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1.
Artigo em Inglês | MEDLINE | ID: mdl-32779303

RESUMO

By leveraging the ability of Shewanella oneidensis MR-1 (S. oneidensis MR-1) to anaerobically catabolize lactate through the transfer of electrons to metal minerals for respiration, a lactate-fueled biohybrid (Bac@MnO2 ) was constructed by modifying manganese dioxide (MnO2 ) nanoflowers on the S. oneidensis MR-1 surface. The biohybrid Bac@MnO2 uses decorated MnO2 nanoflowers as electron receptor and the tumor metabolite lactate as electron donor to make a complete bacterial respiration pathway at the tumor sites, which results in the continuous catabolism of intercellular lactate. Additionally, decorated MnO2 nanoflowers can also catalyze the conversion of endogenous hydrogen peroxide (H2 O2 ) into generate oxygen (O2 ), which could prevent lactate production by downregulating hypoxia-inducible factor-1α (HIF-1α) expression. As lactate plays a critical role in tumor development, the biohybrid Bac@MnO2 could significantly inhibit tumor progression by coupling bacteria respiration with tumor metabolism.

2.
Nat Biomed Eng ; 4(9): 853-862, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32632226

RESUMO

Patients with kidney failure commonly require dialysis to remove nitrogenous wastes and to reduce burden to the kidney. Here, we show that a bacterial cocktail orally delivered in animals with kidney injury can metabolize blood nitrogenous waste products before they diffuse through the intestinal mucosal barrier. The microbial cocktail consists of three strains of bacteria isolated from faecal microbiota that metabolize urea and creatinine into amino acids, and is encapsulated in calcium alginate microspheres coated with a polydopamine layer that is selectively permeable to small-molecule nitrogenous wastes. In murine models of acute kidney injury and chronic kidney failure, and in porcine kidney failure models, the encapsulated microbial cocktail significantly reduced urea and creatinine concentrations in blood, and did not lead to any adverse effects.

3.
Nat Commun ; 11(1): 1985, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332752

RESUMO

The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy. Here, we generate a vaccine-based nanosystem by integrating siRNA for Cd274 into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein. This nanosystem has good biosafety and enhances the therapeutic response rate of anti-tumor immunotherapy. The HPV16 L1 protein activates innate immunity through the type I interferon pathway and exhibits an efficient anti-cancer effect when cooperating with ICB therapy. For both resectable and unresectable breast tumors, the nanosystem decreases 71% tumor recurrence and extends progression-free survival by 67%. Most importantly, the nanosystem successfully induces high response rates in various genetically modified breast cancer models with different antigen loads. The strong immune stimulation elicited by this vaccine-based nanosystem might constitute an approach to significantly improve current ICB immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Nanopartículas/administração & dosagem , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Humanos , Imunidade Inata/genética , Camundongos , Recidiva Local de Neoplasia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Intervalo Livre de Progressão , RNA Interferente Pequeno/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
4.
Biomater Sci ; 8(2): 702-711, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31777864

RESUMO

Although chemotherapy is the most common method in clinical therapeutics with a straightforward mechanism, conventional anti-tumor drugs are still almost incapable of preventing the occurrence of tumor metastasis. In this study, we developed a multi-functional drug delivery system EINP@DOX consisting of a tea-derived polyphenol EGCG, iron ions and DOX. The system integrated the functions of tumor inhibition, diagnosis and metastasis prevention to achieve a systematic tumor treatment. The nanoscale size of EINP@DOX facilitated its accumulation in tumor tissues by means of the enhanced permeability and retention (EPR) effect, and it was then transferred to endosomes. The weakly acidic microenvironment in the endosomes of the tumor cells could destroy the coordination structure of EINP@DOX to realize the release of DOX for tumor therapy. Furthermore, the dissociative EGCG played the role of an adjuvant to restrain EMT and down-regulate the MMP levels, which could prevent the occurrence of tumor metastasis. Meanwhile, iron ions as superior magnetic resonance imaging (MRI) contrast agents provided visual evidence for the accurate location of EINP@DOX. In vitro and in vivo studies demonstrated that EINP@DOX showed a remarkable performance in tumor diagnosis and excellent therapeutic efficacy, inhibiting the metastasis of tumor cells effectively at the same time.

