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1.
Nat Commun ; 11(1): 4907, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999289

RESUMO

Global alterations in the metabolic network provide substances and energy to support tumor progression. To fuel these metabolic processes, extracellular matrix (ECM) plays a dominant role in supporting the mass transport and providing essential nutrients. Here, we report a fibrinogen and thrombin based coagulation system to construct an artificial ECM (aECM) for selectively cutting-off the tumor metabolic flux. Once a micro-wound is induced, a cascaded gelation of aECM can be triggered to besiege the tumor. Studies on cell behaviors and metabolomics reveal that aECM cuts off the mass transport and leads to a tumor specific starvation to inhibit tumor growth. In orthotopic and spontaneous murine tumor models, this physical barrier also hinders cancer cells from distant metastasis. The in vivo gelation provides an efficient approach to selectively alter the tumor mass transport. This strategy results in a 77% suppression of tumor growth. Most importantly, the gelation of aECM can be induced by clinical operations such as ultrasonic treatment, surgery or radiotherapy, implying this strategy is potential to be translated into a clinical combination regimen.


Assuntos
Materiais Biomiméticos/administração & dosagem , Matriz Extracelular/química , Neoplasias/terapia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/efeitos da radiação , Materiais Biomiméticos/química , Materiais Biomiméticos/efeitos da radiação , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia/métodos , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos da radiação , Feminino , Fibrinogênio/administração & dosagem , Fibrinogênio/química , Fibrinogênio/efeitos da radiação , Géis , Humanos , Injeções Intravenosas , Metabolômica , Camundongos , Neoplasias/metabolismo , Trombina/administração & dosagem , Trombina/química , Trombina/efeitos da radiação , Terapia por Ultrassom/métodos , Ondas Ultrassônicas
2.
Artigo em Inglês | MEDLINE | ID: mdl-32779303

RESUMO

By leveraging the ability of Shewanella oneidensis MR-1 (S. oneidensis MR-1) to anaerobically catabolize lactate through the transfer of electrons to metal minerals for respiration, a lactate-fueled biohybrid (Bac@MnO2 ) was constructed by modifying manganese dioxide (MnO2 ) nanoflowers on the S. oneidensis MR-1 surface. The biohybrid Bac@MnO2 uses decorated MnO2 nanoflowers as electron receptor and the tumor metabolite lactate as electron donor to make a complete bacterial respiration pathway at the tumor sites, which results in the continuous catabolism of intercellular lactate. Additionally, decorated MnO2 nanoflowers can also catalyze the conversion of endogenous hydrogen peroxide (H2 O2 ) into generate oxygen (O2 ), which could prevent lactate production by downregulating hypoxia-inducible factor-1α (HIF-1α) expression. As lactate plays a critical role in tumor development, the biohybrid Bac@MnO2 could significantly inhibit tumor progression by coupling bacteria respiration with tumor metabolism.

3.
Sci Adv ; 6(23): eabb0020, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32548273

RESUMO

Although vascular disrupting agents (VDAs) have been extensively implemented in current clinical tumor therapy, the notable adverse events caused by long-term dosing severely limit the therapeutic efficacy. To improve this therapy, we report a strategy for VDA-induced aggregation of gold nanoparticles to further destroy tumor vascular by photothermal effect. This strategy could effectively disrupt tumor vascular and cut off the nutrition supply after just one treatment. In the murine tumor model, this strategy results in notable tumor growth inhibition and gives rise to a 92.7% suppression of tumor growth. Besides, enhanced vascular damage could also prevent cancer cells from distant metastasis. Moreover, compared with clinical therapies, this strategy still exhibits preferable tumor suppression and metastasis inhibition ability. These results indicate that this strategy has great potential in tumor treatment and could effectively enhance tumor vascular damage and avoid the side effects caused by frequent administration.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32374492

