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1.
JACS Au ; 1(7): 998-1013, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34467346

RESUMO

Nitric oxide (NO), a pro-neurogenic and antineuroinflammatory gasotransmitter, features the potential to develop a translational medicine against neuropathological conditions. Despite the extensive efforts made on the controlled delivery of therapeutic NO, however, an orally active NO prodrug for a treatment of chronic neuropathy was not reported yet. Inspired by the natural dinitrosyl iron unit (DNIU) [Fe(NO)2], in this study, a reversible and dynamic interaction between the biomimetic [(NO)2Fe(µ-SCH2CH2OH)2Fe(NO)2] (DNIC-1) and serum albumin (or gastrointestinal mucin) was explored to discover endogenous proteins as a vehicle for an oral delivery of NO to the brain after an oral administration of DNIC-1. On the basis of the in vitro and in vivo study, a rapid binding of DNIC-1 toward gastrointestinal mucin yielding the mucin-bound dinitrosyl iron complex (DNIC) discovers the mucoadhesive nature of DNIC-1. A reversible interconversion between mucin-bound DNIC and DNIC-1 facilitates the mucus-penetrating migration of DNIC-1 shielded in the gastrointestinal tract of the stomach and small intestine. Moreover, the NO-release reactivity of DNIC-1 induces the transient opening of the cellular tight junction and enhances its paracellular permeability across the intestinal epithelial barrier. During circulation in the bloodstream, a stoichiometric binding of DNIC-1 to the serum albumin, as another endogenous protein vehicle, stabilizes the DNIU [Fe(NO)2] for a subsequent transfer into the brain. With aging mice under a Western diet as a disease model for metabolic syndrome and cognitive impairment, an oral administration of DNIC-1 in a daily manner for 16 weeks activates the hippocampal neurogenesis and ameliorates the impaired cognitive ability. Taken together, these findings disclose the synergy between biomimetic DNIC-1 and endogenous protein vehicles for an oral delivery of therapeutic NO to the brain against chronic neuropathy.

2.
Proc Natl Acad Sci U S A ; 118(13)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33753481

RESUMO

The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Sinergismo Farmacológico , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ratos , Receptores CXCR4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
ACS Appl Mater Interfaces ; 12(40): 44407-44419, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32865389

RESUMO

Antiangiogenic therapy is widely administered in many cancers, and the antiangiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, antiangiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME) and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO2 and sorafenib into HCC. We found that MnO2 not only alleviates hypoxia by catalyzing the decomposition of H2O2 to oxygen but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging and drug-release properties upon decomposition into Mn2+ ions in the TME. Moreover, macrophages exposed to MnO2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of tumor-associated macrophages, promoting macrophage polarization toward the immunostimulatory M1 phenotype, and increasing the number of CD8+ cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver antiangiogenic agents, efficiently modulate the hypoxic TME, and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Manganês/farmacologia , Nanopartículas/química , Neovascularização Patológica/tratamento farmacológico , Óxidos/farmacologia , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Carcinoma Hepatocelular/patologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Humanos , Neoplasias Hepáticas/patologia , Masculino , Compostos de Manganês/química , Camundongos , Camundongos Endogâmicos C3H , Neovascularização Patológica/patologia , Óxidos/química , Tamanho da Partícula , Propriedades de Superfície , Células Tumorais Cultivadas , Evasão Tumoral/efeitos dos fármacos , Hipóxia Tumoral/efeitos dos fármacos
4.
Sci Adv ; 6(3): eaax5032, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31998834

RESUMO

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)-cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2-encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.


Assuntos
Biomarcadores Tumorais , Fenômenos Imunogenéticos , Terapia de Alvo Molecular , Nanopartículas , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Nanomedicina Teranóstica , Animais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores/metabolismo , Fosfatos de Cálcio/química , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Terapia Genética , Humanos , Imunoterapia , Lipídeos/química , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Nanotecnologia , Neoplasias/patologia , Plasmídeos/administração & dosagem , Plasmídeos/química , Plasmídeos/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Transdução de Sinais
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