5.
Nano Lett ; 19(11): 8049-8058, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31558023

RESUMO

Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.

6.
Nat Biomed Eng ; 3(9): 717-728, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31332342

RESUMO

The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the higher concentration of the pro-tumoural Fusobacterium nucleatum and the absence of antineoplastic butyrate-producing bacteria in the faecal microbiota of patients with CRC, we show that-in mice with orthotopic colorectal tumours or with spontaneously formed colorectal tumours-oral or intravenous administration of irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages that inhibit the growth of F. nucleatum significantly augments the efficiency of first-line chemotherapy treatments of CRC. We also show that oral administration of the phage-guided irinotecan-loaded nanoparticles in piglets led to negligible changes in haemocyte counts, immunoglobulin and histamine levels, and liver and renal functions. Phage-guided nanotechnology for the modulation of the gut microbiota might inspire new approaches for the treatment of CRC.


Assuntos
Bactérias/efeitos dos fármacos , Bactérias/virologia , Bacteriófagos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/microbiologia , Tratamento Farmacológico/métodos , Microbioma Gastrointestinal/fisiologia , Animais , Antineoplásicos/uso terapêutico , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Butiratos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/microbiologia , Neoplasias Colorretais/patologia , Dextranos , Modelos Animais de Doenças , Fusobacterium nucleatum/efeitos dos fármacos , Fusobacterium nucleatum/crescimento & desenvolvimento , Fusobacterium nucleatum/metabolismo , Fusobacterium nucleatum/virologia , Microbioma Gastrointestinal/efeitos dos fármacos , Imunoglobulinas , Irinotecano/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas
7.
Adv Mater ; 31(16): e1808278, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30803049

RESUMO

Synthetic biology based on bacteria has been displayed in antitumor therapy and shown good performance. In this study, an engineered bacterium Escherichia coli MG1655 is designed with NDH-2 enzyme (respiratory chain enzyme II) overexpression (Ec-pE), which can colonize in tumor regions and increase localized H2 O2 generation. Following from this, magnetic Fe3 O4 nanoparticles are covalently linked to bacteria to act as a catalyst for a Fenton-like reaction, which converts H2 O2 to toxic hydroxyl radicals (•OH) for tumor therapy. In this constructed bioreactor, the Fenton-like reaction occurs with sustainably synthesized H2 O2 produced by engineered bacteria, and severe tumor apoptosis is induced via the produced toxic •OH. These results show that this bioreactor can achieve effective tumor colonization, and realize a self-supplied therapeutic Fenton-like reaction without additional H2 O2 provision.


Assuntos
Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Neoplasias/terapia , Animais , Apoptose , Reatores Biológicos , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Nanopartículas de Magnetita/química , Camundongos Endogâmicos BALB C , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
8.
Nanoscale ; 11(4): 2027-2036, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30644936

RESUMO

An innovative tungsten-based multifunctional nanoplatform composed of polyethylene glycol (PEG)-modified tungsten nitride nanoparticles (WN NPs) is constructed for tumor treatment. The PEG-WN NPs not only possess strong near-infrared (NIR) absorbance, high photothermal conversion efficiency, and excellent photothermal stability, but also effectively inhibit tumor cells upon 808 nm laser irradiation. After coating with thiolated (2-hydroxypropyl)-ß-cyclodextrin (MUA-CD) on the surface, such a nanoplatform can also be used for drug delivery (such as DOX) and presents a synergistic tumor inhibition effect both in vitro and in vivo. Furthermore, the PEG-WN NPs present good contrasting capability for X-ray computed tomography (CT) and photoacoustic (PA) imaging. With PA/CT imaging, the tumor can be accurately positioned for precise treatment. It is worth mentioning that PEG-WN NPs are biodegradable and could be effectively excreted from the body with no appreciable toxicity in vivo. It is expected that this biocompatible multifunctional nanoplatform can serve as a potential candidate for tumor treatment in future clinical applications.