RESUMO

Nanotheranostic agents (NTAs) that integrate diagnostic capabilities and therapeutic functions have great potential for personalized medicine, yet poor tumor specificity severely restricts further clinical applications of NTAs. Here, a pro-NTA (precursor of nanotheranostic agent) activation strategy is reported for in situ NTA synthesis at tumor tissues to enhance the specificity of tumor therapy. This pro-NTA, also called PBAM, is composed of an MIL-100 (Fe)-coated Prussian blue (PB) analogue (K2 Mn[Fe(CN)6 ]) with negligible absorption in the near-infrared region and spatial confinement of Mn2+ ions. In a mildly acidic tumor microenvironment (TME), PBAM can be specifically activated to synthesize the photothermal agent PB nanoparticles, with release of free Mn2+ ions due to the internal fast ion exchange, resulting in the "ON" state of both T1 -weighted magnetic resonance imaging and photoacoustic signals. In addition, the combined Mn2+ -mediated chemodynamic therapy in the TME and PB-mediated photothermal therapy guarantee a more efficient therapeutic performance compared to monotherapy. In vivo data further show that the pro-NTA activation strategy could selectively brighten solid tumors and detect invisible lymph node metastases with high specificity.

5.
Nat Commun ; 11(1): 1985, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332752

RESUMO

The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy. Here, we generate a vaccine-based nanosystem by integrating siRNA for Cd274 into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein. This nanosystem has good biosafety and enhances the therapeutic response rate of anti-tumor immunotherapy. The HPV16 L1 protein activates innate immunity through the type I interferon pathway and exhibits an efficient anti-cancer effect when cooperating with ICB therapy. For both resectable and unresectable breast tumors, the nanosystem decreases 71% tumor recurrence and extends progression-free survival by 67%. Most importantly, the nanosystem successfully induces high response rates in various genetically modified breast cancer models with different antigen loads. The strong immune stimulation elicited by this vaccine-based nanosystem might constitute an approach to significantly improve current ICB immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Nanopartículas/administração & dosagem , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Humanos , Imunidade Inata/genética , Camundongos , Recidiva Local de Neoplasia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Intervalo Livre de Progressão , RNA Interferente Pequeno/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-32147886

RESUMO

Effective reversal of tumor immunosuppression is of critical importance in cancer therapy. A multifunctional delivery vector that can effectively deliver CRISPR-Cas9 plasmid for ß-catenin knockout to reverse tumor immunosuppression is constructed. The multi-functionalized delivery vector is decorated with aptamer-conjugated hyaluronic acid and peptide-conjugated hyaluronic acid to combine the tumor cell/nuclear targeting function of AS1411 with the cell penetrating/nuclear translocation function of TAT-NLS. Due to the significantly enhanced plasmid enrichment in malignant cell nuclei, the genome editing system can induce effective ß-catenin knockout and suppress Wnt/ß-catenin pathway, resulting in notably downregulated proteins involved in tumor progression and immunosuppression. Programmed death-ligand 1 (PD-L1) downregulation in edited tumor cells not only releases the PD-1/PD-L1 brake to improve the cancer killing capability of CD8+ T cells, but also enhances antitumor immune responses of immune cells. This provides a facile strategy to reverse tumor immunosuppression and to restore immunosurveillance and activate anti-tumor immunity.

7.
Anal Chem ; 92(2): 2088-2096, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31855408

RESUMO

To enhance the specificity and sensitivity of molecular beacons (MBs) in detecting mRNA in living tumor cells, we introduced an aptamer (AS1411) to the delivery system of MBs to form an aptamer-decorated nanoprobe (ANP), which was prepared through self-assembly between AS1411-conjugated carboxymethyl chitosan (ACMC) with protamine sulfate (PS)/CaCO3/MB cores. Owing to the specific binding of AS1411 to nucleolin, which is overexpressed in tumor cell membranes and nuclei, an AS1411-decorated MB-delivery system leads to dramatically increased cell uptake of MBs for probing survivin mRNA and thus induces strong intracellular fluorescence emission in targeted tumorous cells and cell nuclei. Furthermore, we demonstrate that ANP can efficiently detect survivin mRNA in mitochondria. In other words, the effective delivery of MBs ensures the precise detection of mRNA distribution in diverse organelles. In addition, we evaluated the efficiency of ANP in probing tumor cells in simulated blood as well as in peripheral blood from a healthy donor and found that the nanoprobe can specifically deliver MBs to tumor cells and identify tumor cells in blood. The targeting delivery system we constructed holds promising applications in precise detection of subcellular distribution of mRNA in living tumor cells as well as in fluorescence-guided cancer detection in liquid biopsy technology. This study provides a facile strategy to effectively improve the specificity and sensitivity of conventional molecular beacons.

