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1.
ACS Nano ; 14(4): 4027-4035, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32223215

RESUMO

Dynamic controlling the nanoscale presentation of synergistic ligands to stem cells by biomimetic single-chain materials can provide critical insights to understand the molecular crosstalk underlying cells and their extracellular matrix. Here, a stimuli-responsive single-chain macromolecular nanoregulator with conformational dynamics is fabricated based on an advanced scale-up single polymeric chain nanogel (SCNG). Such a carefully designed SCNG is capable of mediating a triggered copresentation of the master and cryptic ligands in a single molecule to elicit the synergistic crosstalk between different intracellular signaling pathways, thereby considerably boosting the bioactivity of the presented ligands. This controllable nanoswitching-on of cell-adhesive ligands' presentation allows the regulation of cell adhesion and fate from molecular scale. The modular nature of this synthetic macromolecular nanoregulator makes it a versatile nanomaterial platform to assist basic and fundamental studies in a wide array of research topics.

2.
J Control Release ; 320: 392-403, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32004587

RESUMO

Iron-based nanomaterials as the main ferroptosis-inducing platforms are more promising because iron itself is a key component in the Fenton reaction to produce ROS. However, the Fe dose needs to be very high in order to induce ferroptosis-based cancer treatment using the SPIO NPs. Therefore, it is still of great challenge to enhance the efficacy of ferroptosis-based cancer therapy by associating the iron-based nanomaterials with other components and therapeutic modalities. In this study, sorafenib (SRF) and ultrasmall SPIO nanoparticles were loaded into the mesopores and onto the surface of MPDA NPs to form SRF@MPDA-SPIO nanoparticles. SPIO loading endowed the system with iron-supply for ferroptosis and made the system MRI-visible. Meanwhile, SRF was able to induce ferroptosis in cancer cells with lower Fe dose. Furthermore, the heat generated by MPDA NPs upon laser irradiation offered a moderate PTT to boost the ferroptosis effect. The SRF@MPDA-SPIO exhibited biocompatibility highly desirable for in vivo application and superior anticancer therapy via the combination of ferroptosis and photothermal therapy.

3.
Sci Adv ; 6(6): eaay7785, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32076650

RESUMO

The response to programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) blockade in cancer immunotherapy is limited because of multiple immune evasion mechanisms. Here, a previously unknown strategy is proposed to synergize the nuclear factor κB (NF-κB) inhibition and PD-1 blockade for antitumor immunotherapy. A dual pH-sensitive nanocarrier loading curcumin (CUR) and anti-PD-1 monoclonal antibody (aPD-1) may bind to circulating PD-1+ T cells and then follow their infiltration into the tumor. Furthermore, the nanodrug bound to PD-1+ T cells may be released in the tumor microenvironment, leaving aPD-1 to block PD-1 on T cells and generating a CUR-encapsulated cationic nanodrug that can be easily taken up by tumor cells/tumor associated macrophages (TAMs). Thus, not only the antitumor T cells mediate efficient CUR delivery to tumor but also the efficient CUR delivery promotes the tumor infiltration of antitumor T cells, thereby resulting in effective activation of antitumor immunity.

4.
Small ; 16(7): e1906832, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31990457

RESUMO

Immune checkpoint blockade (ICB) is demonstrating great potential in cancer immunotherapy nowadays. Yet, the low response rate to ICB remains an urgent challenge for tumor immunotherapy. A pH and matrix metalloproteinase dual-sensitive micellar nanocarrier showing spatio-temporally controlled release of anti-PD-1 antibody (aPD-1) and paclitaxel (PTX) in solid tumors is prepared to realize synergistic cancer chemoimmunotherapy. Antitumor immunity can be activated by PTX-induced immunogenic cell death (ICD), while aPD-1 blocks the PD-1/PD-L1 axis to suppress the immune escape due to PTX-induced PD-L1 up-regulation, thus resulting in a synergistic antitumor chemoimmunotherapy. Through decoration with a sheddable polyethylene glycol (PEG) shell, the nanodrug may better accumulate in tumors to boost the synergistic antitumor treatment in a mouse melanoma model. The present study demonstrates a potent antitumor chemoimmunotherapy utilizing tumor microenvironment-sensitive micelles bearing a sheddable PEG layer to mediate site-specific sequential release of aPD-1 and PTX.

