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1.
J Transl Med ; 20(1): 85, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35148758

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a progressive systemic autoimmune disease that is characterized by infiltration of inflammatory cells into the hyperplastic synovial tissue, resulting in subsequent destruction of adjacent articular cartilage and bone. Methotrexate (MTX), the first conventional disease-modifying antirheumatic drug (DMARD), could alleviate articular damage in RA and is implicated in humoral and cellular immune responses. However, MTX has several side effects, so efficient delivery of low-dose MTX is important. METHODS: To investigate the efficacy of MTX-loaded nanoparticles (MTX-NPs) against experimental model of RA, free MTX or MTX-NPs were administered as subcutaneous route to mice with collagen-induced arthritis (CIA) at 3 weeks after CII immunization. The levels of inflammatory factors in tissues were determined by immunohistochemistry, confocal microscopy, real-time PCR, and flow cytometry. RESULTS: MTX-NPs ameliorated arthritic severity and joint destruction in collagen-induced arthritis (CIA) mice compared to free MTX-treated CIA mice. The levels of inflammatory cytokines, including interleukin (IL)-1ß, tumor necrosis factor-α, and vascular endothelial growth factor, were reduced in MTX-NPs-treated mice. Number of CD4 + IL-17 + cells decreased whereas the number of CD4 + CD25 + Foxp3 + cells increased in spleens from MTX- NPs-treated CIA mice compared to MTX-treated CIA mice. The frequency of CD19 + CD25 + Foxp3 + regulatory B cells increased in ex vivo splenocytes from MTX-loaded NPs-treated CIA mice compared to MTX-treated CIA mice. CONCLUSION: The results suggest that MTX-loaded NPs have therapeutic potential for RA.


Assuntos
Artrite Experimental , Doenças Autoimunes , Nanopartículas , Animais , Artrite Experimental/patologia , Interleucina-17 , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Camundongos , Linfócitos T Reguladores , Fator A de Crescimento do Endotélio Vascular
2.
J Nanobiotechnology ; 19(1): 411, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34876140

RESUMO

BACKGROUND: Combination therapy using more than one drug can result in a synergetic effect in clinical treatment of cancer. For this, it is important to develop an efficient drug delivery system that can contain multiple drugs and provide high accumulation in tumor tissue. In particular, simultaneous and stable loading of drugs with different chemical properties into a single nanoparticle carrier is a difficult problem. RESULTS: We developed rhamnolipid-coated double emulsion nanoparticles containing doxorubicin and erlotinib (RL-NP-DOX-ERL) for efficient drug delivery to tumor tissue and combination chemotherapy. The double emulsion method enabled simultaneous loading of hydrophilic DOX and hydrophobic ERL in the NPs, and biosurfactant RL provided stable surface coating. The resulting NPs showed fast cellular uptake and synergetic tumor cell killing in SCC7 cells. In real-time imaging, they showed high accumulation in SCC7 tumor tissue in mice after intravenous injection. Furthermore, enhanced tumor suppression was observed by RL-NP-DOX-ERL in the same mouse model compared to control groups using free drugs and NPs containing a single drug. CONCLUSIONS: The developed RL-NP-DOX-ERL provided efficient delivery of DOX and ERL to tumor tissue and successful tumor therapy with a synergetic effect. Importantly, this study demonstrated the promising potential of double-emulsion NPs and RL coating for combination therapy.


Assuntos
Antineoplásicos , Emulsões/química , Glicolipídeos/química , Nanopartículas , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Quimioterapia Combinada , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacocinética , Cloridrato de Erlotinib/farmacologia , Camundongos , Nanopartículas/química , Nanopartículas/metabolismo , Imagem Óptica
3.
Nanomedicine ; 32: 102329, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33181275

RESUMO

We used antioxidant-containing nanoparticles (NPs) to treat acute hearing loss. Alpha-lipoic acid (ALA) served as the antioxidant; we employed Pluronic F127 to fabricate NPs. In vitro, ALA-NPs protected cells of the organ of Corti in HEI-OC1 mice, triggering nuclear translocation of NRF2 and increases in the levels of antioxidant proteins, including Nrf2, HO-1, SOD-1, and SOD-2. In vivo, the hearing of mice that received ALA-NP injections into the middle ear cavity was better preserved after induction of ototoxicity than in control animals. The cochlear Nrf2 level increased in test mice, indicating that the ALA-NPs protected hearing via the antioxidant mechanism observed in vitro. ALA-NPs effectively protected against acute hearing loss by activating the Nrf2/HO-1 pathway.