8.
ACS Appl Mater Interfaces ; 11(42): 38385-38394, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31556589

RESUMO

To enhance the treatment efficiency in tumor therapy, we developed a tumor-targeting protein-based delivery system, DOX&ICG@BSA-KALA/Apt, to efficiently integrate multimodal therapy with tumor imaging and realize synchronous photodynamic therapy/photothermal therapy/chemotherapy. In the delivery system, a chemotherapeutic drug (doxorubicin, DOX) and an optotheranostic agent (indocyanine green, ICG) were co-loaded in bovine serum albumin (BSA) via a hydrophobic-interaction-induced self-assembly to form stable DOX&ICG@BSA nanoparticles. After the decoration of a surface layer composed of a tumor-targeting aptamer (AS1411) and a cell-penetrating peptide (KALA), the obtained DOX&ICG@BSA-KALA/Apt nanoparticles exhibit a significantly improved multimodal cancer therapeutic efficiency due to the enhanced cancer cellular uptake mediated by AS1411 and KALA. In vitro and in vivo studies show that the multimodal theranostic system can efficiently inhibit tumor growth. In addition, the near-infrared fluorescent/photothermal dual-mode imaging enables accurate visualization of the therapeutic action in tumor sites. This study provides a facile strategy to construct self-assembled multimodal theranostic systems, and the functional protein-based theranostic system prepared holds great promise in multimodal cancer therapeutics.


Assuntos
Doxorrubicina/química , Portadores de Fármacos/química , Verde de Indocianina/química , Nanopartículas/química , Soroalbumina Bovina/química , Animais , Aptâmeros de Nucleotídeos/química , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos/química , Oxigênio Singlete/química , Propriedades de Superfície , Nanomedicina Teranóstica , Distribuição Tecidual
9.
Nat Biomed Eng ; 3(9): 717-728, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31332342

RESUMO

The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the higher concentration of the pro-tumoural Fusobacterium nucleatum and the absence of antineoplastic butyrate-producing bacteria in the faecal microbiota of patients with CRC, we show that-in mice with orthotopic colorectal tumours or with spontaneously formed colorectal tumours-oral or intravenous administration of irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages that inhibit the growth of F. nucleatum significantly augments the efficiency of first-line chemotherapy treatments of CRC. We also show that oral administration of the phage-guided irinotecan-loaded nanoparticles in piglets led to negligible changes in haemocyte counts, immunoglobulin and histamine levels, and liver and renal functions. Phage-guided nanotechnology for the modulation of the gut microbiota might inspire new approaches for the treatment of CRC.


Assuntos
Bactérias/efeitos dos fármacos , Bactérias/virologia , Bacteriófagos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/microbiologia , Tratamento Farmacológico/métodos , Microbioma Gastrointestinal/fisiologia , Animais , Antineoplásicos/uso terapêutico , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Butiratos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/microbiologia , Neoplasias Colorretais/patologia , Dextranos , Modelos Animais de Doenças , Fusobacterium nucleatum/efeitos dos fármacos , Fusobacterium nucleatum/crescimento & desenvolvimento , Fusobacterium nucleatum/metabolismo , Fusobacterium nucleatum/virologia , Microbioma Gastrointestinal/efeitos dos fármacos , Imunoglobulinas , Irinotecano/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas
10.
ACS Appl Mater Interfaces ; 11(27): 23870-23879, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31257851