Assuntos
Nanopartículas Metálicas/química , Tungstênio/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Feminino , Hipertermia Induzida , Lasers , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Tamanho da Partícula , Técnicas Fotoacústicas , Fototerapia , Polietilenoglicóis/química , Nanomedicina Teranóstica , Tomografia Computadorizada por Raios X , beta-Ciclodextrinas/química
9.
J Mater Chem B ; 7(5): 778-785, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32254852

RESUMO

In recent decades, drug self-delivery systems (DSDSs) have appeared with extraordinary superiority for cancer therapy while realizing intracellular delivery without supererogatory drug carriers. Here, we have designed and programmed a novel self-delivery system to realize tumor targeting therapy. The amphiphilic proapoptotic peptide KLAKLAKKLAKLAKGCK(Fmoc)2 (KLA) was used to form a self-assembled structure (KD) by encapsulating the hydrophobic anticarcinogen doxorubicin (DOX). Then, tumor recognizing hyaluronic acid (HA) was coated on the surface of KD to obtain a tumor targeting self-delivery system (KDH). The protective layer of HA could protect the therapeutic agents from being inactivated during blood circulation, and further specifically recognize tumor cells by the CD44 receptor after KDH had located the tumor regions. Additionally, hyaluronidase (HAase) overexpressed in the endosome of tumor cells could degrade the protective layer of HA and accelerate the liberation of KLA and DOX. The proapoptotic peptide KLA had the ability to locate mitochondria and induce mitochondrial dysfunction; meanwhile the anticarcinogen DOX diffused to the nuclei to inhibit the growth of tumor cells. Both in vitro and in vivo studies identified that our self-delivery system KDH possessed precise tumor targeting, and exhibited fantastic antitumor efficacy as well as negligible side effects.


Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/normas , Liberação Controlada de Fármacos , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Hialuronoglucosaminidase/metabolismo
10.
Adv Mater ; 30(31): e1801622, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29926990

RESUMO

Cytotherapy has received considerable attention in the field of cancer therapy, and various chemical or genetic methods have been applied to remold natural cells for improved therapeutic outcome of cytotherapy. A simple method to modify lymphocytes for cancer treatment by using a clinically used molecule, δ-aminolevulinic acid (δ-ALA), is reported here. After incubation with this molecule, tumor-targeted lymphocytes spontaneously synthesize anti-neoplastic drug protoporphyrin X (PpIX), and specifically accumulate in cancer tissue. Under periodic 630 nm laser irradiation, lymphocytes generate vesicle-like apoptotic body (Ab) containing the above-produced PpIX, and the facilitated delivery of PpIX from Ab makes an excellent therapeutic effect for Ras-mutated cancer cells under a second irradiation. Importantly, a microfluidic device is further fabricated to simplify cell sorting and drug synthesis with a one-step operation, which could promote generalization of this strategy. In vitro and in vivo studies confirm the success of such an easy-operated and global-regulated strategy for cancer therapy.


Assuntos
Ácido Aminolevulínico/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Ácido Aminolevulínico/metabolismo , Ácido Aminolevulínico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Lasers , Ácidos Levulínicos/farmacologia , Ácidos Levulínicos/uso terapêutico , Linfonodos/metabolismo , Linfonodos/patologia , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Microscopia de Fluorescência , Fotoquimioterapia , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/química , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual , Proteínas ras/genética
11.
ACS Nano ; 12(6): 6218-6227, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29791792

RESUMO

Tumor hypoxia has attained the status of a core hallmark of cancer that globally affects the entire tumor phenotype. Reversing tumor hypoxia might offer alternative therapeutic opportunities for current anticancer therapies. In this research, a photosynthetic leaf-inspired abiotic/biotic nano-thylakoid (PLANT) system was designed by fusing the thylakoid membrane with synthetic nanoparticles for efficient O2 generation in vivo. Under 660 nm laser irradiation, the PLANT system exhibited intracellular O2 generation and the anaerobic respiration of the multicellular tumor spheroid was suppressed by PLANT as well. In vivo, it was found that PLANT could not only normalize the entire metabolic network but also adjust the abnormal structure and function of the tumor vasculature. It was demonstrated that PLANT could significantly enhance the efficacy of phototherapy or antiangiogenesis therapy. This facile approach for normalizing the tumor microenvironment will find great potential in tumor therapy.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Nanopartículas/química , Neovascularização Patológica/terapia , Fotossíntese , Tilacoides/metabolismo , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Oxigênio/metabolismo , Fototerapia/métodos , Esferoides Celulares/metabolismo
12.
Nat Commun ; 9(1): 1680, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29700283