Assuntos
Perda Auditiva/tratamento farmacológico , Nanopartículas/química , Poloxâmero/química , Ácido Tióctico/administração & dosagem , Ácido Tióctico/uso terapêutico , Membrana Timpânica/patologia , Animais , Antioxidantes/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Perda Auditiva/patologia , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Nanopartículas/ultraestrutura , Ácido Tióctico/farmacologia
4.
Nanomedicine ; 24: 102151, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31927135

RESUMO

To evaluate the effect of drug hydrophobicity on nanoparticle delivery in vivo, we conducted a comparative study using different photosensitizer-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). Chlorin e6 (Ce6) and pheophorbide a (Pba) with similar structure but different hydrophobicity were loaded into PLGA-NPs separately. We observed release profiles and photodynamic effects in vitro from the resulting Ce6- and Pba-PLGA-NPs. After intravenous injection into SCC7 tumor-bearing mice, biodistribution and accumulation of two drugs in tumor tissue were observed by real-time fluorescence imaging. Finally, in vivo photodynamic therapy with Ce6- and Pba-PLGA-NPs provided different therapeutic results according to imaging data. The results demonstrated that drug hydrophobicity is an important factor in nanoparticle drug delivery and should be considered for efficient drug delivery in vivo.


Assuntos
Nanopartículas/química , Fármacos Fotossensibilizantes/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Clorofila/análogos & derivados , Clorofila/química , Clorofilídeos , Sistemas de Liberação de Medicamentos/métodos , Citometria de Fluxo , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Fotoquimioterapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Porfirinas/química
5.
Biochem Biophys Res Commun ; 508(1): 326-331, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502086

RESUMO

Nanoparticles have been widely used as drug carriers, and finding new materials for them is important for efficient drug delivery. Herein, we developed a new nanoparticle using emulsan and flax seed oil. Emulsan is one of the representative biosurfactants obtained from Acinetobacter calcoaceticus RAG-1. The resulting nanoparticles have an emulsan shell and a hydrophobic oil core, into which pheophorbide a (Pba) was loaded as a model drug. The nanoparticles were about 165.7 nm and were stably dispersed in an aqueous condition for more than one week. They demonstrated fast uptake in SCC7 mouse squamous cell carcinoma cells and killed the tumor cells after laser irradiation due to the photodynamic effect of Pba. After injection into SCC7 tumor-bearing mice via the tail vein, the particles showed longer blood circulation and 3.04-fold higher tumor accumulation in tissue than free Pba. These results demonstrate that emulsan-based nanoparticles have promising potential in drug delivery.


Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Polissacarídeos Bacterianos/química , Neoplasias Cutâneas/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Camundongos , Camundongos Endogâmicos C3H , Imagem Óptica
6.
Biochem Biophys Res Commun ; 515(1): 207-213, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31146921

RESUMO

For efficient drug delivery, we introduce a click-chemistry-mediated two-step tumor-targeting strategy for nanoparticles (NPs). We modified HER2-binding trastuzumab with trans-cyclooctene (TCO-Trb), and fabricated tetrazine-modified NPs containing the anticancer drug, SN38 (SN38-Tz-NPs). To target tumor cells with the Tz-NPs, the tumor cells are first treated with TCO-Trb. The TCO-Trb binds HER2s and presents multiple TCO groups on the cell surface. Subsequently, the cells are treated with SN38-Tz-NPs that can bind the cell surface via click chemistry between Tz and TCO. This click chemistry-mediated binding resulted in enhanced tumor-targeting of Tz-NPs to the target tumor cells. In our study, this strategy was performed and analyzed in vitro and in vivo, and the results show that this is a promising strategy for tumor-targeted drug delivery by NPs.