5.
Mol Pharm ; 17(3): 817-826, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31910019

RESUMO

Biomedical nanoplatforms have been widely investigated for ultrasound (US) imaging and cancer therapy. Herein, perfluorocarbon (PFC) is encapsulated into biocompatible polydopamine (PDA) to form a theranostic nanosystem, followed by the modification of polyethylene glycol (PEG) to stabilize the nanoparticle via a facile one-pot method. Under 808 nm near-infrared laser irradiation, PDA can generate hyperthermia to transform PFC droplets to bubbles with high US imaging sensitivity. The US imaging detection of the PFC-PDA-PEG nanosystem is achievable in a time span of up to 25 min in vitro at a low US frequency and mechanical index, manifesting a US imaging performance for in vivo application. Moreover, tumor cells incubated with the nanosystem are ablated effectively under laser irradiation at 808 nm. The results illustrate the potential of the PDA-based theranostic agent in US imaging-guided photothermal therapy of tumor.

6.
J Mater Chem B ; 7(40): 6139-6147, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31553351

RESUMO

Glioma, the most severe primary brain malignancy, has very low survival rates and a high level of recurrence. Nowadays, conventional treatments for these patients are suffering a similar plight owing to the distinctive features of the malignant gliomas, for example chemotherapy is limited by the blood-brain barrier while surgery and radiation therapy are affected by the unclear boundaries of tumor from normal tissue. In the present study, a novel superparamagnetic iron oxide (SPIO) nanoprobe for enhanced T2-weighted magnetic resonance imaging (MRI) was developed. A frequently used MRI probe, SPIO nanoparticles, was coated with a silica outer layer and for the first time was covalently modified with interleukin-6 receptor targeting peptides (I6P7) to promote transportation through the blood-brain barrier and recognition of low-grade gliomas. The efficiency of transcytosis across the blood-brain barrier was examined in vitro using a transwell invasion model and in vivo in nude mice with orthotopic low-grade gliomas. The targeting nanoprobe showed significant MRI enhancement and has potential for use in the diagnosis of low-grade gliomas.

7.
J Mater Chem B ; 7(32): 4953-4962, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31411627

RESUMO

Malignant solid tumors are composed of tumor cells, stromal cells and the complex networks of the tumor microenvironment (TME), which is the underlying cause of the unsatisfactory outcome of conventional chemotherapy approaches only aimed at cancer cell killing. In this study, a novel TME-responsive polymeric micelle has been developed for the programmed site-specific delivery of the angiostatin sunitinib and chemotherapeutic paclitaxel (PTX). The pH-sensitive micelle core encapsulates PTX, while ß-cyclodextrin molecules being conjugated to the micelle shell via matrix metalloproteinase 2 (MMP-2) sensitive peptides include sunitinib. Following the pH and MMP-2 dual sensitive structure design, the micelle may sequentially release sunitinib inside the tumor extracellular matrix and PTX into cancer cells through responding to enriched MMP-2 levels and decreased pH, respectively. Consequently, the anti-angiogenesis effect of sunitinib and tumor cell-killing effect of PTX synergize, resulting in highly efficient tumor treatment.

8.
Adv Sci (Weinh) ; 6(16): 1900037, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31453054

RESUMO

Hypoxia leads to up-regulation of PD-L1 and decreases T lymphocyte infiltration, thus boosting immunotherapeutic resistance of tumors. Moreover, tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) correlate with potent immune suppressive activity and resistance to the immune checkpoint blocking (ICB) in tumor sites. Here, a multifunctional nanoregulator incorporating MnO2 particles and small molecular IPI549 is developed, which can reshape the tumor immune microenvironment (TIME) to unleash the immune system. The intravenously administered nanoregulator effectively accumulates in tumor sites to alleviate hypoxia via oxygen-generating reduction of MnO2 and to inhibit PI3Kγ on MDSCs via IPI549 release in the tumor microenvironment (TME), which results in concurrent downregulation of PD-L1 expression, polarization of tumor associated macrophages (TAMs) toward pro-inflammatory M1-like phenotype (tumor-suppressive), enhanced infiltration of CD4+ helper T lymphocytes (Th cells), and cytotoxic CD8+ T lymphocytes (Tc cells), and suppressed infiltration of regulatory T lymphocytes (Treg cells) for effective tumor immunotherapy. Furthermore, the local generation of Mn2+ in TME allows tumor-specific magnetic resonance imaging (MRI). More excitingly, the nanoregulator-reshaped TIME is effectively reserved due to the synergistic effect of hypoxia alleviation and MDSC PI3Kγ inhibition, leading to remarkable post-medication inhibition of tumor re-growth and metastasis in an animal study.