RESUMO

Bacteria preferentially accumulating in tumor microenvironments can be utilized as natural vehicles for tumor targeting. However, neither current chemical nor genetic approaches alone can fully satisfy the requirements on both stability and high efficiency. Here, we propose a strategy of "charging" bacteria with a nano-photocatalyst to strengthen their metabolic activities. Carbon nitride (C3N4) is combined with Escherichia coli (E. coli) carrying nitric oxide (NO) generation enzymes for photo-controlled bacterial metabolite therapy (PMT). Under light irradiation, photoelectrons produced by C3N4 can be transferred to E. coli to promote the enzymatic reduction of endogenous NO3- to cytotoxic NO with a 37-fold increase. In a mouse model, C3N4 loaded bacteria are perfectly accumulated throughout the tumor and the PMT treatment results in around 80% inhibition of tumor growth. Thus, synthetic materials-remodeled microorganism may be used to regulate focal microenvironments and increase therapeutic efficiency.


Assuntos
Terapia Biológica , Escherichia coli/metabolismo , Escherichia coli/efeitos da radiação , Neoplasias/terapia , Nitrilos/química , Animais , Apoptose , Linhagem Celular Tumoral , Escherichia coli/enzimologia , Escherichia coli/genética , Feminino , Humanos , Luz , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Neoplasias/microbiologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Processos Fotoquímicos
13.
Nano Lett ; 18(4): 2373-2380, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29558152

RESUMO

Oral drug administration is widely adopted for diverse drugs and is convenient to use due to the capability of reaching different parts of the body via the bloodstream. However, it is generally not feasible for biomacromolecular antitumor drugs such as protein and nucleic acids due to the limited absorption through gastrointestinal tract (GIT) and the poor tumor targeting. Here, we report a noninvasive thermally sensitive programmable therapetic system using bacteria E. coli MG1655 as an vehicle for tumor treatments via oral administration. Thermally sensitive programmable bacteria (TPB) are transformed with plasmids expressing therapeutic protein TNF-α and then decorated with biomineralized gold nanoparticles (AuNPs) to obtain TPB@Au. AuNPs and TNF-α plasmids efficaciously protected by TPB in the gut can be transported into internal microcirculation via transcytosis of microfold cells (M cells). After that, the bacteria-based antitumor vehicles accumulate at tumor sites due to the anaerobic bacterial feature of homing to tumor microenvironments. In vitro and in vivo experiments verify the successful delivery of AuNPs and TNF-α plasmids by TPB. Importantly, under remote activation the expression of TNF-α in tumor sites can be procisely controlled by the heat generated from photothermal AuNPs to exert therapeutic actions. The biological security evaluation demonstrates that this strategy would not disturb the balance of intestinal flora.


Assuntos
Neoplasias da Mama/terapia , Escherichia coli/genética , Técnicas de Transferência de Genes , Plasmídeos/genética , Fator de Necrose Tumoral alfa/genética , Administração Oral , Animais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Feminino , Expressão Gênica , Terapia Genética , Ouro/química , Humanos , Nanopartículas Metálicas/química , Camundongos Endogâmicos BALB C , Imagem Óptica , Plasmídeos/administração & dosagem , Temperatura , Transformação Genética
14.
Small ; 13(48)2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29125688

RESUMO

As a characteristic trait of most tumor types, metastasis is the major cause of the death of patients. In this study, a photothermal agent based on gold nanorod is coated with metal (Gd3+ )-organic (polyphenol) network to realize combination therapy for metastatic tumors. This nanotheranostic system significantly enhances antitumor therapeutic effects in vitro and in vivo with the combination of photothermal therapy (PTT) and chemotherapy, also can remarkably prevent the invasion and metastasis due to the presence of polyphenol. After the treatment, an 81% decrease in primary tumor volumes and a 58% decrease in lung metastasis are observed. In addition, the good performance in magnetic resonance imaging, computerized tomography, and photothermal imaging of the nanotheranostic system can realize image-guided therapy. The multifunctional nanotheranostic system will find a great potential in diagnosis and treatment integration in tumor treatments, and broaden the applications of PTT treatment.