RESUMO

A multiple-functionalized targeting delivery system was prepared by self-assembly for efficient delivery of Cas9/sgRNA plasmids to targeted tumor cell nuclei. The Cas9/sgRNA plasmids were compacted by protamine in the presence of calcium ions to form nanosized cores, which were further decorated by peptide and aptamer conjugated alginate derivatives. With the help of the nuclear location signal peptide and AS1411 aptamer with specific affinity for nucleolin in the tumor cell membrane and nuclei, the delivery vector can specifically deliver the plasmid to the nuclei of tumorous cells for knocking out the protein tyrosine kinase 2 (PTK2) gene to down-regulate focal adhesion kinase (FAK). The tumor cell apoptosis induced by genome editing is mitochondrial-dependent. In addition, FAK knockout results in negative regulation on the PI3K/AKT signaling pathway. Meanwhile, favorable modulation on various proteins involved in tumor progression can be realized by genome editing. The enhanced E-cadherin and decreased MMPs, vimentin, and VEGF imply the desirable effects of genome editing on suppression of tumor development. Wound healing and transwell assays confirm that the genome editing system can suppress tumor invasion and metastasis in edited cells efficiently. The investigation provides a facile and effective strategy to fabricate multiple-functionalized delivery vectors for genome editing.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Técnicas de Transferência de Genes , Neoplasias , Peptídeos , Plasmídeos , Apoptose/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Células HEK293 , Células HeLa , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Peptídeos/química , Peptídeos/farmacologia , Plasmídeos/química , Plasmídeos/genética , Plasmídeos/farmacologia , Transdução de Sinais/genética
11.
Mol Pharm ; 16(6): 2616-2625, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31013098

RESUMO

To efficiently deliver CpG oligodeoxynucleotides (ODNs) to macrophages for the reversal of cancer-induced immunosuppression, nanoparticles ODN@MCBSA with mannosylated cationic albumin (MCBSA) as a macrophage targeting vector were constructed. Compared with ODN@CBSA with cationic albumin (CBSA) as a vector, ODN@MCBSA exhibited significantly improved cellular uptake mediated by mannose moieties, resulting in significantly enhanced secretion of proflammatory cytokines including IL-12, IL-6, TNF-α, and iNOS. The modulation of macrophages toward the favorable M1 phenotype was confirmed by the upregulated CD80 expression after being treated by ODN delivery systems. In addition to immune cells, the effects of the ODN delivery system on cancerous HeLa cells were also investigated. The results showed that ODN@MCBSA did not affect the overall tumor cell viability. However, enhanced NF-κB, p-Akt, PIK3R3, Fas, and FasL, as well as upregulated caspases were observed in tumor cells, implying the pleiotropic effects on tumor cells. Our study provides a more in-depth understanding on the immunotherapeutic effects of CpG ODNs and highlights the importance of macrophage targeting delivery to minimize the effects on tumor cells. These results indicate that MCBSA could serve as a promising delivery vector of CpG ODNs to macrophages for cancer immunotherapy.


Assuntos
Macrófagos/metabolismo , Nanopartículas/química , Oligodesoxirribonucleotídeos/metabolismo , Células HeLa , Humanos , Interleucina-12/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Adv Mater ; 31(16): e1808278, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30803049

RESUMO

Synthetic biology based on bacteria has been displayed in antitumor therapy and shown good performance. In this study, an engineered bacterium Escherichia coli MG1655 is designed with NDH-2 enzyme (respiratory chain enzyme II) overexpression (Ec-pE), which can colonize in tumor regions and increase localized H2 O2 generation. Following from this, magnetic Fe3 O4 nanoparticles are covalently linked to bacteria to act as a catalyst for a Fenton-like reaction, which converts H2 O2 to toxic hydroxyl radicals (•OH) for tumor therapy. In this constructed bioreactor, the Fenton-like reaction occurs with sustainably synthesized H2 O2 produced by engineered bacteria, and severe tumor apoptosis is induced via the produced toxic •OH. These results show that this bioreactor can achieve effective tumor colonization, and realize a self-supplied therapeutic Fenton-like reaction without additional H2 O2 provision.