Assuntos
Ciclo-Octanos/química , Sistemas de Liberação de Medicamentos/métodos , Irinotecano/química , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Trastuzumab/química , Animais , Linhagem Celular Tumoral , Química Click/métodos , Irinotecano/administração & dosagem , Irinotecano/farmacocinética , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ligação Proteica , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Distribuição Tecidual , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacocinética , Trastuzumab/administração & dosagem , Trastuzumab/metabolismo , Trastuzumab/farmacocinética
7.
J Nanobiotechnology ; 17(1): 50, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953510

RESUMO

BACKGROUND: Improving the water solubility of hydrophobic photosensitizer and increasing its accumulation in tumor tissue are essential for in vivo photodynamic therapy (PDT). Considering commercialization or clinical application in future, it will be promising to achieve these purposes by developing new agents with simple and non-toxic structure. RESULTS: We conjugated multiple chlorin e6 (Ce6) molecules to gelatin polymer, synthesizing two types of gelatin-Ce6 conjugates with different amounts of Ce6: gelatin-Ce6-2 and gelatin-Ce6-8. The resulting conjugates remained soluble in aqueous solutions for a longer time than hydrophobic Ce6. The conjugates could generate singlet oxygen and kill tumor cells upon laser irradiation. After intravenous injection into SCC-7 tumor-bearing mice, gelatin-Ce6-2 showed prolonged blood circulation and highly increased accumulation in tumor tissue as observed in real-time imaging in vivo. After laser irradiation, gelatin-Ce6-2 suppressed tumor growth completely and enabled improved PDT compared to free Ce6 and gelatin-Ce6-8. CONCLUSIONS: This work demonstrates that a simple structure based on photosensitizer and gelatin can highly improve water solubility and stability. Superior tumor tissue accumulation and increased therapeutic efficacy of gelatin-Ce6 during in vivo PDT showed its high potential for clinical application.


Assuntos
Gelatina/química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Clorofilídeos , Portadores de Fármacos , Humanos , Camundongos , Transplante de Neoplasias , Fototerapia , Polímeros/química , Porfirinas/química , Oxigênio Singlete/metabolismo , Solubilidade , Distribuição Tecidual
8.
Nanomedicine ; 19: 12-21, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30981820

RESUMO

Herein, we report the development of self-assembled nanoparticles using rhamnolipid, a biosurfactant. Rhamnolipid is produced by Pseudomonas aeruginosa, and has an amphiphilic structure that is suitable for the formation of a nanoparticle shell. These rhamnolipid nanoparticles were loaded with pheophorbide a (Pba), a hydrophobic photosensitizer. The resulting nanoparticles had about 136.1-nm-diameter spherical shapes and had excellent water solubility without aggregation for one month. These nanoparticles showed fast uptake into SCC7 tumor cells and induced photodynamic damage upon laser irradiation. After intravenous injection to SCC7 tumor-bearing mice, their long blood circulation time and high accumulation in tumor tissue were observed in real-time fluorescence imaging. Upon laser irradiation, these rhamnolipid nanoparticles showed complete tumor suppression by photodynamic therapy in vivo. These promising results demonstrate the potential of rhamnolipid nanoparticles for drug delivery, and suggest that further attention to rhamnolipid research would be fruitful.