Assuntos
Metais/química , Metástase Neoplásica/terapia , Polifenóis/farmacologia , Nanomedicina Teranóstica/métodos , Animais , Morte Celular , Movimento Celular , Ouro/química , Células HeLa , Humanos , Masculino , Metabolômica , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dióxido de Silício/química
15.
Adv Mater ; 29(44)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29024101

RESUMO

Continuous exposure to carbon monoxide (CO) can sensitize cancer cells to chemotherapy while protect normal cells from apoptosis. The Janus face of CO thus provides an ideal strategy for cancer therapy. Here, a photocatalytic nanomaterial (HisAgCCN) is introduced to transform endogenous CO2 to CO for improving cancer therapy in vivo. The CO production rate of HisAgCCN reaches to 65 µmol h-1 gmat-1 , which can significantly increase the cytotoxicity of anticancer drug (doxorubicin, DOX) by 70%. Interestingly, this study finds that HisAgCCN can enhance mitochondria biogenesis and aggravate oxidative stress in cancer cells, whereas protect normal cells from chemotherapy-induced apoptosis as well. Proteomics and metabolomics studies reveal that HisAgCCN can enhance mitochondria biogenesis and aggravate oxidative stress in cancer cells specifically. In vivo studies indicate that HisAgCCN/DOX combination therapy presents a synergetic tumor inhibition, which might provide a new direction for clinical cancer therapy.


Assuntos
Dióxido de Carbono/química , Antineoplásicos , Apoptose , Linhagem Celular Tumoral , Doxorrubicina , Humanos , Neoplasias
16.
Macromol Rapid Commun ; 38(21)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28960608

RESUMO

In recent decades, diverse drug delivery systems (DDS) constructed by self-assembly of dendritic peptides have shown advantages and improvable potential for cancer treatment. Here, an arginine-enriched dendritic amphiphilic chimeric peptide CRRK(RRCG(Fmoc))2 containing multiple thiol groups is programmed to form drug-loaded nano-micelles by self-assembly. With a rational design, the branched hydrophobic groups (Fmoc) of the peptides provide a strong hydrophobic force to prevent the drug from premature release, and the reduction-sensitive disulfide linkages formed between contiguous peptides can control drug release under reducing stimulation. As expected, specific to multidrug resistance (MDR) tumor cells, the arginine-enriched peptide/drug (PD) nano-micelles show accurate nuclear localization ability to prevent the drug being pumped by P-glycoprotein (P-gp) in vitro, as well as exhibiting satisfactory efficacy for MDR tumor treatment in vivo. This design successfully realizes stimuli-responsive drug release aimed at MDR tumor cells via an ingenious sequence arrangement.


Assuntos
Dendrímeros/química , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Peptídeos/química , Animais , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Micelas , Células NIH 3T3 , Nanopartículas/química , Neoplasias/patologia , Tela Subcutânea/efeitos dos fármacos
17.
Biomaterials ; 139: 116-126, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28600977

RESUMO

Tumor metastasis is the leading cause of death in cancer patients, and epithelial-mesenchymal transition (EMT) is an essential step in tumor metastasis. Unfortunately, during the chemotherapy, EMT could be induced under the selective pressure of clinical cytotoxic drugs. Here, to solve this problem, we have synthesized multi-functional epigallocatechin gallate/iron nano-complexes (EIN) as a versatile coating material to improve conventional therapies. In vitro studies showed that this strategy could eliminate EMT-type cancer cells. Mechanism studies also revealed that EIN was able to down-regulate the downstream expression of metastasis-associated factors, decrease the migration ability of cancer cells and prevent cancer cells from gaining drug resistance. In vivo investigation revealed that EIN had superior ability to enhance the therapeutic effect of conventional nanomedicines and inhibit the EMT process. Our study indicates the promising use of EIN to make up for the deficiencies of chemotherapy may provide insights into systematic cancer therapy to overcome tumor metastasis and drug resistance.


