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1.
Biomater Sci ; 12(3): 808-809, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38240308

RESUMO

Correction for 'An E-selectin targeting and MMP-2-responsive dextran-curcumin polymeric prodrug for targeted therapy of acute kidney injury' by Jing-Bo Hu et al., Biomater. Sci., 2018, 6, 3397-3409, https://doi.org/10.1039/C8BM00813B.

2.
J Nanobiotechnology ; 20(1): 524, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36496411

RESUMO

BACKGROUND: Excessive extracellular matrix (ECM) deposition in pancreatic ductal adenocarcinoma (PDAC) severely limits therapeutic drug penetration into tumors and is associated with poor prognosis. Collagen is the most abundant matrix protein in the tumor ECM, which is the main obstacle that severely hinders the diffusion of chemotherapeutic drugs or nanomedicines. METHODS: We designed a collagenase-functionalized biomimetic drug-loaded Au nanoplatform that combined ECM degradation, active targeting, immune evasion, near-infrared (NIR) light-triggered drug release, and synergistic antitumor therapy and diagnosis into one nanoplatform. PDAC tumor cell membranes were extracted and coated onto doxorubicin (Dox)-loaded Au nanocages, and then collagenase was added to functionalize the cell membrane through lipid insertion. We evaluated the physicochemical properties, in vitro and in vivo targeting, penetration and therapeutic efficacy of the nanoplatform. RESULTS: Upon intravenous injection, this nanoplatform efficiently targeted the tumor through the homologous targeting properties of the coated cell membrane. During penetration into the tumor tissue, the dense ECM in the PDAC tissues was gradually degraded by collagenase, leading to a looser ECM structure and deep penetration within the tumor parenchyma. Under NIR irradiation, both photothermal and photodynamic effects were produced and the encapsulated chemotherapeutic drugs were released effectively, exerting a strong synergistic antitumor effect. Moreover, this nanoplatform has X-ray attenuation properties that could serve to guide and monitor treatment by CT imaging. CONCLUSION: This work presented a unique and facile yet effective strategy to modulate ECM components in PDAC, enhance tumor penetration and tumor-killing effects and provide therapeutic guidance and monitoring.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Fotoquimioterapia , Humanos , Nanopartículas/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Matriz Extracelular , Linhagem Celular Tumoral , Fototerapia/métodos
3.
ACS Nano ; 16(8): 12964-12978, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-35968927

RESUMO

The tumor microenvironment (TME) is characterized by several immunosuppressive factors, of which weak acidity and l-arginine (l-arg) deficiency are two common features. A weak acidic environment threatens the survival of immune cells, and insufficient l-arg will severely restrain the effect of antitumor immune responses, both of which affect the efficiency of cancer treatments (especially immunotherapy). Meanwhile, l-arg is essential for tumor progression. Thus, two strategies, l-arg supplementation and l-arg deprivation, are developed for cancer treatment. However, these strategies have the potential risk of promoting tumor growth and impairing immune responses, which might lead to a paradoxical therapeutic effect. It is optimal to limit the l-arg availability of tumor cells from the microenvironment while supplying l-arg for immune cells. In this study, we designed a multivesicular liposome technology to continuously supply alkaline l-arg, which simultaneously changed the acidity and l-arg deficiency in the TME, and by selectively knocking down the CAT-2 transporter, l-arg starvation of tumors was maintained while tumor-killing immune cells were enriched in the TME. The results showed that our strategy promoted the infiltration and activation of CD8+ T cells in tumor, increased the proportion of M1 macrophages, inhibited melanoma growth, and prolonged survival. In combination with anti-PD-1 antibody, our strategy reversed the low tumor response to immune checkpoint blockade therapy, showing a synergistic antitumor effect. Our work provided a reference for improving the TME combined with regulating nutritional competitiveness to achieve the sensitization of immunotherapy.


Assuntos
Melanoma , Microambiente Tumoral , Humanos , Arginina/farmacologia , Imunoterapia/métodos , Fatores Imunológicos/farmacologia , Imunidade , Suplementos Nutricionais , Linhagem Celular Tumoral
4.
J Nanobiotechnology ; 19(1): 361, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749740

RESUMO

BACKGROUND: Hepatocellular carcinoma is insensitive to many chemotherapeutic agents. Ferroptosis is a form of programmed cell death with a Fenton reaction mechanism. It converts endogenous hydrogen peroxide into highly toxic hydroxyl radicals, which inhibit hepatocellular carcinoma progression. METHODS: The morphology, elemental composition, and tumour microenvironment responses of various organic/inorganic nanoplatforms were characterised by different analytical methods. Their in vivo and in vitro tumour-targeting efficacy and imaging capability were analysed by magnetic resonance imaging. Confocal microscopy, flow cytometry, and western blotting were used to investigate the therapeutic efficacy and mechanisms of complementary ferroptosis/apoptosis mediated by the nanoplatforms. RESULTS: The nanoplatform consisted of a silica shell doped with iron and disulphide bonds and an etched core loaded with doxorubicin that generates hydrogen peroxide in situ and enhances ferroptosis. It relied upon transferrin for targeted drug delivery and could be activated by the tumour microenvironment. Glutathione-responsive biodegradability could operate synergistically with the therapeutic interaction between doxorubicin and iron and induce tumour cell death through complementary ferroptosis and apoptosis. The nanoplatform also has a superparamagnetic framework that could serve to guide and monitor treatment under T2-weighted magnetic resonance imaging. CONCLUSION: This rationally designed nanoplatform is expected to integrate cancer diagnosis, treatment, and monitoring and provide a novel clinical antitumour therapeutic strategy.