Assuntos
Sistemas de Liberação de Medicamentos , Glicolipídeos/química , Nanopartículas/química , Fotoquimioterapia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofila/análogos & derivados , Clorofila/química , Clorofila/farmacologia , Camundongos , Nanopartículas/ultraestrutura , Oxigênio Singlete/química , Distribuição Tecidual/efeitos dos fármacos
9.
Int J Mol Sci ; 20(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416237

RESUMO

We fabricated poly (ethylene glycol)-block-polycaprolactone (PEG-b-PCL) nanoemulsion for drug delivery and photodynamic therapy. PEG-b-PCL effectively stabilized the interface between water and soybean oil, and the resulting nanoemulsion was about 220.3 nm in diameter with spherical shape. For photodynamic therapy (PDT), chlorin e6 (Ce6) was loaded into the nanoemulsion as a photosensitizer (PS). These chlorin e6-loaded PEG-PCL nanoemulsions (Ce6-PCL-NEs) showed efficient cellular uptake and, upon laser irradiation, generated singlet oxygen to kill tumor cells. Particularly, Ce6-PCL-NEs showed prolonged blood circulation and about 60% increased tumor accumulation compared to free Ce6 after intravenous injection to 4T1 tumor-bearing mice. These results demonstrate the promising potential of Ce6-PCL-NEs for efficient PDT and in vivo drug delivery to tumor tissue.


Assuntos
Portadores de Fármacos/química , Emulsões , Lactonas/química , Nanopartículas , Polietilenoglicóis/química , Porfirinas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Clorofilídeos , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Emulsões/química , Camundongos , Modelos Animais , Nanopartículas/química , Nanopartículas/ultraestrutura , Fotoquimioterapia , Porfirinas/química , Porfirinas/farmacocinética , Radiossensibilizantes/química , Distribuição Tecidual
10.
Biochem Biophys Res Commun ; 498(3): 523-528, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29518390

RESUMO

Targeted drug delivery has been an important issue for tumor therapy including photodynamic therapy (PDT). The purpose of our study is to increase the targeting efficiency of photosensitizer (PS) using folate-modified nanoparticles (NPs) to tumor site in vivo. Folate receptor is over-expressed on the surface of many human cancer cells. We prepared poly (lactic-co-glycolic acid) (PLGA) NPs containing pheophorbide a (Pba), a PS that is used in PDT and generates free radical for killing cancer cells. The surface of NPs was composed of phospholipids modified with polyethylene glycol (PEG) and folate (FA). The size of the resulting FA-PLGA-Pba NPs was about 200 nm in PBS at pH 7.4 and they were stable for long time. They showed faster cellular uptake to MKN28 human gastric cancer cell line than control PLGA-Pba NPs by high-affinity binding with folate receptors on cell surface. In MTT assay, FA-PLGA-Pba NPs also showed enhanced tumor cell killing compared to control PLGA-Pba NPs. In vivo and ex vivo imaging showed high accumulation of FA-PLGA-Pba NPs in tumor site during 24 h after intravenous injection to MKN28 tumor-bearing mice model. These results demonstrate that our FA-PLGA-Pba NPs are useful for tumor-targeted delivery of PS for cancer treatment by PDT.


Assuntos
Clorofila/análogos & derivados , Ácido Fólico/química , Ácido Láctico/química , Nanopartículas/química , Fármacos Fotossensibilizantes/administração & dosagem , Ácido Poliglicólico/química , Neoplasias Gástricas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Clorofila/administração & dosagem , Clorofila/farmacocinética , Clorofila/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Camundongos Nus , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Neoplasias Gástricas/patologia
11.
Bioconjug Chem ; 28(1): 124-134, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-27788580

RESUMO

Recently, nanotechnology has provided significant advances in biomedical applications including diagnosis and therapy. In particular, nanoparticles have emerged as valuable outcomes of nanotechnology due to their unique physicochemical properties based on size, shape, and surface properties. Among them, a large amount of research has reported imaging and therapeutic applications using inorganic nanoparticles with special properties. Inorganic nanoparticles developed for imaging and therapy contain metal (Au), metal oxide (Fe3O4, WO3, WO2.9), semiconductor nanocrystal (quantum dots (QDs)), and lanthanide-doped upconversion nanoparticles (UCNPs). Based on their intrinsic properties, they can generate heat, reactive oxygen species (ROS), or energy transfer, so that they can be used for both imaging and therapy. In this review, we introduce biocompatible inorganic nanoparticles for image-guided thermal and photodynamic therapy, and discuss their promising results from in vitro and in vivo studies for biomedical applications.