Assuntos
Anticarcinógenos/uso terapêutico , Catequina/análogos & derivados , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Nanopartículas Metálicas/uso terapêutico , Metástase Neoplásica/prevenção & controle , Animais , Anticarcinógenos/síntese química , Anticarcinógenos/farmacologia , Catequina/síntese química , Catequina/farmacologia , Catequina/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ferro/química , Nanopartículas Metálicas/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Nano Lett ; 17(1): 284-291, 2017 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-28027643

RESUMO

Discovering advanced materials for regulating cell death is of great importance in the development of anticancer therapy. Herein, by harnessing the recently discovered oxidative stress regulation ability of p53 and the Fenton reaction inducing capability of metal-organic network (MON), MON encapsulated with p53 plasmid (MON-p53) was designed to eradicate cancer cells via ferroptosis/apoptosis hybrid pathway. After confirming the detailed mechanism of MON-p53 in evoking ferroptosis, we further discovered that MON-p53 mediated a "bystander effect" to further sensitize cancer cells toward the MON-p53 induced ferroptosis. A 75-day anticancer experiment indicated that MON-p53 treatment not only suppressed the tumor growth but also prolonged the life-span of tumor bearing mice. Owing to its ability to promote intracellular oxidative stress, MON-p53 decreased the blood metastasis, lung metastasis, and liver metastasis. As a consequence, discovering methods to induce cell ferroptosis would provide a new insight in designing anticancer materials.


Assuntos
Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Estruturas Metalorgânicas/administração & dosagem , Neoplasias/terapia , Polifenóis/química , Proteína Supressora de Tumor p53/genética , Antineoplásicos/farmacologia , Morte Celular , Linhagem Celular Tumoral , Genes p53 , Terapia Genética , Humanos , Estruturas Metalorgânicas/farmacologia , Nanoestruturas , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Plasmídeos , Propriedades de Superfície
19.
Biomaterials ; 117: 92-104, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27939904

RESUMO

In this work, mitochondria-targeting gold nanostar (AuNS) and anticarcinogen DOX were co-encapsulated in hyaluronic acid (HA) protective shell for tumor-targeting synergistic photothermal/chemo-therapy. Cationic peptide R8 and mitochondria-targeting pro-apoptotic peptide TPP-KLA were co-decorated on AuNS to form AuNS-pep via Au-S bonds. Then, electronegative HA was further coated on the surface via electrostatic interaction for cancer cell targeting. During the coating process, DOX was also introduced via electrostatic interaction to obtain a versatile nanoplatform AuNS-pep/DOX@HA. It was found that the nanoplatform could be internalized into tumor cells via CD44 receptor-mediated recognition. Followed digestion by hyaluronidase (HAase), the therapeutic nanoplatform was able to release DOX for chemotherapy and mitochondria-targeting nanoheater AuNS-pep for near infrared (NIR) light triggered subcellular photothermal therapy (PTT). This tumor-targeting nanoplatform AuNS-pep/DOX@HA displayed prominent non-resistant or resistant tumor inhibition both in vitro and in vivo.


Assuntos
Doxorrubicina/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Mitocôndrias/efeitos dos fármacos , Nanocápsulas/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Terapia Combinada/métodos , Doxorrubicina/química , Tratamento Farmacológico/métodos , Feminino , Ouro/administração & dosagem , Ouro/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanocápsulas/química , Neoplasias Experimentais/patologia , Tamanho da Partícula , Resultado do Tratamento
20.
ACS Nano ; 10(9): 8715-22, 2016 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-27532320

RESUMO

Hypoxia, a typical feature of solid tumors, remarkably restricts the efficiency of photodynamic therapy (PDT). Here, a carbon nitride (C3N4)-based multifunctional nanocomposite (PCCN) for light-driven water splitting was used to solve this problem. Carbon dots were first doped with C3N4 to enhance its red region absorption because red light could be used to trigger the in vivo water splitting process. Then, a polymer containing a protoporphyrin photosensitizer, a polyethylene glycol segment, and a targeting Arg-Gly-Asp motif was synthesized and introduced to carbon-dot-doped C3N4 nanoparticles. In vitro study showed that PCCN, thus obtained, could increase the intracellular O2 concentration and improve the reactive oxygen species generation in both hypoxic and normoxic environments upon light irradiation. Cell viability assay demonstrated that PCCN fully reversed the hypoxia-triggered PDT resistance, presenting a satisfactory growth inhibition of cancer cells in an O2 concentration of 1%. In vivo experiments also indicated that PCCN had superior ability to overcome tumor hypoxia. The use of water splitting materials exhibited great potential to improve the intratumoral oxygen level and ultimately reverse the hypoxia-triggered PDT resistance and tumor metastasis.


Assuntos
Nanopartículas , Fotoquimioterapia , Carbono , Hipóxia Celular , Humanos , Neoplasias/terapia , Nitrilos , Água/química
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