KEGG and GO databases, so that the immune-related DEGs (IRDs) can be identified and classified. Then, the interesting IRDs were screened to build heat map, and the reliability of the transcriptome data was validated by qPCR. In order to clarify the mechanism of signal transduction in the anti-bacterial immunity, the signaling pathway initiated by TLRs was predicted. In this pathway, TLR25 and TLR5 mediate the NF-κB and AP-1 signals via MyD88-dependent pathway. Meanwhile, the type I IFN (IFNα/ß) induced by IRF1 and IRF3/7 may play an important role in the anti-bacterial immunity. In conclusion, this study preliminarily provides insights into the mechanism of signal transduction after Ah infection in S. prenanti, which contributes to exploring the complex anti-bacterial immunity.


Assuntos
Cyprinidae/genética , Cyprinidae/imunologia , Doenças dos Peixes/imunologia , Imunidade Inata/genética , Transdução de Sinais/genética , Receptores Toll-Like/fisiologia , Transcriptoma/imunologia , Aeromonas hydrophila/fisiologia , Animais , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Baço/metabolismo , Receptores Toll-Like/genética
9.
Fish Shellfish Immunol ; 82: 361-370, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30081181

RESUMO

TLR25 is a new member of TLR1 family that is only identified in teleosts, but its function in immune response is still unclear. In current study, the coding sequence (CDS) of TLR25 was cloned from Schizothorax prenanti (named spTLR25), and spTLR25 is 2454 bp in length and coding a protein of 817 aa. The spTLR25 contains a signal peptide, twenty leucine-rich repeat (LRR) domains, a LRR C-terminal (LRRCT) motif, a transmembrane region and a Toll/IL-1 receptor (TIR) domain. Phylogenetic analysis indicates that spTLR25 has the closest relationship with Cyprinus carpio (C. carpio) TLR25-2. The 3D structure of spTLR25 exhibits 5 α-helices and 3 ß-sheets in the TIR domain, and 8 α-helices and 6 ß-sheets in the LRR domains. The spTLR25 is mainly expressed in immune-related tissues and peripheral blood leukocytes (PBL). Furthermore, the expression levels of spTLR25 were upregulated in spleen, head kidney and liver while S. prenanti was challenged with LPS or Aeromonas hydrophila (Ah), and the upregulation was also detected in head kidney leukocytes (HKL) after LPS and Poly (I:C) stimulation. The luciferase reporter assay demonstrated that NF-κB and type I IFNs signaling pathways can be activated by spTLR25, and this process may involve in the cascade amplification of TLR25-MyD88 signaling. In addition, the co-localization analysis showed that spTLR25 localizes to intracellular region. Taken together, our results reveal that teleost-specific TLR25 may be a multifunctional receptor for recognizing both LPS and Poly (I:C) and may activate NF-κB and type I IFNs signaling pathways.


Assuntos
Cyprinidae/genética , Cyprinidae/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Aeromonas hydrophila/fisiologia , Sequência de Aminoácidos , Animais , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Interferon Tipo I , Lipopolissacarídeos/farmacologia , NF-kappa B , Filogenia , Poli I-C/farmacologia , Alinhamento de Sequência/veterinária , Transdução de Sinais , Receptores Toll-Like/química
10.
Int J Mol Sci ; 18(10)2017 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-28991187

RESUMO

Colochirus robustus, a species of sea cucumber, has long been used in East and Southeast Asia as nutritious food as well as for certain medicinal purpose. Studies have shown a number of biological functions associated with consumption of sea cucumber, many of which are attributed to its major component, sea cucumber peptides (SCP). However, how SCP impacts immune system, which is critical for host defense, has not been defined. To address this issue, in the present study, we conducted comprehensive analysis of immune function after oral administration of SCP (0, 25, 50, and 75 mg/kg body weigh) for eight weeks in C57BL/6 mice. We found that SCP treatment significantly enhanced lymphocyte proliferation, serum albumin (ALB) levels, and the natural killer (NK) cell activity. Moreover, SCP promoted functions of helper T cells (Th) as indicated by increased production of Th1 type cytokines of Interleukin (IL)-1ß, IL-2, Interferon (IFN)-γ and TNF-α and Th2 type cytokines (IL-4, IL-6, and IL-10). To determine the effective components, SCP was hydrolyzed into 16 types of constituent amino acids in simulated gastrointestinal digestion and these hydrolytic amino acids (HAA) were used for the mechanistic studies in the in vitro models. Results showed that HAA enhanced lymphocyte proliferation and production of IL-2, IL-10 and IFN-γ. Furthermore, CD3ζ (CD3ζ) and ζ-chain-associated protein kinase 70 (ZAP-70), the signaling molecules essential for activating T lymphocytes, were significantly up-regulated after HAA treatment. In summary, our results suggest that SCP is effective in enhancing immune function by activating T cells via impacting CD3ζ- and ZAP-70-mediated signaling pathway.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína-Tirosina Quinase ZAP-70/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Transdução de Sinais/fisiologia , Células Th1/metabolismo , Células Th2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína-Tirosina Quinase ZAP-70/genética
11.
Fish Shellfish Immunol ; 62: 13-23, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28063952