Assuntos
Compostos Inorgânicos/química , Nanopartículas/química , Humanos , Hipertermia Induzida , Imageamento por Ressonância Magnética , Pontos Quânticos
12.
Mol Pharm ; 14(5): 1558-1570, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28191852

RESUMO

Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin αvß3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.


Assuntos
Química Click/métodos , Nanopartículas/química , Azidas/química , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Quitosana/química , Feminino , Humanos , Neoplasias Pulmonares/metabolismo
13.
Biochem Biophys Res Commun ; 479(4): 779-786, 2016 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-27693784

RESUMO

Labeling of stem cells aims to distinguish transplanted cells from host cells, understand in vivo fate of transplanted cells, particularly important in stem cell therapy. Adipose-derived mesenchymal stem cells (ASCs) are considered as an emerging therapeutic option for tissue regeneration, but much remains to be understood regarding the in vivo evidence. In this study, a simple and efficient cell labeling method for labeling and tracking of stem cells was developed based on bio-orthogonal copper-free click chemistry, and it was applied in a mouse hindlimb ischemia model. The human ASCs were treated with tetra-acetylated N-azidoacetyl-d-mannosamine (Ac4ManNAz) to generate glycoprotein with unnatural azide groups on the cell surface, and the generated azide groups were fluorescently labeled by specific binding of dibenzylcyclooctyne-conjugated Cy5 (DBCO-Cy5). The safe and long-term labeling of the hASCs by this method was first investigated in vitro. Then the DBCO-Cy5-hASCs were transplanted into the hindlimb ischemia mice model, and we could monitor and track in vivo fate of the cells using optical imaging system. We could clearly observe the migration potent of the hASCs toward the ischemic lesion. This approach to design and tailor new method for labeling of stem cells may be useful to provide better understanding on the therapeutic effects of transplanted stem cells into the target diseases.


Assuntos
Rastreamento de Células/métodos , Isquemia/terapia , Células-Tronco Mesenquimais/citologia , Tecido Adiposo/citologia , Animais , Azidas/química , Química Click/métodos , Modelos Animais de Doenças , Corantes Fluorescentes/química , Membro Posterior , Humanos , Imageamento Tridimensional , Isquemia/patologia , Transplante de Células-Tronco Mesenquimais , Camundongos
14.
Bioconjug Chem ; 27(11): 2601-2604, 2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27779857

RESUMO

We demonstrate a chemically detachable cell-glue system based on linkers containing disulfide bonds as well as functional groups for metabolic glycoengineering and bioorthogonal click chemistry. Azide groups are generated on the cell surface by metabolic glycoengineering, and they are further modified into tetrazine (Tz) or trans-cyclooctene (TCO) using rationally designed cross-linkers. When the Tz-modified and TCO-modified cells are mixed together, cell gluing between these two cell groups is established by Tz-TCO click chemistry. This artificial cell-cell adhesion can be broken by the administration of glutathione (5 mM), which triggers the degradation of disulfide bonds. Both the gluing and detachment processes are rapid (<10 min) and minimally cytotoxic.


Assuntos
Glutationa/farmacologia , Células A549 , Azidas/química , Adesão Celular/efeitos dos fármacos , Química Click , Ciclo-Octanos/química , Dissulfetos/química , Glutationa/química , Humanos , Células Jurkat , Cinética , Engenharia Metabólica
15.
Mol Pharm ; 13(11): 3700-3711, 2016 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-27654060