9.
Biomater Sci ; 7(9): 3821-3831, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31268075

RESUMO

Minimal drug leakage during blood circulation and intracellular drug delivery in tumor sites are of great significance in chemotherapeutics. Herein we propose an interlayer crosslinked polymeric micelle with tumor acidity and reduction dual sensitivity for highly efficient drug delivery to cancer cells. A novel copolymer mPEG-C[double bond, length as m-dash]N-PAsp(MEA)-CA was synthesized and self-assembled into a dual-sensitive interlayer-crosslinked micelle (ICM). The micelle was composed of a tumor acidity sheddable PEG outer layer, a reduction-sensitive disulfide-crosslinked interlayer (PAsp(MEA)) and a hydrophobic core of cholic acid (CA) for doxorubicin (DOX) delivery. The nano-sized ICM was stable and showed little drug leakage in a neutral physiological environment. In tumor microenvironments (TMEs) with mild acidity, the PEG outer layer was readily detached due to the hydrolysis of the Schiff base linker, and the surface of the ICM was switched to positively charged to enhance the cellular uptake. Furthermore, inside tumor cells DOX was rapidly released due to the reduction of disulfide bonds by glutathione (GSH). The DOX-loaded ICM exhibited an effective anticancer effect against C6 glioma and reduced side effects both in vitro and in vivo. The study reveals that this pH and reduction dual-sensitive micelle may have great potential to mediate effective anticancer therapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Nanopartículas/química , Polímeros/química , Microambiente Tumoral/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Micelas , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Imagem Óptica , Oxirredução , Relação Estrutura-Atividade , Células Tumorais Cultivadas
11.
Adv Healthc Mater ; 8(16): e1900409, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148393

RESUMO

Photothermal therapy (PTT) as an emerging technique for cancer treatment has drawn great attention owing to its minimally invasive nature. However, it is difficult to achieve a complete tumor regression due to the heterogeneous heat distribution over the tumor. Application of photothermal conversion agents may enhance PTT efficiency, and a multifunctional imaging may provide guidance for the implementation of PTT. Herein, an L-menthol/IR-780 loaded liposome (MIL) is prepared to achieve NIR-triggered cavitation for enhancing photothermal ablation. The synthesized MIL possesses outstanding colloidal stability and photoacoustic/near infrared fluorescence/ultrasound (PA/NIRF/US) imaging contrast to offer multimodal imaging-guided photothermal therapy of cancer. Upon irradiation, the IR-780 acts as the photoabsorber to convert NIR light into heat energy. More importantly, the produced hyperthermia can not only induce ablation of tumor cells but also trigger vaporization and bubbling of encapsulated L-menthol (menthol). Consequently, the generated menthol bubbles obviously enhance the US imaging signal and promote photothermal ablation of the tumor.

12.
ACS Nano ; 13(6): 7036-7049, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31141661

RESUMO

Among various inflammatory factors/mediators, autocrine and paracrine prostaglandin 2 (PGE2), which are abundant in various tumors, promote the proliferation and chemoresistance of cancer cells. Thus, eliminating the cytoprotective effect of PGE2 may strengthen the antitumor effect of chemotherapy. Chemo/anti-inflammatory combination therapy requires the programmed activities of two different kinds of drugs that critically depend on their spatiotemporal manipulation inside the tumor. Here, a micellar polymeric nanosphere, encapsulating chemotherapeutic paclitaxel (PTX) in the core and conjugating anti-inflammatory celecoxib (CXB) to the shell through a peptide linker (PLGLAG), was developed. The PLGLAG linker was cleavable by the enzyme matrix metalloproteinase-2 (MMP-2) in the tumor tissue, causing CXB release and turning the negatively charged nanosphere into a positively charged one to facilitate PTX delivery into cancer cells. The released CXB not only acted on cyclooxygenase-2 (COX-2) to suppress the production of pro-inflammatory PGE2 in multiple cell types but also suppressed the expression of the anti-apoptotic Bcl-2 gene to sensitize cancer cells to chemotherapy, thus resulting in a synergistic anticancer effect of PTX and CXB. This study represents an example of using a surface charge-switchable nanosphere with on-demand drug release properties to act on multiple cell types for highly effective chemo/anti-inflammatory combination therapy of cancer.

