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1.
Adv Mater ; : e2000376, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134530

RESUMO

Traditional phototherapies face the issue that the insufficient penetration of light means it is difficult to reach deep lesions, which greatly reduces the feasibility of cancer therapy. Here, an implantable nitric oxide (NO)-release device is developed to achieve long-term, long-distance, remote-controllable gas therapy for cancer. The device consists of a wirelessly powered light-emitting diode (wLED) and S-nitrosoglutathione encapsulated with poly(dimethylsiloxane) (PDMS), obtaining the NO-release wLED (NO-wLED). It is found that NO release from the NO-wLED can be triggered by wireless charging and the concentration of produced NO reaches 0.43 × 10-6 m min-1 , which can achieve a killing effect on cancer cells. In vivo anticancer experiments exhibit obvious inhibitory effect on the growth of orthotopic cancer when the implanted NO-wLED is irradiated by wireless charging. In addition, recurrence of cancer can be prevented by NO produced from the NO-wLED after surgery. By illumination in the body, this strategy overcomes the poor penetration and long-wavelength dependence of traditional phototherapies, which also provides a promising approach for in vivo gas therapy remote-controlled by wireless charging.

2.
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.

3.
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.

4.
Biomaterials ; 223: 119472, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31499254

RESUMO

Inflammation during photothermal therapy (PTT) of tumor usually results in adverse consequences. Here, a biomembrane camouflaged nanomedicine (mPDAB) containing polydopamine and ammonia borane was designed to enhance PTT efficacy and mitigate inflammation. Polydopamine, a biocompatible photothermal agent, can effectively convert light into heat for PTT. Ammonia borane was linked to the surface of polydopamine through the interaction of hydrogen bonding, which could destroy redox homoeostasis in tumor cells and reduce inflammation by H2 release in tumor microenvironment. Owing to the same origin of outer biomembranes, mPDAB showed excellent tumor accumulation and low systemic toxicity in a breast tumor model. Excellent PTT efficacy and inflammation reduction made the mPDAB completely eliminate the primary tumors, while also restraining the outgrowth of distant dormant tumors. The biomimetic nanomedicine shows potentials as a universal inflammation-self-alleviated platform to ameliorate inflammation-related disease treatment, including but not limited to PTT for tumor.

5.
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.

6.
ACS Nano ; 13(8): 8618-8629, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31246413

RESUMO

Natural nanoparticles have been extensively studied due to their diverse properties and easy accessibility. Here, the nanoparticles extracted from cuttlefish ink (CINPs) with significant antitumor efficacy are explored. These CINPs, with spherical morphology, good dispersibility, and biocompatibility, are rich in melanin and contain a variety of amino acids and monosaccharides. Through the activation of mitogen-activated protein kinase (MAPK) signaling pathway, CINPs can efficiently reprogram tumor-associated macrophages (TAMs) from immune-suppressive M2-like phenotype to antitumor M1-like phenotype. Besides, under near-infrared (NIR) irradiation, CINPs exhibit high photothermal effect and tumor cell killing ability, which make them a potential candidate in photothermal therapy (PTT) of tumor. In vivo, CINPs can increase the proportion of M1 macrophages and foster the recruitment of cytotoxic T lymphocytes (CTLs) to tumors, leading to reduced primary tumor growth and lung metastasis. In combination with their photothermal effect, which can induce tumor-specific antigens release, CINPs could almost completely inhibit tumor growth accompanied by more active immune responses. Collectively, these CINPs described here can provide both tumor immunotherapy and PTT, implying that CINPs are promising for tumor treatment.

7.
J Hematol Oncol ; 12(1): 18, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777106

RESUMO

BACKGROUND: Gastric cancer (GC) is a common cancer in Asia and currently lacks a targeted therapy approach. Mesothelin (MSLN) has been reported to be expressed in GC tissue and could be targeted by chimeric antigen receptor (CAR) T cells. Mesothelin targeting CAR-T has been reported in mesothelioma, lung cancer, breast cancer, and pancreas cancer. However, the feasibility of using anti-MSLN CAR T cells to treat GC remains to be studied. METHODS: We verified MSLN expression in primary human GC tissues and GC cell lines and then redirected T cells with a CAR containing the MSLN scFv (single-chain variable fragment), CD3ζ, CD28, and DAP10 intracellular signaling domain (M28z10) to target MSLN. We evaluated the function of these CAR T cells in vitro in terms of cytotoxicity, cytokine secretion, and surface phenotype changes when they encountered MSLN+ GC cells. We also established four different xenograft GC mouse models to assess in vivo antitumor activity. RESULTS: M28z10 T cells exhibited strong cytotoxicity and cytokine-secreting ability against GC cells in vitro. In addition, cell surface phenotyping suggested significant activation of M28z10 T cells upon target cell stimulation. M28z10 T cells induced GC regression in different xenograft mouse models and prolonged the survival of these mice compared with GFP-transduced T cells in the intraperitoneal and pulmonary metastatic GC models. Importantly, peritumoral delivery strategy can lead to improved CAR-T cells infiltration into tumor tissue and significantly suppress the growth of GC in a subcutaneous GC model. CONCLUSION: These results demonstrate that M28z10 T cells possess strong antitumor activity and represent a promising therapeutic approach to GC.

