RESUMO
Immunotherapy is currently an important adjuvant therapy for malignant tumors besides surgical treatment. However, the heterogeneity and low immunogenicity of the tumor are two main challenges of the immunotherapy. Here, we have constructed a nanoplatform (CP@mRBC-PpIX) to realize reversion of the tumor acidosis and hypoxia through alkali and oxygen generation triggered by tumor acidosis. By targeting tumor universal features other than endogenous biomarkers, it was found that CP@mRBC-PpIX could polarize tumor-associated macrophages to anti-tumor M1 phenotype macrophages to enhance tumor immune response. Furthermore, under regional light irradiation, the reactive oxygen species produced by photosensitizers located in CP@mRBC-PpIX could increase the immunogenicity of tumors, so that tumor changes from an immunosuppressive "cold tumor" to an immunogenic "hot tumor," thereby increasing the infiltration and response of T cells, further amplifying the effect of immunotherapy. This strategy circumvented the problem of tumor heterogeneity to realize a kind of broad-spectrum immunotherapy, which could effectively prevent tumor metastasis and recurrence.
Assuntos
Antineoplásicos/uso terapêutico , Membrana Eritrocítica/química , Nanopartículas Metálicas/uso terapêutico , Neoplasias/tratamento farmacológico , Protoporfirinas/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Cobre/química , Cobre/uso terapêutico , Humanos , Imunidade/efeitos dos fármacos , Imunoterapia , Luz , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/efeitos da radiação , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/metabolismo , Peróxidos/química , Peróxidos/uso terapêutico , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/química , Protoporfirinas/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacosRESUMO
Tumor hypoxia severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a liposome-based nanoparticle (designated as LipoMB/CaO2 ) with O2 self-sufficient property for dual-stage light-driven PDT is demonstrated to address this problem. Through a short time irradiation, 1 O2 activated by the photosensitizer methylene blue (MB) can induce lipid peroxidation to break the liposome, and enlarge the contact area of CaO2 with H2 O, resulting in accelerated O2 production. Accelerated O2 level further regulates hypoxic tumor microenvironment and in turn improves 1 O2 generation by MB under another long time irradiation. In vitro and in vivo experiments also demonstrate the superior competence of LipoMB/CaO2 to alleviate tumor hypoxia, suppress tumor growth and antitumor metastasis with low side-effect. The O2 self-sufficient LipoMB/CaO2 nanoplatform with dual-stage light manipulation is a successful attempt for PDT against hypoxic tumor.
Assuntos
Luz , Nanopartículas/química , Oxigênio/química , Fotoquimioterapia , Hipóxia Tumoral , Animais , Apoptose , Peso Corporal , Compostos de Cálcio/química , Linhagem Celular Tumoral , Lipossomos , Azul de Metileno , Camundongos , Nanopartículas/ultraestrutura , Necrose , Óxidos/química , Carga Tumoral , Difração de Raios XRESUMO
Selectively cuting off the nutrient supply and the metabolism pathways of cancer cells would be a promising approach to improve the efficiency of cancer treatment. Here, a cancer targeted cascade bioreactor (designated as mCGP) was constructed for synergistic starvation and photodynamic therapy (PDT) by embedding glucose oxidase (GOx) and catalase in the cancer cell membrane-camouflaged porphyrin metal-organic framework (MOF) of PCN-224 (PCN stands for porous coordination network). Due to biomimetic surface functionalization, the immune escape and homotypic targeting behaviors of mCGP would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, mCGP was found to promote microenvironmental oxygenation by catalyzing the endogenous hydrogen peroxide (H2O2) to produce oxygen (O2), which would subsequently accelerate the decomposition of intracellular glucose and enhance the production of cytotoxic singlet oxygen (1O2) under light irradiation. Consequently, mCGP displayed amplified synergistic therapeutic effects of long-term cancer starvation therapy and robust PDT, which would efficiently inhibit the cancer growth after a single administration. This cascade bioreactor would further facilitate the development of complementary modes for spatiotemporally controlled cancer treatment.
Assuntos
Catalase/uso terapêutico , Glucose Oxidase/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Animais , Células COS , Catalase/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Chlorocebus aethiops , Glucose/metabolismo , Glucose Oxidase/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Oxigênio/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Porfirinas/química , Células RAW 264.7RESUMO
In this study, we developed a general method to decorate plasmonic gold nanorods (GNRs) with a CD44-targeting functional polymer, containing a hyaluronic acid (HA)-targeting moiety and a small molecule Glut1 inhibitor of diclofenac (DC), to obtain GNR/HA-DC. This nanosystem exhibited the superiority of selectively sensitizing tumor cells for photothermal therapy (PTT) by inhibiting anaerobic glycolysis. Upon specifically targeting CD44, sequentially time-dependent DC release could be achieved by the trigger of hyaluronidase (HAase), which abundantly existed in tumor tissues. The released DC depleted the Glut1 level in tumor cells and induced a cascade effect on cellular metabolism by inhibiting glucose uptake, blocking glycolysis, decreasing ATP levels, hampering heat shock protein (HSP) expression, and ultimately leaving malignant cells out from the protection of HSPs to stress (e.g., heat), and then tumor cells were more easy to kill. Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tumor cells could be significantly damaged by PTT with an enhanced therapeutic efficiency in vitro and in vivo.
Assuntos
Anaerobiose/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Temperatura Alta , Fototerapia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células COS , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Diclofenaco/química , Diclofenaco/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Ouro/farmacologia , Células HeLa , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Nanopartículas Metálicas/química , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7RESUMO
In this work, a matrix metalloproteinase (MMP)-triggered tumor targeted mesoporous silica nanoparticle (MSN) is designed to realize near-infrared (NIR) photothermal-responsive drug release and combined chemo/photothermal tumor therapy. Indocyanine green (ICG) and doxorubicin (DOX) are both loaded in the MSN modified with thermal-cleavable gatekeeper (Azo-CD), which can be decapped by ICG-generated hyperthermia under NIR illumination. A peptidic sequence containing a short PEG chain, matrix metalloproteinase (MMP) substrate (PLGVR) and tumor cell targeting motif (RGD) are further decorated on the MSN via a host-guest interaction. The PEG chain can protect the MSN during the circulation and be cleaved off in the tumor tissues with overexpressed MMP, and then the RGD motif is switched on to target tumor cells. After the tumor-triggered targeting process, the NIR irradiation guided by ICG fluorescence can trigger cytosol drug release and realize combined chemo/photothermal therapy.