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1.
Nanoscale ; 12(5): 2966-2972, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31971210

RESUMO

Lactate, the main contributor to the acidic tumor microenvironment, not only promotes the proliferation of tumor cells, but also closely relates to tumor invasion and metastasis. Here, a tumor targeting nanoplatform, designated as Me&Flu@MSN@MnO2-FA, was fabricated for effective tumor suppression and anti-metastasis by interfering with lactate metabolism of tumor cells. Metformin (Me) and fluvastatin sodium (Flu) were incorporated into MnO2-coated mesoporous silicon nanoparticles (MSNs), the synergism between Me and Flu can modulate the pyruvate metabolic pathway to produce more lactate, and concurrently inhibit lactate efflux to induce intracellular acidosis to kill tumor cells. As a result of the restricted lactate efflux, the extracellular lactate concentration is reduced, and the ability of the tumor cells to migrate is also weakened. This ingenious strategy based on Me&Flu@MSN@MnO2-FA showed an obvious inhibitory effect on tumor growth and resistance to metastasis.

2.
Biomaterials ; 234: 119772, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31945618

RESUMO

Photodynamic therapy (PDT) is a promising treatment modality for tumor suppression. However, the hypoxic state of most solid tumors might largely hinder the efficacy of PDT. Here, a functional covalent organic framework (COF) is fabricated to enhance PDT efficacy by remodeling the tumor extracellular matrix (ECM). Anti-fibrotic drug pirfenidone (PFD) is loaded in an imine-based COF (COFTTA-DHTA) and followed by the decoration of poly(lactic-co-glycolic-acid)-poly(ethylene glycol) (PLGA-PEG) to fabricate PFD@COFTTA-DHTA@PLGA-PEG, or PCPP. After injected intravenously, PCPP can accumulate and release PFD in tumor sites, leading to down-regulation of ECM compenents such as hyaluronic acid (HA) and collagen I. Such depletion of tumor ECM reduces the intratumoral solid stress, a compressive force exerted by the ECM and cells, decompresses tumor blood vessels, and increases the density of effective vascular areas, resulting in significantly improved oxygen supply in tumor. Furthermore, PCPP-mediated tumor ECM depletion also enhances the tumor uptake of subsequently injected Protoporphyrinl IX (PPIX)-conjugated peptide formed nanomicelles (NM-PPIX) due to the improved enhanced permeability and retention (EPR) effect. Both the alleviated tumor hypoxia and improved tumor homing of photosensitizer (PS) molecules after PCPP treatment significantly increase the reactive oxygen species (ROS) generation in tumor and therefore realize greatly enhanced PDT effect of tumor in vivo.

3.
Adv Mater ; 31(51): e1904639, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31692128

RESUMO

Regulating the tumor microenvironment (TME) has been a promising strategy to improve antitumor therapy. Here, a red blood cell membrane (mRBC)-camouflaged hollow MnO2 (HMnO2 ) catalytic nanosystem embedded with lactate oxidase (LOX) and a glycolysis inhibitor (denoted as PMLR) is constructed for intra/extracellular lactic acid exhaustion as well as synergistic metabolic therapy and immunotherapy of tumor. Benefiting from the long-circulation property of the mRBC, the nanosystem can gradually accumulate in a tumor site through the enhanced permeability and retention (EPR) effect. The extracellular nanosystem consumes lactic acid in the TME by catalyzing its oxidation reaction via LOX. Meanwhile, the intracellular nanosystem releases the glycolysis inhibitor to cut off the source of lactic acid, as well as achieve antitumor metabolic therapy through the blockade of the adenosine triphosphate (ATP) supply. Both the extracellular and intracellular processes can be sensitized by O2 , which can be produced during the decomposition of endogenous H2 O2 catalyzed by the PMLR nanosystem. The results show that the PMLR nanosystem can ceaselessly remove lactic acid, and then lead to an immunocompetent TME. Moreover, this TME regulation strategy can effectively improve the antitumor effect of anti-PDL1 therapy without the employment of any immune agonists to avoid the autoimmunity.