13.
Adv Sci (Weinh) ; 6(5): 1801809, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30886803

RESUMO

Liver fibrosis, as one of the leading causes of liver-related morbidity and mortality, has no Food and Drug Administration (FDA)-approved antifibrotic therapy yet. Although microRNA-29b (miRNA-29b) and microRNA-122 (miRNA-122) have great potential in treating liver fibrosis via regulating profibrotic genes in hepatic stellate cells (HSCs), it is still a challenge to achieve a HSC-targeted and meanwhile noninvasively trackable delivery of miRNAs in vivo. Herein, a pH-sensitive and vitamin A (VA)-conjugated copolymer VA-polyethylene glycol-polyethyleneimine-poly(N-(N',N'-diisopropylaminoethyl)-co-benzylamino) aspartamide (T-PBP) is synthesized and assembled into superparamagnetic iron oxide (SPIO)-decorated cationic micelle for miRNA delivery. The T-PBP micelle efficiently transports the miRNA-29b and miRNA-122 to HSC in a magnetic resonance imaging-visible manner, resulting in a synergistic antifibrosis effect via downregulating the expression of fibrosis-related genes, including collagen type I alpha 1, α-smooth muscle actin, and tissue inhibitor of metalloproteinase 1. Consequently, the HSC-targeted combination therapy with miRNA-29b and miRNA-122 demonstrates a prominent antifibrotic efficacy in terms of improving liver function and relieving hepatic fibrosis.

14.
Biomater Sci ; 7(4): 1529-1542, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30681081

RESUMO

Emerging pH-sensitive polymeric nanocarriers carrying therapeutic drugs are bringing about new opportunities for the effective treatment of cancer. A big challenge remains though to develop pH-sensitive polymers, which is hard to achieve via introducing only one kind of pH-sensitive chemical structure with a specific pKa. Consequently, in this study, an amphiphilic block copolymer, poly(ethylene glycol)-b-poly(ß-benzyl l-aspartate) (mPEG-PBLA), was synthesized, and its PBLA block was aminolyzed by N,N-diisopropylamino ethylamine (DIP) and N,N-dibutalamino ethylamine (DBA) at different molar ratios. The copolymer mPEG-PAsp(DBA75%&DIP25%) (PPAP75%) with an appropriate pKa was screened out to form a pH-sensitive micelle, which could encapsulate a high content of the hydrophobic anticancer drug doxorubicin (DOX) and magnetic resonance imaging (MRI) contrast agent superparamagnetic iron oxide nanoparticles (SPIONs) at neutral pH, but disassemble rapidly under weak acidic conditions. The micellar nanodrug was efficiently taken up by HepG2 cells and intracellular DOX release was readily triggered inside acidic lysosomal compartments to allow migration of the free drug to the cell nucleus. In vivo fluorescence and MR bimodal imaging showed that the pegylated nanodrug with a suitable size and weak positive charge could stay longer in the blood circulation and extravasate preferentially into a tumor. The nanodrug not only exhibited high cytotoxicity in HepG2 cells but also significantly prolonged the survival time of tumor-bearing mice, thereby demonstrating the great potential of this pH-sensitive and MRI-visible micelle for the effective treatment of cancer.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Imagem por Ressonância Magnética , Animais , Antibióticos Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/diagnóstico por imagem , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/diagnóstico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Imagem Óptica , Células Tumorais Cultivadas
15.
Nanotechnology ; 30(1): 015101, 2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30370902

RESUMO

Various nanoformulations of perfluorocarbon have been developed thus far, to achieve ultrasound imaging of tumors and tumor-targeted therapy. However, their application has been greatly limited by their short sonographic duration and large size distribution. A novel theranostic agent was constructed based on gold nanoshell cerasome-encapsulated L-menthol (GNC-LM). Owing to the sustained and controllable generation of L-menthol bubbles under near-infrared laser irradiation, GNC-LM showed good performance in contrast enhancement of ultrasound imaging in vivo. GNC-LM could be imaged for 30 min, which is much longer than the imaging time of SonoVue (commercially used microbubbles). Moreover, photothermal therapy (PTT) based on the light-to-heat conversion of the nanosystem effectively ablated the tumor. Our study demonstrated the promising potential of the obtained GNC-LM to serve as a therapeutic nanoprobe for ultrasound contrast imaging and PTT of tumors.