Assuntos
Ferro , Neoplasias Hepáticas/metabolismo , Nanopartículas , Estresse Oxidativo/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Ferroptose/efeitos dos fármacos , Células Hep G2 , Humanos , Ferro/química , Ferro/farmacologia
5.
ACS Nano ; 15(12): 19394-19408, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34806870

RESUMO

The dense extracellular matrix (ECM) in tumor tissues resists drug diffusion into tumors and leads to a poor prognosis. To address this problem, glucose oxidase (GOx)-modified ferritin loaded with luminol-curcumin was fabricated. Once delivered to the tumor, this luminol-based self-illuminating nanocage could actively convert glucose to reactive oxygen species (ROS) to achieve starvation therapy. Then, excessive ROS were transmitted to luminol, thereby emitting 425 nm blue-violet light. Momentarily, light was further absorbed by curcumin and ROS production was amplified. Abundant ROS helps break down the ECM network to penetrate deep into tumors. In addition, ROS produced after cell internalization can induce apoptosis of tumor cells by decreasing the mitochondrial membrane potential and can promote ferroptosis by consuming reduced glutathione. Effective penetration and multiple pathways inducing tumor cell death contributed to the efficient antitumor effect (tumor inhibition rate of GOx-modified ferritin loaded with luminol-curcumin: 71.73%). This study developed a glucose-driven self-illuminating nanocage for active tumor penetration via ROS-mediated destruction of the ECM and provided the synergetic mechanism of apoptosis and ferroptosis.


Assuntos
Ferroptose , Neoplasias , Glucose Oxidase , Humanos , Luminol , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio
6.
Biomater Sci ; 6(12): 3397-3409, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30371703

RESUMO

Based on the overproduction of matrix metalloproteinase-2 (MMP-2) in renal tissue during acute kidney injury (AKI) occurrence, we developed a MMP-2 enzyme-triggered polymeric prodrug with sialic acid (SA) as the targeting group to the inflamed vascular endothelial cells for enhanced therapeutic outcomes. An MMP-2-responsive peptide, PVGLIG, was used to endow the polymeric prodrug with the ability to rapidly release the anti-inflammatory drug, curcumin (CUR), after the targeted site is reached and to improve the drug concentration in the target tissue. The sialic acid-dextran-PVGLIG-curcumin (SA-DEX-PVGLIG-CUR) polymeric prodrug was successfully synthesized via multi-step chemical reactions and characterized by 1H NMR. The water solubility of CUR was significantly increased in the polymeric prodrug and was approximately 23-fold higher than that of free CUR. The in vitro drug release results showed that the release rate of SA-DEX-PVGLIG-CUR was significantly enhanced compared to that of SA-DEX-CUR in a dissolving medium containing the MMP-2 enzyme, suggesting that SA-DEX-PVGLIG-CUR had rapid drug release characteristics in an inflammatory environment. A cellular uptake test confirmed that SA-DEX-PVGLIG-CUR was effectively internalized by inflamed vascular endothelial cells in comparison with that by normal cells, and the mechanism was associated with the specific interaction between SA and E-selectin receptors specifically expressed on inflamed vascular endothelial cells. Bio-distribution results further demonstrated the rapid and increased renal accumulation of SA-DEX-PVGLIG-CUR in AKI mice. Benefiting from the rapid drug release in renal tissue, SA-DEX-PVGLIG-CUR effectively ameliorated the pathological progression of AKI compared with free CUR and SA-DEX-CUR, as reflected by the improved renal functions, histopathological changes, pro-inflammatory cytokine production, oxidative stress and expression of apoptosis related proteins. Altogether, this study provided a new therapeutic strategy for the treatment of AKI.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Curcumina/química , Dextranos/química , Selectina E/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Pró-Fármacos/química , Animais , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular/métodos , Ácido N-Acetilneuramínico/química , Oligopeptídeos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico
7.
Biomaterials ; 131: 36-46, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28376364

RESUMO

The development of combinational anti-tumor therapy is of great value. Here, the thermal-sensitive and hepatic tumor cell targeting peptide-A54 modified polymer, A54-poly(ethylene glycol)-g-poly(acrylamide-co-acrylonitrile) (A54-PEG-g-p(AAm-co-AN)) can self-assemble into an 80 nm-sized micelle, which shows a thermal-sensitive behavior with an upper critical solution temperature (UCST) of 43 °C. This self-assembled and targeted A54-PEG-g-p(AAm-co-AN) micelle can co-encapsulate anti-tumor drug doxorubicin (DOX) and magnetic nanoparticles (MNPs) taking advantage of the hydrophobic core of the core-shell micellar structure, when the temperature is lower than 43 °C. A much higher accumulation of the MNPs@A54-PEG-g-p(AAm-co-AN) to the tumor navigated by the A54 targeting peptide is achieved. Due to the thermal-agent effect of the accumulated MNPs in tumor, the mild microwave (8 W) applied afterwards specifically elevates the local tumor temperature by 13 °C, compared to 6 °C without MNPs accumulation in 30 min. The greater temperature rise resulted from the thermal-agent effect of MNPs doesn't only activate the drug release inside tumor cells, but also achieve an augmented hyperthermia. A mild microwave activated, chemo-thermal combinational tumor therapy is thus developed.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Preparações de Ação Retardada/química , Doxorrubicina/uso terapêutico , Neoplasias Hepáticas/terapia , Nanopartículas de Magnetita/uso terapêutico , Micelas , Resinas Acrílicas/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Terapia Combinada , Doxorrubicina/administração & dosagem , Feminino , Humanos , Hipertermia Induzida , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Nus , Micro-Ondas , Peptídeos/química , Polietilenoglicóis/química
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