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1.
Biomaterials ; 273: 120854, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33932703

RESUMO

The development of photodynamic therapy (PDT) is severely limited by short half-life of singlet oxygen (1O2) and the hypoxic microenvironment. In this work, a plasma membrane targeted photodynamic O2 economizer (designated as P-POE) is developed to improve the subcellular delivery of photosensitizers and alleviate the tumor hypoxia for enhanced PDT effect. After self-assembly into nanomicelles, P-POE has a relatively high stability and a favorable photochemical performance, which are conducive to boosting the 1O2 production. Besides, the plasma membrane anchoring of P-POE contributes to enhancing the preferential retention and cellular accumulation of photosensitizers on tumor tissues and cells. More importantly, P-POE-induced mitochondrial respiratory depression is demonstrated to reduce the O2 consumption of tumor cells to relieve the hypoxia. Consequently, P-POE still exhibits a robust PDT effect against hypoxic tumors, which greatly inhibits the proliferation of breast cancer with low adverse reactions. This innovative combination of subcellular targeting and hypoxic alleviation would advance the development of individualized drug delivery systems for photodynamic therapy against hypoxic tumors.


Assuntos
Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Membrana Celular , Humanos , Hipóxia/tratamento farmacológico , Oxigênio , Fármacos Fotossensibilizantes/uso terapêutico
2.
Acta Biomater ; 117: 349-360, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33010514

RESUMO

Development of antitumor agents with high efficiency and low toxicity is one of the most important goals for biomedical research. However, most traditional therapeutic strategies were limited due to their non-specificity and abnormal tumor microenvironments, causing a poor therapeutic efficiency and severe side effects. In this paper, a tumor targeted self-synergistic nanoplatform (designated as PAO@PCN@HA) was developed for chemotherapy sensitized photodynamic therapy (PDT) against hypoxic tumors. The efficient drug loading of phenylarsine oxide (PAO) in porphyrinic metal organic framework of PCN-224 as well as the surface modification of hyaluronic acid (HA) improved the targeted drug delivery and reduced the side effects of PAO at the therapeutic dose. Particularly, PAO as an arsenical-based chemotherapeutic agent could not only induce cell apoptosis by generating reactive oxygen species (ROS), but also regulate tumor microenvironments to improve the PDT effect of PCN-224 by mitigating hypoxia and consuming cellular GSH. Both in vitro and in vivo investigations confirmed an effective self-synergy of PAO@PCN@HA in hypoxic tumor therapy with a low systemic toxicity. This integration of microenvironment adjustment with tumor targeted self-synergistic mechanism might provide a new insight for the development of arsenic-based antitumor strategy for clinical applications.


Assuntos
Antineoplásicos , Arsênio , Neoplasias , Fotoquimioterapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Arsênio/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente Tumoral
3.
Biomaterials ; 224: 119497, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31541935

RESUMO

In recent years, epigenetics has attracted great attentions in the field of biomedicine, which is used to denote the heritable changes in gene expression without any variation in DNA sequence, including DNA methylation, histone modification and so on. Inspired by it, a simple and versatile amino acids modification strategy is proposed in this paper to regulate the subcellular distribution of photosensitizer for plasma membrane targeted photodynamic therapy (PDT). Particularly, the plasma membrane anchoring ability and photo toxicity of the photosensitizer against different cell lines could be effectively manipulated at a single amino acid level. Systematic researches indicate that the number and variety of amino acids have a significant influence on the plasma membrane targeting effect of the photosensitizer. Furthermore, after self-assembling into nanoparticles, the obtained nano photosensitizers (NPs) also exhibit a good biocompatibility and plasma membrane targeting ability, which are conducive to enhancing the PDT therapeutic effect under light irradiation. Both in vitro and in vivo investigations confirm a robust tumor inhibition effect of NPs with a good biocompatibility. This epigenetics-inspired photosensitizer modification strategy would contribute to the development of structure-based drug design for tumor precision therapy.


Assuntos
Membrana Celular/metabolismo , Epigênese Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Células 3T3 , Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/farmacologia , Protoporfirinas/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Distribuição Tecidual/efeitos dos fármacos
4.
Biomaterials ; 211: 14-24, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078049