Assuntos
Meios de Contraste/química , Ouro/química , Hipertermia Induzida , Lipídeos/química , Mentol/química , Nanoconchas/química , Neoplasias/terapia , Fototerapia , Animais , Morte Celular , Camundongos Endogâmicos BALB C , Nanoconchas/ultraestrutura , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Ultrassonografia
16.
Nat Commun ; 9(1): 3430, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143633

RESUMO

There exists an urgent medical demand at present to develop therapeutic strategies which can improve the treatment outcome of hepatocellular carcinoma (HCC). Here, we explore the biological functions and clinical significance of PBOV1 in HCC in order to push forward the diagnosis and treatment of HCC. Using theranostical nanomedicines, PBOV1 is verified to be a key oncogene which greatly promotes HCC proliferation, epithelial-to-mesenchymal transition, and stemness by activating the Wnt/ß-catenin signaling pathway. Therefore, single-chain antibody for epidermal growth factor receptor (scAb-EGFR)-targeted nanomedicine effectively silencing the PBOV1 gene exhibits potent anticancer effects. In vivo HCC-targeting siRNA delivery mediated by the theranostical nanomedicine remarkably inhibits the tumor growth and metastasis. In addition, the superparamagnetic iron oxide nanocrystals (SPION)-encapsulated nanomedicines possess high MRI detection sensitivity, which endows them with the potential for MRI diagnosis of HCC. This study shows that PBOV1 represents a prognostic biomarker and therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Terapia Genética/métodos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Nanomedicina/métodos , Proteínas de Neoplasias/metabolismo , Carcinoma Hepatocelular/genética , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Marcação In Situ das Extremidades Cortadas , Neoplasias Hepáticas/genética , Imagem por Ressonância Magnética , Microscopia de Fluorescência , Proteínas de Neoplasias/genética , Cicatrização/genética , Cicatrização/fisiologia
17.
ACS Appl Mater Interfaces ; 10(34): 28471-28482, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30067011

RESUMO

The inexpensive hypolipidemic drug simvastatin (SIM), which promotes bone regeneration by enhancing bone morphogenetic protein 2 (BMP-2) expression, has been regarded as an ideal alternative to BMP-2 therapy. However, SIM has low bioavailability and may induce the upregulation of the BMP-2-antagonistic noggin protein, which greatly limits the osteogenic effect. Here, a pH-sensitive copolymer, monomethoxy-poly(ethylene glycol)- b-branched polyethyleneimine- b-poly( N-( N', N'-diisopropylaminoethyl)- co-benzylamino)aspartamide (mPEG-bPEI-PAsp(DIP-BzA)) (PBP), was synthesized and self-assembled into a cationic micelle. SIM and siRNA targeting the noggin gene (N-siRNA) were loaded into the PAsp(DIP-BzA) core and the cationic bPEI interlayer of the micelle via hydrophobic and electrostatic interactions, respectively. The SIM-loaded micelle effectively delivered SIM into preosteoblast MC3T3-E1 cells and rapidly released it inside the acidic lysosome, resulting in the elevated expression of BMP-2. Meanwhile, the codelivered N-siRNA effectively suppressed the expression of noggin. Consequently, SIM and N-siRNA synergistically increased the BMP-2/noggin ratio and resulted in an obviously higher osteogenetic effect than did simvastatin or N-siRNA alone, both in vitro and in vivo.


Assuntos
Sinvastatina/química , Regeneração Óssea , Diferenciação Celular , Concentração de Íons de Hidrogênio , Osteogênese , RNA Interferente Pequeno
18.
Nanomedicine ; 14(7): 2215-2226, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29964220