RESUMO

Herein, we elucidated the mechanisms and key factors for the tumor-targeting ability of nanoparticles that presented high targeting efficiency for liver tumor. We used several different nanoparticles with sizes of 200-300 nm, including liposome nanoparticles (LNPs), polystyrene nanoparticles (PNPs) and glycol chitosan-5ß-cholanic acid nanoparticles (CNPs). Their sizes are suitable for the enhanced permeation and retention (EPR) effect in literature. Different in vitro characteristics, such as the particle structure, stability, and bioinertness, were carefully analyzed with and without serum proteins. Also, pH-dependent tumor cell uptakes of nanoparticles were studied using fluorescence microscopy. Importantly, CNPs had sufficient stability and bioinertness to maintain their nanoparticle structure in the bloodstream, and they also presented prolonged circulation time in the body (blood circulation half-life T1/2 = about 12.2 h), compared to the control nanoparticles. Finally, employing liver tumor bearing mice, we also observed that CNPs had excellent liver tumor targeting ability in vivo, while LNPs and PNPs demonstrated lower tumor-targeting efficiency due to the nonspecific accumulation in normal liver tissue. Liver tumor models were produced by laparotomy and direct injection of HT29 tumor cells into the left lobe of the liver of athymic nude mice. This study provides valuable information concerning the key factors for the tumor-targeting ability of nanoparticles such as stability, bioinertness, and rapid cellular uptake at targeted tumor tissues.


Assuntos
Quitosana/administração & dosagem , Quitosana/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Neoplasias Hepáticas/metabolismo , Nanopartículas/química , Animais , Microscopia Crioeletrônica , Eletroforese em Gel de Poliacrilamida , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica , Células RAW 264.7 , Ratos
16.
Angew Chem Int Ed Engl ; 55(47): 14698-14703, 2016 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-27762044

RESUMO

Recently, metabolic glycoengineering with bioorthogonal click reactions has focused on improving the tumor targeting efficiency of nanoparticles as delivery vehicles for anticancer drugs or imaging agents. It is the key technique for developing tumor-specific metabolic precursors that can generate unnatural glycans on the tumor-cell surface. A cathepsin B-specific cleavable substrate (KGRR) conjugated with triacetylated N-azidoacetyl-d-mannosamine (RR-S-Ac3 ManNAz) was developed to enable tumor cells to generate unnatural glycans that contain azide groups. The generation of azide groups on the tumor cell surface was exogenously and specifically controlled by the amount of RR-S-Ac3 ManNAz that was fed to target tumor cells. Moreover, unnatural glycans on the tumor cell surface were conjugated with near infrared fluorescence (NIRF) dye-labeled molecules by a bioorthogonal click reaction in cell cultures and in tumor-bearing mice. Therefore, our RR-S-Ac3 ManNAz is promising for research in tumor-specific imaging or drug delivery.


Assuntos
Catepsina B/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Imagem Óptica , Catepsina B/administração & dosagem , Catepsina B/metabolismo , Linhagem Celular , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Injeções Intravenosas , Nanopartículas/administração & dosagem , Neoplasias/patologia
17.
Small ; 11(48): 6458-66, 2015 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-26768353

RESUMO

Artificial methods of cell adhesion can be effective in building functional cell complexes in vitro, but methods for in vivo use are currently lacking. Here, a chemical cell glue based on bioorthogonal click chemistry with high stability and robustness is introduced. Tetrazine (Tz) and trans-cyclooctene (TCO) conjugated to the cell surface form covalent bonds between cells within 10 min in aqueous conditions. Glued, homogeneous, or heterogeneous cell pairs remain viable and stably attached in a microfluidic flow channel at a shear stress of 20 dyn cm(-2) . Upon intravenous injection of assembled Jurkat T cells into live mice, fluorescence microscopy shows the trafficking of cell pairs in circulation and their infiltration into lung tissues. These results demonstrate the promising potential of chemically glued cell pairs for various applications ranging from delivering therapeutic cells to studying cell-cell interactions in vivo.