RESUMO

Targeted delivery of the drug to its therapeutically active site with low immunogenicity and system toxicity is critical for optimal tumor therapy. In this paper, exosomes as naturally-derived nano-sized membrane vesicles are engineered by chimeric peptide for plasma membrane and nucleus targeted photosensitizer delivery and synergistic photodynamic therapy (PDT). Importantly, a dual-stage light strategy is adopted for precise PDT by selectively and sequentially destroying the plasma membrane and nucleus of tumor cells. Briefly, plasma membrane-targeted PDT of chimeric peptide engineered exosomes (ChiP-Exo) could directly disrupt the membrane integrity and cause cell death to some extent. More interestingly, the photochemical internalization (PCI) and lysosomal escape triggered by the first-stage light significantly improve the cytosolic delivery of ChiP-Exo, which could enhance its nuclear delivery due to the presence of nuclear localization signals (NLS) peptide. Upon the second-stage light irradiation, the intranuclear ChiP-Exo would activate reactive oxygen species (ROS) in situ to disrupt nuclei for robust and synergistic PDT. Based on exosomes, this dual-stage light guided subcellular dual-targeted PDT strategy exhibits a greatly enhanced therapeutic effect on the inhibition of tumor growth with minimized system toxicity, which also provides a new insight for the development of individualized biomedicine for precise tumor therapy.


Assuntos
Exossomos/transplante , Neoplasias/terapia , Peptídeos/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/patologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem
5.
Nanoscale ; 11(18): 9008-9014, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31020984

RESUMO

An abnormal pH microenvironment results from the development of tumors, and also affects the therapeutic efficiency of anti-tumor drugs. In this work, a Förster resonance energy transfer (FRET)-based theranostic fluorescent nanoprobe was constructed for simultaneous ratiometric pH sensing and tumor-targeted photodynamic therapy. Based on the FRET process between rhodamine B and protoporphyrin IX (PpIX), the fabricated nanoprobe exhibited excellent pH responsiveness in both solutions and live cells with the ratiometric fluorescence changes. Moreover, this ratiometric pH fluorescent nanoprobe also possessed the capability for pH-responsive singlet oxygen (1O2) generation under light irradiation, guiding robust photodynamic therapy in a pH-dependent manner. Benefiting from the enhanced permeability and retention (EPR) effect, the nanoprobe could significantly inhibit tumor growth and metastasis via targeted photodynamic therapy in vivo. This work presents a novel paradigm for precise tumor theranostics by ratiometric pH fluorescence imaging-guided photodynamic therapy.


Assuntos
Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Microscopia Confocal , Neoplasias/diagnóstico por imagem , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Rodaminas/química , Oxigênio Singlete/metabolismo , Transplante Heterólogo
6.
Biomaterials ; 195: 75-85, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616030

RESUMO

Targeted drug delivery with precisely controlled drug release and activation is highly demanding and challenging for tumor precision therapy. Herein, a biomimetic cascade nanoreactor (designated as Mem@GOx@ZIF-8@BDOX) is constructed for tumor targeted starvation therapy-amplified chemotherapy by assembling tumor cell membrane cloak and glucose oxidase (GOx) onto zeolitic imidazolate framework (ZIF-8) with the loading prodrug of hydrogen peroxide (H2O2)-sensitive BDOX. Biomimetic membrane camouflage affords superior immune evasion and homotypic binding capacities, which significantly enhance the tumor preferential accumulation and uptake for targeted drug delivery. Moreover, GOx-induced glycolysis would cut off glucose supply and metabolism pathways for tumor starvation therapy with the transformation of tumor microenvironments. Importantly, this artificial adjustment could trigger the site-specific BDOX release and activation for cascade amplified tumor chemotherapy regardless of the complexity and variability of tumor physiological environments. Both in vitro and in vivo investigations indicate that the biomimetic cascade nanoreactor could remarkably improve the therapeutic efficacy with minimized side effects through the synergistic starvation therapy and chemotherapy. This biomimetic cascade strategy would contribute to developing intelligent drug delivery systems for tumor precision therapy.


Assuntos
Biomimética/métodos , Nanopartículas/química , Animais , Glucose Oxidase/química , Humanos , Peróxido de Hidrogênio/química , Estruturas Metalorgânicas , Pró-Fármacos/química , Zeolitas/química
7.
Front Chem ; 7: 868, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31921785

RESUMO

Hypoxia is a common feature for most malignant tumors, which was also closely related to the oxygen-dependent photodynamic therapy. Based on Förster resonance energy transfer (FRET), a smart nanoprobe (designated as H-Probe) was designed in this paper for hypoxia imaging and photodynamic tumor therapy. Due to the FRET process, H-Probe could respond to hypoxia with a significant fluorescence recovery. Moreover, abundant in vitro investigations demonstrated that the photosensitizer of PpIX in H-Probe could generate large amounts of singlet oxygen to kill cancer cells in the presence of oxygen and light with appropriate wavelength. Also, intravenously injected H-Probe with light irradiation achieved an effective tumor inhibition in vivo with a reduced side effect. This original strategy of integrating hypoxia imaging and tumor therapy in one nanoplatform would promote the development of theranostic nanoplatform for tumor precision therapy.