RESUMO

Schizothorax prenanti (S. prenanti) is an important economical cold-water fish species in southwestern China, but it is susceptible to various pathogens infection. In order to clearly elucidate the antiviral mechanism, in this study, we have analyzed the transcriptome of S. prenanti spleen after challenge with the virus mimic, poly (I:C) (pIC), using next generation sequencing technology (RNA-seq). A total of 313 differential expressed genes (DEGs) in spleen at 12 h were obtained after pIC treatment, including 268 significantly up-regulated unigenes (fold change > 2) and 45 significantly down-regulated unigenes (fold change > 2). Through the immune-related DEGs (IRDs) screening, 47 IRDs were used to establish heat map, which intuitively showed a significantly difference after pIC treatment. To validate the RNA-seq data and observe gene expression, the expression levels of 14 IRDs were detected by qPCR after pIC treatment at 0, 4, 8, 12, and 24 h. The results indicated that the qPCR data presented a positive line correlation with RNA-seq data, and the 14 IRDs were responsive to pIC stimulation except IL-1ß. Thus, based on the RNA-seq and qPCR data, we inferred that MDA5- and Jak-mediated signaling pathways may involve in the antiviral signaling transduction, and induce type I IFNs and ISGs to block virus invasion, respectively. Unfortunately, TLR3 and TLR22, as receptors of virus dsRNA, were no significantly expressed in this study. Nonetheless, our study still provides useful mRNA sequences of antiviral immunity for further immunological research, and facilitates improving disease restriction in S. prenanti.


Assuntos
Cyprinidae/imunologia , Proteínas de Peixes/genética , Imunidade Inata , Poli I-C/farmacologia , Transcriptoma , Animais , Cyprinidae/virologia , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Sequenciamento de Nucleotídeos em Larga Escala/veterinária , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Transdução de Sinais , Baço/imunologia , Baço/metabolismo
12.
ACS Nano ; 11(1): 416-429, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28005335

RESUMO

Chemotherapy resistance remains a serious impediment to successful antitumor therapy around the world. However, existing chemotherapeutic approaches are difficult to cope with the notorious multidrug resistance in clinical treatment. Herein, we developed tumor-specific multiple stimuli-activated dendrimeric nanoassemblies with a metabolic blockade to completely combat both physiological barriers and cellular factors of multidrug resistance. With a sophisticated molecular and supramolecular engineering, this type of tumor-specific multiple stimuli-activated nanoassembly based on dendrimeric prodrugs can hierarchically break through the sequential physiological barriers of drug resistance, including stealthy dendritic PEGylated corona to optimize blood transportation, robust nanostructures for efficient tumor passive targeting and accumulation, enzyme-activated tumor microenvironment targeted to deepen tumor penetration and facilitate cellular uptake, cytoplasmic redox-sensitive disintegration for sufficient release of encapsulated agents, and lysosome acid-triggered nucleus delivery of antitumor drugs. In the meantime, we proposed a versatile tactic of a tumor-specific metabolism blockade for provoking several pathways (ATP restriction, apoptotic activation, and anti-apoptotic inhibition) to restrain multiple cellular factors of drug resistance. The highly efficient antitumor activity to drug-resistant MCF-7R tumor in vitro and in vivo supports this design and strongly defeats both physiological barriers and cellular factors of chemotherapy resistance. This work sets up an innovative dendrimeric nanosystem to surmount multidrug resistance, contributing to the development of a comprehensive nanoparticulate strategy for future clinical applications.


Assuntos
Antineoplásicos/farmacologia , Dendrímeros/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanopartículas/química , Pró-Fármacos/farmacologia , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/química , Relação Dose-Resposta a Droga , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pró-Fármacos/química , Relação Estrutura-Atividade , Microambiente Tumoral/efeitos dos fármacos
13.
Theranostics ; 6(9): 1293-305, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375780

RESUMO

Recently, self-assembling small dendrimers into supramolecular dendritic systems offers an alternative strategy to develop multifunctional nanoplatforms for biomedical applications. We herein report a dual-responsive supramolecular PEGylated dendritic system for efficient platinum-based drug delivery and near-infrared (NIR) tracking. With a refined molecular/supramolecular engineering, supramolecular dendritic systems were stabilized by bioreducible disulfide bonds and endowed with NIR fluorescence probes, and PEGylated platinum derivatives coordinated onto the abundant peripheral groups of supramolecular dendritic templates to generate pH/redox dual-responsive theranostic supramolecular PEGylated dendritic systems (TSPDSs). TSPDSs markedly improved the pharmacokinetics and biodistribution of platinum-based drugs, owing to their stable nanostructures and PEGylated shells during the blood circulation. Tumor intracellular environment (low pH value and high glutathione concentration) could trigger the rapid disintegration of TSPDSs due to acid-labile coordination bonds and redox-cleavable disulfide linkages, and then platinum-based drugs were delivered into the nuclei to exert antitumor activity. In vivo antitumor treatments indicated TSPDSs not only provided high antitumor efficiency which was comparable to clinical cisplatin, but also reduced renal toxicity of platinum-based drugs. Moreover, NIR fluorescence of TSPDSs successfully visualized in vitro and in vivo fate of nanoplatforms and disclosed the intracellular platinum delivery and pharmacokinetics. These results confirm tailor-made supramolecular dendritic system with sophisticated nanostructure and excellent performance is a promising candidate as smart theranostic nanoplatforms.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Corantes Fluorescentes/análise , Raios Infravermelhos , Nanopartículas/administração & dosagem , Platina/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Portadores de Fármacos/química , Xenoenxertos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/química , Oxirredução , Platina/farmacocinética , Nanomedicina Teranóstica/métodos , Resultado do Tratamento
14.
Angew Chem Int Ed Engl ; 54(14): 4289-94, 2015 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-25727937