Assuntos
Adesivos/farmacologia , Química Click/métodos , Animais , Circulação Sanguínea/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular , Citometria de Fluxo , Ensaios de Triagem em Larga Escala , Humanos , Interleucina-2/metabolismo , Engenharia Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Microfluídica , Células NIH 3T3
18.
Adv Sci (Weinh) ; 11(16): e2304861, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38355304

RESUMO

An ideal hydrogel for stem cell therapy would be injectable and efficiently promote stem cell proliferation and differentiation in body. Herein, an injectable, single-component hydrogel with hyaluronic acid (HA) modified with phenylboronic acid (PBA) and spermidine (SM) is introduced. The resulting HAps (HA-PBA-SM) hydrogel is based on the reversible crosslinking between the diol and the ionized PBA, which is stabilized by the SM. It has a shear-thinning property, enabling its injection through a syringe to form a stable hydrogel inside the body. In addition, HAps hydrogel undergoes a post-injection "self-curing," which stiffens the hydrogel over time. This property allows the HAps hydrogel to meet the physical requirements for stem cell therapy in rigid tissues, such as bone, while maintaining injectability. The hydrogel enabled favorable proliferation of human mesenchymal stem cells (hMSCs) and promoted their differentiation and mineralization. After the injection of hMSCs-containing HAps into a rat femoral defect model, efficient osteogenic differentiation of hMSCs and bone regeneration is observed. The study demonstrates that simple cationic modification of PBA-based hydrogel enabled efficient gelation with shear-thinning and self-curing properties, and it would be highly useful for stem cell therapy and in vivo bone regeneration.


Assuntos
Regeneração Óssea , Ácidos Borônicos , Diferenciação Celular , Hidrogéis , Células-Tronco Mesenquimais , Animais , Regeneração Óssea/fisiologia , Ratos , Hidrogéis/química , Células-Tronco Mesenquimais/citologia , Humanos , Ácido Hialurônico/química , Ratos Sprague-Dawley , Encapsulamento de Células/métodos , Proliferação de Células , Osteogênese/fisiologia , Modelos Animais de Doenças , Espermidina/farmacologia , Espermidina/química
19.
J Control Release ; 366: 104-113, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38128883

RESUMO

Although peptides notoriously have poor intrinsic pharmacokinetic properties, it is well-known that nanostructures with excellent pharmacokinetic properties can be designed. Noticing that peptide inhibitors are generally nonpolar, here, we consolidate the peptide inhibitor targeting intracellular protein-protein interactions (PPIs) as an integral part of biodegradable self-assembled depsipeptide nanostructures (SdPNs). Because the peptide inhibitor has the dual role of PPI inhibition and self-assembly in this design, problems associated with the poor pharmacokinetics of peptides and encapsulation/entrapment processes can be overcome. Optimized SdPNs displayed better tumor targeting and PPI inhibition properties than the comparable small molecule inhibitor in vivo. Kinetics of PPI inhibition for SdPNs were gradual and controllable in contrast to the rapid inhibition kinetics of the small molecule. Because SdPN is modular, any appropriate peptide inhibitor can be incorporated into the platform without concern for the poor pharmacokinetic properties of the peptide.


Assuntos
Depsipeptídeos , Nanoestruturas , Cinética
20.
Chem Soc Rev ; 41(7): 2656-72, 2012 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-22189429

RESUMO

Nanomedicine is the biomedical application of nanoscale materials for diagnosis and therapy of disease. Recent advances in nanotechnology and biotechnology have contributed to the development of multifunctional nanoparticles as representative nanomedicine. They were initially developed to enable the target-specific delivery of imaging or therapeutic agents for biomedical applications. Due to their unique features including multifunctionality, large surface area, structural diversity, and long circulation time in blood compared to small molecules, nanoparticles have emerged as attractive preferences for optimized therapy through personalized medicine. Multimodal imaging and theragnosis are the cutting-edge technologies where the advantages of nanoparticles are maximized. Because each imaging modality has its pros and cons, the integration of several imaging agents with different properties into multifunctional nanoparticles allows precise and fast diagnosis of disease through synergetic multimodal imaging. Moreover, nanoparticles are not only used for molecular imaging but also applied to deliver therapeutic agents to the disease site in order to accomplish the simultaneous imaging and therapy called theragnosis. This tutorial review will highlight the recent advances in the development of multifunctional nanoparticles and their biomedical applications to multimodal imaging and theragnosis as nanomedicine.


Assuntos
Diagnóstico por Imagem , Sistemas de Liberação de Medicamentos , Nanomedicina/métodos , Nanopartículas/química , Humanos
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