8.
Macromol Biosci ; 19(4): e1800410, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30576082

RESUMO

In this paper, a self-delivery chimeric peptide PpIX-PEG8 -KVPRNQDWL is designed for photodynamic therapy (PDT) amplified immunotherapy against malignant melanoma. After self-assembly into nanoparticles (designated as PPMA), this self-delivery system shows high drug loading rate, good dispersion, and stability as well as an excellent capability in producing reactive oxygen species (ROS). After cellular uptake, the ROS generated under light irradiation could induce the apoptosis and/or necrosis of tumor cells, which would subsequently stimulate the anti-tumor immune response. On the other hand, the melanoma specific antigen (KVPRNQDWL) peptide could also activate the specific cytotoxic T cells for anti-tumor immunity. Compared to immunotherapy alone, the combined photodynamic immunotherapy exhibits significantly enhanced inhibition of melanoma growth. Both in vitro and in vivo investigations confirm that PDT of PPMA has a positive effect on anti-tumor immune response. This self-delivery system demonstrates a great potential of this PDT amplified immunotherapy strategy for advanced or metastatic tumor treatment.


Assuntos
Antígenos de Neoplasias/farmacologia , Sistemas de Liberação de Medicamentos , Imunoterapia , Melanoma Experimental/terapia , Peptídeos/farmacologia , Fotoquimioterapia , Animais , Antígenos de Neoplasias/imunologia , Células COS , Chlorocebus aethiops , Imunidade Celular/efeitos dos fármacos , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia
9.
Biomaterials ; 188: 1-11, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30312907

RESUMO

Mitochondria and cell membrane play important roles in maintaining cellular activity and stability. Here, a single-agent self-delivery chimeric peptide based nanoparticle (designated as M-ChiP) was developed for mitochondria and plasma membrane dual-targeted photodynamic tumor therapy. Without additional carrier, M-ChiP possessed high drug loading efficacy as well as the excellent ability of producing reactive oxygen species (ROS). Moreover, the dual-targeting property facilitated the effective subcellular localization of photosensitizer protoporphyrin IX (PpIX) to generate ROS in situ for enhanced photodynamic therapy (PDT). Notably, plasma membrane-targeted PDT would enhance the membrane permeability to improve the cellular delivery of M-ChiP, and even directly disrupt the cell membrane to induce cell necrosis. Additionally, mitochondria-targeted PDT would decrease mitochondrial membrane potential and significantly promote the cell apoptosis. Both in vitro and in vivo investigations indicated that this combinatorial PDT in mitochondria and plasma membrane could achieve the therapeutic effect maximization with reduced side effects. The single-agent self-delivery system with dual-targeting strategy was demonstrated to be a promising nanoplatform for synergistic tumor therapy.


Assuntos
Membrana Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Peptídeos/química , Fármacos Fotossensibilizantes/administração & dosagem , Protoporfirinas/administração & dosagem , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Camundongos , Mitocôndrias/metabolismo , Nanopartículas/química , Neoplasias/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/farmacocinética , Protoporfirinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
10.
Oncol Lett ; 9(1): 411-417, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25436001

RESUMO

Low expression levels of the programmed cell death 5 (PDCD5) gene have been reported in numerous human cancers, however, PDCD5 expression has not been investigated in hepatic cancer. The present study aims to investigate the biological behavior of PDCD5 overexpression in hepatocellular carcinoma (HCC) cells. The PDCD5 gene was stably transfected into the HepG2 HCC cell line (HepG2-PDCD5), and the expression levels of PDCD5 were examined by quantitative polymerase chain reaction and western blotting. An MTT assay was used to assess the cellular proliferating ability, and propidium iodide (PI) staining was used to evaluate the cell cycle by flow cytometry. The cells were incubated with 2 ng/ml transforming growth factor (TGF)-ß for 7 days in order to induce invasion and epithelial-mesenchymal transition (EMT). Apoptosis was measured by Annexin V-fluorescein isothiocyanate and PI double labeling. A Boyden chamber invasion assay was carried out to detect tumor invasion. Western blotting was performed to detect the protein expression levels of PDCD5, insulin-like growth factor (IGF)-1 and the EMT marker, Snail. The results showed that the HepG2-PDCD5 cells exhibited slower proliferation rates and high G2/M cell numbers compared with those of the HepG2 and HepG2-Neo controls (P<0.05). The PDCD5 transfected cells showed higher sensitivity to cisplatin treatment than the HepG2-Neo cells, with a higher p53 protein expression level. PDCD5 overexpression can attenuate tumor invasion, EMT and the level of IGF-1 protein induced by TGF-ß treatment. In conclusion, stable transfection of the PDCD5 gene can inhibit growth and induce cell cycle arrest in HepG2 cells, and its also notably improves the apoptosis-inducing effects of cisplatin, and reverses invasion and EMT induced by TGF-ß. The use of PDCD5 is a novel strategy for improving the chemotherapeutic effects on HCC.

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