RESUMO

Bioinspired tryptophan-rich peptide dendrimers (TRPDs) are designed as a new type of dendritic peptide drugs for efficient tumor therapy. The TRPDs feature a precise molecular structure and excellent water solubility and are obtained in a facile process. Based on the unique features of peptide dendrimers, including highly branched structures, abundant terminal groups, and globular-protein-like architectures, the therapeutic dendrimers show significant supramolecular interactions with DNA through the tryptophan residues (indole rings and amino groups). Further experimental results indicate that TRPDs are efficient antitumor agents both in vitro and in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Dendrímeros/uso terapêutico , Neoplasias/tratamento farmacológico , Peptídeos/uso terapêutico , Linhagem Celular Tumoral , Dendrímeros/química , Humanos , Microscopia Eletrônica de Transmissão
15.
ACS Nano ; 8(9): 9255-64, 2014 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-25184443

RESUMO

Currently, supramolecular self-assembly of dendrons and dendrimers emerges as a powerful and challenging strategy for developing sophisticated nanostructures with excellent performances. Here we report a supramolecular hybrid strategy to fabricate a bio-inspired dendritic system as a versatile delivery nanoplatform. With a rational design, dual-functionalized low-generation peptide dendrons (PDs) self-assemble onto inorganic nanoparticles via coordination interactions to generate multifunctional supramolecular hybrid dendrimers (SHDs). These SHDs exhibit well-defined nanostructure, arginine-rich peptide corona, and fluorescent signaling properties. As expected, our bio-inspired supramolecular hybrid strategy largely enhances the gene transfection efficiency of SHDs approximately 50 000-fold as compared to single PDs at the same R/P ratio. Meanwhile the bio-inspired SHDs also (i) provide low cytotoxicity and serum resistance in gene delivery; (ii) provide inherent fluorescence for tracking intracellular pathways including cellular uptake, endosomal escape, and gene release; and (iii) work as an alternative reference for monitoring desired protein expression. More importantly, in vivo animal experiments demonstrate that SHDs offer considerable gene transfection efficiency (in muscular tissue and in HepG2 tumor xenografts) and real-time bioimaging capabilities. These SHDs will likely stimulate studies on bio-inspired supramolecular hybrid dendritic systems for biomedical applications both in vitro and in vivo.


Assuntos
Rastreamento de Células , Dendrímeros/química , Peptidomiméticos/química , Transfecção , DNA/química , DNA/genética , DNA/metabolismo , Células Hep G2 , Humanos , Espaço Intracelular/metabolismo , Modelos Moleculares , Conformação Molecular
16.
Small ; 10(6): 1133-40, 2014 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-24155260

RESUMO

A novel type of nanovehicle (NV) based on stimuli-responsive supramolecular peptide-amphiphiles (SPAs, dendritic poly (L-lysine) non-covalently linked poly (L-leucine)) is developed for intracellular drug delivery. To determine the pH-dependent mechanism, the supramolecular peptide-amphiphile system (SPAS) is investigated at different pH conditions using a variety of physical and chemical approaches. The pH-triggered disassembly of SPAS can be attributed to the disappearance of non-covalent interactions within SPAs around the isoelectric point of poly (L-leucine). SPAS is found to encapsulate guest molecules at pH 7.4 but release them at pH 6.2. In this way, SPAS is able to act as a smart NV to deliver its target to tumor cells using intracellular pH as a trigger. The DOX-loaded NVs are approximately 150 nm in size. In vitro release profiles and confocal laser scanning microscopy (CLSM) images of HepG2 cells confirm that lower pH conditions can trigger the disassembly of NVs and so achieve pH-dependent intracellular DOX delivery. In vitro cytotoxicity of the DOX-loaded NVs to HepG2 cells demonstrate that the smart NVs enhance the efficacy of hydrophobic DOX. Fluorescence-activated cell sorting (FACS) and CLSM results show that the NVs can enhance the endocytosis of DOX into HepG2 cells considerably and deliver DOX to the nuclei.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Espaço Intracelular/metabolismo , Nanopartículas/química , Peptídeos/química , Tensoativos/química , Animais , Morte Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Fluoresceína-5-Isotiocianato/metabolismo , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Espaço Intracelular/efeitos dos fármacos , Camundongos , Microscopia de Força Atômica , Células NIH 3T3 , Nanopartículas/ultraestrutura , Tamanho da Partícula
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