Assuntos
Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Neoplasias/terapia , Animais , Apoptose , Reatores Biológicos , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Nanopartículas de Magnetita/química , Camundongos Endogâmicos BALB C , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
13.
Biomaterials ; 199: 1-9, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30716690

RESUMO

Although photothermal therapy (PTT) and photodynamic therapy (PDT) are widely commended for tumor treatment recently, they still suffer severe challenges due to the non-specificity of photothermal agents (PTAs)/photosensitizers (PSs) and hypoxic tumor microenvironment. Here, an oxygen independent biomimetic nanoplatform based on carbon sphere dotted with cerium oxide and coated by cell membrane (MCSCe) was designed and synthesized with good biocompatibility, homologous targeting ability, and improved photophysical activity. Notably, MCSCe could realize accumulation of hydrogen peroxide (H2O2) in tumor cells and hyperthermia under single laser (808 nm) irradiation, which were simultaneously utilized by itself to produce more toxic hydroxyl radical (OH). Resultantly, the synergistic therapeutic effect against tumor cells was obtained under near infrared (NIR) laser irradiation.

14.
ACS Appl Mater Interfaces ; 11(1): 226-237, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30540162

RESUMO

Accurate and efficient delivery of genome editing plasmids to targeted cells is of critical importance in genome editing. Herein, we prepared a multifunctional delivery vector with a combination of ligand-mediated selectivity and peptide-mediated transmembrane function to effectively deliver plasmids to targeted cancerous cells. In the delivery system, the clustered regularly interspaced short palindromic repeat-associated Cas9 nuclease (CRISPR-Cas9) plasmid is combined with protamine with membrane and nuclear translocating activities and co-precipitated with CaCO3, which is further decorated by AS1411-functionalized carboxymethyl chitosan and cell penetrating peptide (TAT)-functionalized carboxymethyl chitosan. The AS1411-mediated tumor cell/nuclear targeting and TAT-induced enhanced endocytosis result in obviously increased cellular uptake and nuclear transport. As a result, the CRISPR-Cas9 plasmid can be efficiently delivered to cancer cell nuclei to mediate genome editing, resulting in an efficacious knockout of CTNNB1 gene encoding ß-catenin. More importantly, downregulation of ß-catenin could effectively prevent its enrichment in nuclei and then significantly downregulate the expression of proteins, such as vimentin, Snail, MMP-2, MMP-9, CD44, Nanog, and Oct4 to prevent tumor progression and metastasis. The edited cancerous cells exhibit favorable remodulated properties including inhibited growth, suppressed migration and invasion, and reduced cancer stemness.


Assuntos
Peptídeos Penetradores de Células , Edição de Genes/métodos , Técnicas de Transferência de Genes , Vetores Genéticos , Proteínas de Neoplasias , Neoplasias , Oligodesoxirribonucleotídeos , Plasmídeos , beta Catenina , Proteína 9 Associada à CRISPR , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Vetores Genéticos/farmacologia , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/farmacologia , Plasmídeos/genética , Plasmídeos/metabolismo , Plasmídeos/farmacologia , beta Catenina/genética , beta Catenina/metabolismo
15.
Nanoscale ; 10(45): 21209-21218, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30417194

RESUMO

To effectively reverse tumor malignization by genome editing, a multi-functional self-assembled nanovector for the delivery of a genome editing plasmid specifically to tumor cells was developed. The nanovector core consisting of protamine and calcium carbonate entrapping the CRISPR-Cas9 plasmid is decorated by aptamer incorporated heparin. Owing to a high affinity between a MUC1 specific aptamer and mucin 1 (MUC1) overexpressed in tumor cells as well as the interaction between AS1411 and nucleolin on the tumor cell surface and cell nuclei, the nanovector can target the nuclei of tumorous cells for the knockout of focal adhesion kinase (FAK). Notably, the genome editing mediated by our delivery systems can effectively modulate cell behaviors and thus reverse tumor malignization. Up-regulated p53, p16, p21, E-cadherin, CD80, MICA, MICB and Fas, together with down-regulated MMP-9, vimentin, VEGF, TGF-ß, CD47 and CD133 in genome edited cells indicate that the genome editing system can inhibit cancerous cell growth, prevent tumor invasion and metastasis, reverse tumor-induced immune suppression, and inhibit cancer stemness. More importantly, the edited cells can maintain the modulated cellular function after succeeding subcultures.


