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1.
Small ; 15(20): e1900561, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977296

RESUMO

Multivalent ligand-receptor interactions play essential roles in biological recognition and signaling. As the receptor arrangement on the cell surface can alter the outcome of cell signaling and also provide spatial specificity for ligand binding, controlling the presentation of ligands has become a promising strategy to manipulate or selectively target protein receptors. The lack of adjustable universal tools to control ligand positions at the size of a few nanometers has prompted the development of polyproline tri-helix macrocycles as scaffolds to present ligands in designated patterns. Model lectin Helix pomatia agglutinin has shown selectivity toward the matching GalNAc ligand pattern matching its binding sites arrangement. The GalNAc pattern selectivity is also observed on intact asialoglycoprotein receptor oligomer on human hepatoma cells showing the pattern-selective interaction can be achieved not only on isolated protein oligomers but also the receptors arranged on the cell surface. As the scaffold design allows convenient creation of versatile ligand patterns, it can be expected as a promising tool to probe the arrangement of receptors on the cell surface and as nanomedicine to manipulate signaling or cell recognition.


Assuntos
Lectinas/química , Lectinas/metabolismo , Compostos Macrocíclicos/química , Nanopartículas/química , Tamanho da Partícula , Peptídeos/química , Multimerização Proteica , Sequência de Aminoácidos , Receptor de Asialoglicoproteína/química , Linhagem Celular Tumoral , Ciclização , Galactosamina/química , Glicoconjugados/síntese química , Glicoconjugados/química , Humanos , Ligantes , Peptídeos/síntese química , Ligação Proteica , Espectroscopia de Prótons por Ressonância Magnética
2.
Biomacromolecules ; 19(6): 2330-2339, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29808997

RESUMO

Successful siRNA therapy requires suitable delivery systems with targeting moieties such as small molecules, peptides, antibodies, or aptamers. Galactose (Gal) residues recognized by the asialoglycoprotein receptor (ASGPR) can serve as potent targeting moieties for hepatocellular carcinoma (HCC) cells. However, efficient targeting to HCC via galactose moieties rather than normal liver tissues in HCC patients remains a challenge. To achieve more efficient siRNA delivery in HCC, we synthesized various galactoside derivatives and investigated the siRNA delivery capability of nanoparticles modified with those galactoside derivatives. In this study, we assembled lipid/calcium/phosphate nanoparticles (LCP NPs) conjugated with eight types of galactoside derivatives and demonstrated that phenyl ß-d-galactoside-decorated LCP NPs (L4-LCP NPs) exhibited a superior siRNA delivery into HCC cells compared to normal hepatocytes. VEGF siRNAs delivered by L4-LCP NPs downregulated VEGF expression in HCC in vitro and in vivo and led to a potent antiangiogenic effect in the tumor microenvironment of a murine orthotopic HCC model. The efficient delivery of VEGF siRNA by L4-LCP NPs that resulted in significant tumor regression indicates that phenyl galactoside could be a promising HCC-targeting ligand for therapeutic siRNA delivery to treat liver cancer.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Galactose , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas , RNA Interferente Pequeno , Animais , Receptor de Asialoglicoproteína/antagonistas & inibidores , Receptor de Asialoglicoproteína/biossíntese , Receptor de Asialoglicoproteína/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Galactose/química , Galactose/farmacologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
3.
J Control Release ; 352: 920-930, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36334859

RESUMO

While immunotherapy has emerged as a promising strategy to treat glioblastoma multiforme (GBM), the limited availability of immunotherapeutic agents in tumors due to the presence of the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment dampens efficacy. Nitric oxide (NO) plays a role in modulating both the BBB and tumor vessels and could thus be delivered to disrupt the BBB and improve the delivery of immunotherapeutics into GBM tumors. Herein, we report an immunotherapeutic approach that utilizes CXCR4-targeted lipid­calcium-phosphate nanoparticles with NO donors (LCP-NO NPs). The delivery of NO resulted in enhanced BBB permeability and thus improved gene delivery across the BBB. CXCR4-targeted LCP-NO NPs delivered siRNA against the immune checkpoint ligand PD-L1 to GBM tumors, silenced PD-L1 expression, increased cytotoxic T cell infiltration and activation in GBM tumors, and suppressed GBM progression. Thus, the codelivery of NO and PD-L1 siRNA by these CXCR4-targeted NPs may serve as a potential immunotherapy for GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Nanopartículas , Humanos , Glioblastoma/tratamento farmacológico , Antígeno B7-H1 , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Óxido Nítrico/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Imunoterapia , Microambiente Tumoral , Linhagem Celular Tumoral , Receptores CXCR4/genética
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
5.
Biophys Chem ; 212: 1-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26945551

RESUMO

The mechanisms of the strong inward rectification in inward rectifier K(+) (Kir) channels are controversial because the drop in electrical potential due to the movement of the blocker and coupling ions is insufficient to explain the steep voltage-dependent block near the equilibrium potential. Here, we study the "driving force"-dependent block in Kir channels with a novel approach incorporating concepts from the non-equilibrium thermodynamics of small systems, and computer kinetic simulations based on the experimental data of internal Ba(2+) block on Kir2.1 channels. The steep exponential increase in the apparent binding rate near the equilibrium potential is explained, when the encounter frequency is construed as the likelihood of transfer events down or against the electrochemical potential gradient. The exponent of flux ratio, nf=2.62, implies that the blockage of the internal blocker may be coupled with the outward transport of 2 to 3K(+) ions. The flux-coupled block in the single-file multi-ion pore can be demonstrated by the concentration gradient alone, as well as when the driving force is the electrochemical potential difference across the membrane.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização/química , Bário/química , Cátions Bivalentes , Cátions Monovalentes , Simulação por Computador , Cinética , Potássio/química , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Termodinâmica
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