8.
iScience ; 23(1): 100778, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31901818

RESUMO

Natural enzymes are mainly composed by the protein part and metallic cofactor part, both of which work cooperatively to achieve high catalytic activity. Here, natural melanin particles (NMPs) were extracted from human hair and further bound with metal ions to mimic natural enzymes. The different metal-bound NMPs (M-NMPs) exhibited different enzyme-like activities with great promise in diverse biomedical applications. It was found that Fe-bound NMPs (Fe-NMPs) showed outstanding peroxidase (POD)-like activity that possessed potential in antibacterial applications, and Mn-bound NMPs (Mn-NMPs) displayed catalase (CAT)-like activity with a remarkable radiotherapy sensitization effect in cancer therapy. Besides, Cu-bound NMPs (Cu-NMPs) could serve as combined POD, superoxide dismutase (SOD), and CAT alternatives, which exhibited prominent reactive oxygen species (ROS) scavenging ability, revealing great potential in anti-inflammation. The versatile enzyme-like activities of M-NMPs derived from hair might give extensive perspective for designing biomedical materials and provide a promising tool in solving biomedical problems.

9.
Adv Mater ; 30(52): e1805038, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30378187

RESUMO

Adenosine triphosphate (ATP) is the most important immediate energy source for driving intracellular biochemical reactions in nearly all life forms. Controllable generation of ATP in life is still an unrealized goal. Here, thylakoid fragments are recombined with lipid molecules to synthesize a synthetic/biological hybrid proteoliposome, named highly efficient life-support intracellular opto-driven system (HELIOS) for the generation of ATP. With red light irradiation, HELIOS can improve the intracellular ATP concentration to 1.38-2.45 times in various cell lines. Moreover, it is noticed that HELIOS-mediated ATP generation can comprehensively promote cell functions such as protein synthesis and insulin secretion. At organ and individual levels, it is also proved that HELIOS can rescue a mouse heart from myocardial infarction and sustain life of fasting zebrafish Danio rerio models. The photo-powered artificial organelle can deepen our understanding of metabolism and enable the development of optical therapy that targets intracellular energy supply.


Assuntos
Trifosfato de Adenosina , Células Artificiais , Infarto do Miocárdio/terapia , Fototerapia , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Animais Geneticamente Modificados , Células Artificiais/química , Células Artificiais/efeitos da radiação , Células COS , Modelos Animais de Doenças , Jejum/metabolismo , Glucose/deficiência , Espaço Intracelular/metabolismo , Luz , Camundongos , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Processos Fotoquímicos , Ratos Sprague-Dawley , Peixe-Zebra
10.
Small ; 14(37): e1802403, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30129176

RESUMO

Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs-mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD-1) to enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA-Psi-DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme-activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP-2. It is found that HA-Psi-DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon-γ. This cytokine promotes the expression of programmed cell death protein-ligand 1 (PD-L1) on tumor cells, which will cause immunosuppression after interacting with PD-1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA-Psi-DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti-PD-1 antibody (α-PD1) due to the neutralization of immunosuppression by blocking the interaction between PD-L1 and PD-1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Imunoterapia , Nanopartículas/química , Polímeros/química , Pró-Fármacos/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacocinética , Feminino , Ácido Hialurônico/síntese química , Ácido Hialurônico/química , Interferon gama/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura , Metástase Neoplásica , Pró-Fármacos/farmacocinética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Citotóxicos/efeitos dos fármacos
11.
Small ; 14(28): e1801120, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29882235

RESUMO

Hypoxia is reported to participate in tumor progression, promote drug resistance, and immune escape within tumor microenvironment, and thus impair therapeutic effects including the chemotherapy and advanced immunotherapy. Here, a multifunctional biomimetic core-shell nanoplatform is reported for improving synergetic chemotherapy and immunotherapy. Based on the properties including good biodegradability and functionalities, the pH-sensitive zeolitic imidazolate framework 8 embedded with catalase and doxorubicin constructs the core and serves as an oxygen generator and drug reservoir. Murine melanoma cell membrane coating on the core provides tumor targeting ability and elicits an immune response due to abundance of antigens. It is demonstrated that this biomimetic core-shell nanoplatform with oxygen generation can be partial to accumulate in tumor and downregulate the expression of hypoxia-inducible factor 1α, which can further enhance the therapeutic effects of chemotherapy and reduce the expression of programmed death ligand 1 (PD-L1). Combined with immune checkpoints blockade therapy by programmed death 1 (PD-1) antibody, the dual inhibition of the PD-1/PD-L1 axis elicits significant immune response and presents a robust effect in lengthening tumor recurrent time and inhibiting tumor metastasis. Consequently, the multifunctional nanoplatform provides a potential strategy of synergetic chemotherapy and immunotherapy.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Biomimética/métodos , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Hipóxia Tumoral/efeitos dos fármacos , Animais , Linfócitos T CD8-Positivos/metabolismo , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Doxorrubicina/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imidazóis/química , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/ultraestrutura , Neoplasias/imunologia , Neoplasias/patologia , Oxigênio/farmacologia , Zeolitas/química
12.
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
13.
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
14.
Adv Mater ; 30(27): e1800836, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29782675