Assuntos
Aptâmeros de Nucleotídeos/química , Edição de Genes/métodos , Nanopartículas/química , Aptâmeros de Nucleotídeos/metabolismo , Sistemas CRISPR-Cas/genética , Movimento Celular , Sobrevivência Celular , Portadores de Fármacos/química , Proteína-Tirosina Quinases de Adesão Focal/deficiência , Proteína-Tirosina Quinases de Adesão Focal/genética , Células HEK293 , Células HeLa , Humanos , Microscopia Confocal , Mucina-1/genética , Mucina-1/metabolismo , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
16.
J Control Release ; 291: 90-98, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30339905

RESUMO

For effective regulation of cell behaviors and prevention of tumor development by genome editing, we constructed multi-functional self-assembled nanoparticles based on natural polymers to deliver CRISPR-Cas9 plasmid to tumorous cells. The CRISPR based gene editing plasmid to knockout CDK11 gene was complexed with protamine sulfate, and then the complex was decorated by a multi-functional outer layer composed of an endosomolytic peptide (KALA) and aptamer AS1411 incorporated carboxymethyl chitosan. The resultant multi-functional nanoparticles, which exhibit significantly enhanced delivery efficiency, can specifically deliver the plasmid into tumor cell nuclei owing to the favorable effects of KALA in cellular uptake and endosomal escape, together with the cancer cell and cell nucleus targeting capability of AS1411 ligands. The genome editing mediated by the nanoparticles leads to a dramatic decrease (>75%) in CDK11 expression, which results in further modulation of cancer cells with significant down-regulation of the proteins (MMP-9 and VEGF) involved in tumor development and metastasis as well as up-regulation of the tumor suppressor protein p53. More importantly, the detection of immune-related proteins after genome editing shows that the significantly enhanced Fas, CD80, MICA, MICB, and HLA-1 expression and decreased CD47 and MUC1 expression, indicating the genome editing is favorable for reversal of tumor-induced immunosuppression and prevention of tumor development.


Assuntos
Sistemas CRISPR-Cas , Quinases Ciclina-Dependentes/genética , Edição de Genes/métodos , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Neoplasias/terapia , Terapia Genética/métodos , Vetores Genéticos/uso terapêutico , Humanos , Células MCF-7 , Neoplasias/genética , Plasmídeos/genética , Plasmídeos/uso terapêutico
17.
Nanoscale ; 10(33): 15578-15587, 2018 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-30090893

RESUMO

To achieve effective tumor eradication using anti-tumor immunotherapies, a fusion peptide functionalized gene delivery system for macrophage and tumor targeting delivery of the plasmid DNA encoding the IL-12 gene (pDNA IL-12) was prepared for macrophage re-polarization as well as reversal of cancer immunosuppression. A fusion peptide containing the tuftsin sequence that can interact with Fc receptors and neuropilin-1, and hyaluronic acid (HA) that can interact with CD44 were introduced into the delivery system by self-assembly to form peptide/hyaluronic acid/protamine/CaCO3/DNA nanoparticles (PHNP) with both macrophage targeting and tumor targeting capabilities. PHNP provides an efficient immunoregulation on J774A.1 cells to shift the anti-inflammatory M2 phenotype to the anti-tumor M1 phenotype with enhanced secretion of pro-inflammatory cytokines and increased expression of M1 markers. Owing to the improved delivery efficiency caused by the fusion peptide and HA, the transfection mediated by multi-functional PHNP can up-regulate IL-12 as well as down-regulate IL-10 and IL-4 more effectively as compared with the nanoparticles without HA and/or peptide decoration. More importantly, the gene delivery system can also deliver pDNA IL-12 to targeted cancerous HeLa cells to realize the secretion of IL-12. PHNP not only enables tumorous cells to produce pDNA IL-12, but also down-regulates CD47 and up-regulate CD80 and HLA-1 in the malignant cells, indicating that the gene delivery system can effectively reverse tumor induced immunosuppression.