4.
Adv Mater ; 31(43): e1904495, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31497903

RESUMO

Natural killer (NK) cells can not only recognize and eliminate abnormal cells but also recruit and re-educate immune cells to protect the host. However, the functions of NK cells are often limited in the immunosuppressive tumor microenvironment (TME). Here, artificial NK cells (designated as aNK) with minor limitations of TME for specific tumor killing and renegade macrophage re-education are created. The red blood cell membrane (RBCM) cloaks perfluorohexane (PFC) and glucose oxidase (GOX) to construct the aNK. The aNK can directly kill tumor cells by exhausting glucose and generating hydrogen peroxide (H2 O2 ). The generated H2 O2 is also similar to cytokines and chemokines for recruiting immune cells and re-educating survived macrophages to attack tumor cells. In addition, the oxygen-carried PFC can strengthen the catalytic reaction of GOX and normalize the hypoxic TME. In vitro and in vivo experiments display that aNK with slight TME limitations exhibit efficient tumor inhibition and immune activation. The aNK will provide a new sight to treat tumor as the supplement of aggressive NK cells.


Assuntos
Biomimética , Células Matadoras Naturais/imunologia , Macrófagos/imunologia , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Glucose/metabolismo , Glucose Oxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Células Matadoras Naturais/metabolismo , Camundongos , Microambiente Tumoral/imunologia
5.
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.

6.
Nat Commun ; 10(1): 3199, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324770

RESUMO

Most cancer vaccines are unsuccessful in eliciting clinically relevant effects. Without using exogenous antigens and adoptive cells, we show a concept of utilizing biologically reprogrammed cytomembranes of the fused cells (FCs) derived from dendritic cells (DCs) and cancer cells as tumor vaccines. The fusion of immunologically interrelated two types of cells results in strong expression of the whole tumor antigen complexes and the immunological co-stimulatory molecules on cytomembranes (FMs), allowing the nanoparticle-supported FM (NP@FM) to function like antigen presenting cells (APCs) for T cell immunoactivation. Moreover, tumor-antigen bearing NP@FM can be bio-recognized by DCs to induce DC-mediated T cell immunoactivation. The combination of these two immunoactivation pathways offers powerful antitumor immunoresponse. Through mimicking both APCs and cancer cells, this cytomembrane vaccine strategy can develop various vaccines toward multiple tumor types and provide chances for accommodating diverse functions originating from the supporters.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Membrana Celular/imunologia , Nanopartículas/uso terapêutico , Animais , Fusão Celular , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Imunoterapia , Ativação Linfocitária , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/imunologia , Transcriptoma , Transplante Heterólogo
7.
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.

8.
Adv Mater ; 31(18): e1900499, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30907473

RESUMO

Using the cytomembranes (FMs) of hybrid cells acquired from the fusion of cancer and dendritic cells (DCs), this study offers a biologically derived platform for the combination of immunotherapy and traditional oncotherapy approaches. Due to the immunoactivation implicated in the cellular fusion, FMs can effectively express whole cancer antigens and immunological co-stimulatory molecules for robust immunotherapy. FMs share the tumor's self-targeting character with the parent cancer cells. In bilateral tumor-bearing mouse models, the FM-coated nanophotosensitizer causes durable immunoresponse to inhibit the rebound of primary tumors post-nanophotosensitizer-induced photodynamic therapy (PDT). The FM-induced immunotherapy displays ultrahigh antitumor effects even comparable to that of PDT. On the other hand, PDT toward primary tumors enhances the immunotherapy-caused regression of the irradiation-free distant tumors. Consequently, both the primary and the distant tumors are almost completely eliminated. This tumor-specific immunotherapy-based nanoplatform is potentially expandable to multiple tumor types and readily equipped with diverse functions owing to the flexible nanoparticle options.


Assuntos
Membrana Celular/química , Células Dendríticas/citologia , Imunoterapia , Nanoestruturas/química , Animais , Anticorpos/química , Anticorpos/imunologia , Linhagem Celular Tumoral , Células Dendríticas/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Receptores de Hialuronatos/imunologia , Estruturas Metalorgânicas/química , Camundongos , Camundongos Nus , Nanoestruturas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Porfirinas/uso terapêutico , Transplante Heterólogo , Zircônio/química
9.
Adv Mater ; 30(35): e1802006, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30015997