RESUMO

With the prominent progress of biomedical engineering, materials with high biocompatibility and versatile functions are urgently needed. So far, hierarchical structures in nature have shed some light on the design of high performance materials both in concept and implementation. Inspired by these, the hierarchical micro-/nanostructures of human hair are explored and human hair is further broken into hierarchical microparticles (HMP) and hierarchical nanoparticles (HNP) with top-down procedures. Compared with commercialized carriers, such as liposomes or albumin nanoparticles, the obtained particles exhibit high hemocompatibility and negligible immunogenicity. Furthermore, these materials also display attentional abilities in the aspects of light absorption and free radical scavenging. It is found that HMP and HNP can prevent skin from UV-induced damage and relieve symptoms of cataract in vitro. Besides, both HMP and HNP show satisfactory photothermal conversion ability. By using microcomputed tomography and intravital fluorescence microscopy, it is found that warfarin-loaded HMP can rescue mice from vein thrombosis. In another aspect, HNP modified with tumor targeted aptamers exhibit dramatic antineoplastic effect, and suppress 96.8% of tumor growth in vivo. Thus, the multifaceted materials described here might provide a new tool for addressing biomedical challenges.


Assuntos
Nanoestruturas , Animais , Antineoplásicos , Cabelo , Humanos , Camundongos , Nanopartículas , Microtomografia por Raio-X
15.
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
16.
Biomacromolecules ; 19(6): 2043-2052, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29584410

RESUMO

Biomimetic nanoengineering built through integrating the specific cell membrane with artificially synthetic nanomedicines represents one of the most promising directions for the actualization of personalized therapy. For addressing the technical hurdle against the development of this biomimetic technology, the present report describes the in-depth exploration and optimization over each critical preparation step, including establishment of a nanoparticle-stabilized dispersion system, cargo loading, membrane coating, and product isolation. Magnetic iron oxide nanoparticles loaded with DOX is used as a typical model for the coating with cancer cell membranes, providing compact DNP@CCCM nanostructure well-characterized by various techniques. Furthermore, the feasibility of this optimized approach in constructing biomimetic membrane-coated nanomedicines has been validated on the basis of the remarkably improved biofunctions, such as the targetability, magnetic property, hemolysis risk, macrophage evasion, in vitro cytotoxicity, in vivo circulation duration, and in vivo principal component analysis postinjection. We hope this study regarding technique optimization will prompt the advancement of biomembrane-camouflaged nanoparticles as a newly emerging biomimetic technology.


Assuntos
Antibióticos Antineoplásicos/farmacocinética , Membrana Celular/química , Nanopartículas de Magnetita/química , Nanomedicina/métodos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Materiais Biomiméticos/química , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Estabilidade de Medicamentos , Feminino , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Coelhos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
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 Ambiente , Transformação Genética
18.
ACS Nano ; 12(2): 1978-1989, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29420012

RESUMO

Metastasis and recurrence are two unavoidable and intractable problems in cancer therapy, despite various robust therapeutic approaches. Currently, it seems that immunotherapy is an effective approach to solve these problems, but the high heterogeneity of tumor tissue, inefficient presentation of tumor antigen, and deficient targeting ability of therapy usually blunt the efficacy of immunotherapy and hinder its clinical application. Herein, an approach based on combining photodynamic and immunological therapy was designed and developed. We synthesized a chimeric peptide, PpIX-1MT, which integrates photosensitizer PpIX with immune checkpoint inhibitor 1MT via a caspase-responsive peptide sequence, Asp-Glu-Val-Asp (DEVD), to realize a cascaded synergistic effect. The PpIX-1MT peptide could form nanoparticles in PBS and accumulate in tumor areas via the enhanced penetration retention effect. Upon 630 nm light irradiation, the PpIX-1MT nanoparticles produced reactive oxygen species, induced apoptosis of cancer cells, and thus facilitated the expression of caspase-3 and the production of tumor antigens, which could trigger an intense immune response. The subsequently released 1MT upon caspase-3 cleavage could further strengthen the immune system and help to activate CD8+ T cells effectively. This cascaded synergistic effect could inhibit both primary and lung metastasis tumor effectively, which may provide the solution for solving tumor recurrence and metastasis clinically.


Assuntos
Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Peptídeos/uso terapêutico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/uso terapêutico , Animais , Antígenos de Neoplasias/imunologia , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/farmacocinética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Peptídeos/química , Peptídeos/farmacocinética , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Protoporfirinas/química , Protoporfirinas/farmacocinética
19.
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
20.
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
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