RESUMO

Inflammation and oxidative stress are two major factors that are involved in the pathogenesis of atherosclerosis. A smart drug delivery system that responds to the oxidative microenvironment of atherosclerotic plaques was constructed in the present study. Andrographolide-loaded micelle was assembled from the block copolymer of poly(ethylene glycol) and poly(propylene sulphide) (PEG-PPS) for the purpose of simultaneously decreasing inflammatory response and the level of reactive oxygen species (ROS) to treat atherosclerosis. Owing to the ROS-responsive nature of PEG-PPS, the micelle not only serves as a stimuli-responsive drug carrier to quickly release the encapsulated drug, andrographolide, but also consumes ROS by itself at the pathologic sites, upon which the expressions of pro-inflammatory cytokines are effectively suppressed and oxidative stress is alleviated. Consequently, the andrographolide-loaded micelle demonstrated remarkable therapeutic effects both in vitro and in vivo. In conclusion, the andrographolide-loaded PEG-PPS micelle can synchronically alleviate inflammation and oxidative stress, providing a promising and innovative strategy against atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Diterpenos/farmacologia , Sistemas de Liberação de Medicamentos , Inflamação/tratamento farmacológico , Placa Aterosclerótica/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Animais , Aorta/patologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Diterpenos/administração & dosagem , Diterpenos/química , Portadores de Fármacos/química , Feminino , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos Knockout para ApoE , Micelas , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Polietilenoglicóis/química , Polímeros/administração & dosagem , Polímeros/química
19.
Int J Nanomedicine ; 13: 3467-3480, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29942129

RESUMO

Background: The treatment of glioma remains a challenge because conventional chemotherapy is often ineffective by drug resistance. Combinative therapy using chemotherapeutic agents and siRNA has demonstrated potential to improve anticancer outcome through a synergistic effect in various cancers. The current study aims to achieve better glioma treatment through a combinative therapy based on a folate-targeted nanocarrier carrying both temozolomide (TMZ) and anti-BCL-2 siRNA. Methods: A polymeric micelle (TMZ-FaPEC@siRNA) incorporating TMZ and anti-BCL-2 siRNA was prepared based on folate-conjugated triblock copolymer (Fa-PEG-PEI-PCL, Fa-PEC) of poly(ε-caprolactone) (PCL), poly(ethylenimine) (PEI) and poly(ethylene glycol) (PEG). The physicochemical properties and drug release profile of TMZ-FaPEC@siRNA were tested. The Fa-targeted drug delivery and joint effect of siRNA and TMZ to induce glioma apoptosis and tumor growth inhibition were evaluated both in vitro and in vivo. Results: In vitro cell study demonstrated that the nanocarrier effectively facilitates codelivery of siRNA and TMZ into C6 cells, resulting in a strong apoptotic response of cancer cells by silencing the antiapoptosis BCL-2 gene and activating the proapoptotic Bax gene simultaneously. In vivo study in rat bearing orthotropic glioma showed that tumor growth was inhibited and meanwhile animal survival was prolonged remarkably through intracranial injection of TMZ-FaPEC@siRNA. Conclusion: Our results evidence the strong efficacy of the folate-targeted nanomedicine carrying TMZ and BCL-2 siRNA in treating glioma.


Assuntos
Dacarbazina/análogos & derivados , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Nanopartículas/química , Polímeros/química , RNA Interferente Pequeno/administração & dosagem , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Ácido Fólico/química , Inativação Gênica , Genes bcl-2 , Humanos , Micelas , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Polietilenoimina/química , Espectroscopia de Prótons por Ressonância Magnética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Eletricidade Estática , Temozolomida
20.
Nanoscale ; 10(23): 10991-10998, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29856460

RESUMO

The development of a simple and straightforward strategy to synthesize multifunctional carbon dots for photodynamic therapy (PDT) has been an emerging focus. In this work, diketopyrrolopyrrole-based fluorescent carbon dots (DPP CDs) were designed and synthesized through a facile one-pot hydrothermal method by using diketopyrrolopyrrole (DPP) and chitosan (CTS) as raw materials. DPP CDs not only maintained the ability of DPP to generate singlet oxygen (1O2) but also have excellent hydrophilic properties and outstanding biocompatibility. In vitro and in vivo experiments demonstrated that DPP CDs greatly inhibited the growth of tumor cells under laser irradiation (540 nm). This study highlights the potential of the rational design of CDs for efficient cancer therapy.


Assuntos
Carbono/química , Neoplasias Experimentais/tratamento farmacológico , Fotoquimioterapia , Pontos Quânticos , Animais , Quitosana , Feminino , Células Hep G2 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cetonas , Camundongos , Pirróis , Ensaios Antitumorais Modelo de Xenoenxerto
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