RESUMO

Extreme hypoxia of tumors represents the most notable barrier against the advance of tumor treatments. Inspired by the biological nature of red blood cells (RBCs) as the primary oxygen supplier in mammals, an aggressive man-made RBC (AmmRBC) is created to combat the hypoxia-mediated resistance of tumors to photodynamic therapy (PDT). Specifically, the complex formed between hemoglobin and enzyme-mimicking polydopamine, and polydopamine-carried photosensitizer is encapsulated inside the biovesicle that is engineered from the recombined RBC membranes. The mean corpuscular hemoglobin of AmmRBCs reaches about tenfold as high as that of natural RBCs. Owing to the same origin of outer membranes, AmmRBCs share excellent biocompatibility with parent RBCs. The introduced polydopamine plays the role of the antioxidative enzymes existing inside RBCs to effectively prevent the oxygen-carrying hemoglobin from the oxidation damage during the circulation. This biomimetic engineering can accumulate in tumors, permit in situ efficient oxygen supply, and impose strong PDT efficacy toward the extremely hypoxic tumor with complete tumor elimination. The man-made pseudo-RBC shows potentials as a universal oxygen-self-supplied platform to sensitize hypoxia-limited tumor treatment means, including but not limited to PDT. Meanwhile, this study offers ideas to the production of artificial substitutes of packed RBCs for clinical blood transfusion.


Assuntos
Eritrócitos , Animais , Hipóxia Celular , Oxigênio , Fotoquimioterapia , Fármacos Fotossensibilizantes
10.
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
11.
ACS Nano ; 12(5): 4630-4640, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29584395

RESUMO

We report on the benzoporphyrin-based metal-organic framework (TBP-MOF), with 10-connected Zr6 cluster and much improved photophysical properties over the traditional porphyrin-based MOFs. It was found that TBP-MOF exhibited red-shifted absorption bands and strong near-infrared luminescence for bioimaging, whereas the π-extended benzoporphyrin-based linkers of TBP-MOF facilitated 1O2 generation to enhance O2-dependent photodynamic therapy (PDT). It was demonstrated that poly(ethylene glycol)-modified nanoscale TBP-MOF (TBP-nMOF) can be used as an effective PDT agent under hypoxic tumor microenvironment. We also elucidated that the low O2-dependent PDT of TBP-nMOF in combination with αPD-1 checkpoint blockade therapy can not only suppress the growth of primary tumor, but also stimulate an antitumor immune response for inhibiting metastatic tumor growth. We believe this TBP-nMOF has great potential to serve as an efficient photosensitizer for PDT and cancer immunotherapy.


Assuntos
Antineoplásicos/química , Estruturas Metalorgânicas/química , Nanopartículas/química , Metástase Neoplásica/terapia , Fármacos Fotossensibilizantes/química , Porfirinas/química , Zircônio/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Xenoenxertos , Humanos , Imunoterapia , Estruturas Metalorgânicas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Polietilenoglicóis/química , Porfirinas/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Oxigênio Singlete/metabolismo , Distribuição Tecidual , Microambiente Tumoral
12.
Nano Lett ; 16(7): 4341-7, 2016 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-27327876

RESUMO

Fighting metastasis is a major challenge in cancer therapy, and stimulation of the immune system is of particular importance in the treatment of metastatic cancers. Here, an integrated theranostic nanoplatform was developed for the efficient treatment of highly metastatic tumors. Versatile functions including "And" logically controlled drug release, prolonged circulation time, tumor targeting, and anti-metastasis were integrated into doxorubicin (DOX) loaded, highly integrated mesoporous silica nanoparticles (DOX@HIMSNs) for a systemic treatment of highly metastatic triple negative breast cancer (TNBC). It was found that the good therapeutic effect of DOX@HIMSN was only partially attributed to its anticancer cytotoxicity. Most importantly, DOX@HIMSN could induce anticancer immune responses including dendritic cell (DC) maturation and antitumor cytokine release. Compared with the traditional tumor chemotherapy, the integrated theranostic nanoplatform we developed not only improved the tumor specific cytotoxicity but also stimulated antitumor immune responses during the treatment.


Assuntos
Doxorrubicina/administração & dosagem , Imunoterapia , Nanopartículas , Nanomedicina Teranóstica , Linhagem Celular Tumoral , Humanos , Dióxido de Silício
13.
Nanoscale ; 7(38): 16061-70, 2015 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-26372069

RESUMO

Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free "green" post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Animais , Células COS , Células HeLa , Humanos , Nanopartículas , Distribuição Tecidual
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