Assuntos
Polaridade Celular , Técnicas de Transferência de Genes , Interleucina-12/genética , Macrófagos/citologia , Nanopartículas , Animais , Linhagem Celular , Células HEK293 , Células HeLa , Humanos , Receptores de Hialuronatos , Ácido Hialurônico , Camundongos , Neuropilina-1 , Plasmídeos , Protaminas , Receptores Fc , Proteínas Recombinantes de Fusão , Transfecção , Tuftsina , Microambiente Tumoral
18.
Colloids Surf B Biointerfaces ; 171: 24-30, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30005287

RESUMO

Proteins have been extensively explored as versatile nanocarriers for drug delivery due to their complete biocompatibility, ease of surface modification, and lack of toxicity and immunogenicity. In this study, a facile strategy was used to construct aptamer-functionalized albumin-based nanoparticles for effective drug delivery and targeted cancer therapy. A hydrophobic drug, doxorubicin (DOX) was employed to trigger the self-assembly of bovine serum albumin (BSA) to from stable nanoparticles via hydrophobic interaction, and then a tumor targeting aptamer AS1411 was incorporated to the surface of DOX loaded BSA. Due to the specific recognition between AS1411 and its receptor over-expressed on tumor cells, the aptamer-modified nanoparticles show higher cellular uptake and stronger cell inhibitory efficacy against cancerous MCF-7 cells as compared with the nanoparticles without aptamer modification. In addition, DOX loaded aptamer-functionalized nanoparticles can induce more significant down-regulation of Bcl-2 and PCNA as well as up-regulation of pRB, PARP and Bax in MCF-7 cells compared with unmodified nanoparticles, indicating the aptamer modification can induce cell apoptosis more effectively. Besides, aptamer-modified nanoparticles exhibit a significantly improved capability in up-regulating p16, p21 and E-cadherin, and down-regulating EpCAM, vimentin, Snail, MMP-9, CD44 and CD133, implying the favorable effects of drug delivery on the prevention of tumor progression and metastasis.


Assuntos
Antineoplásicos/administração & dosagem , Aptâmeros de Nucleotídeos/química , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Soroalbumina Bovina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Bovinos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Tamanho da Partícula , Propriedades de Superfície
19.
Adv Mater ; 30(27): e1800836, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29782675

RESUMO

With the prominent progress of biomedical engineering, materials with high biocompatibility and versatile functions are urgently needed. So far, hierarchical structures in nature have shed some light on the design of high performance materials both in concept and implementation. Inspired by these, the hierarchical micro-/nanostructures of human hair are explored and human hair is further broken into hierarchical microparticles (HMP) and hierarchical nanoparticles (HNP) with top-down procedures. Compared with commercialized carriers, such as liposomes or albumin nanoparticles, the obtained particles exhibit high hemocompatibility and negligible immunogenicity. Furthermore, these materials also display attentional abilities in the aspects of light absorption and free radical scavenging. It is found that HMP and HNP can prevent skin from UV-induced damage and relieve symptoms of cataract in vitro. Besides, both HMP and HNP show satisfactory photothermal conversion ability. By using microcomputed tomography and intravital fluorescence microscopy, it is found that warfarin-loaded HMP can rescue mice from vein thrombosis. In another aspect, HNP modified with tumor targeted aptamers exhibit dramatic antineoplastic effect, and suppress 96.8% of tumor growth in vivo. Thus, the multifaceted materials described here might provide a new tool for addressing biomedical challenges.


Assuntos
Nanoestruturas , Animais , Antineoplásicos , Cabelo , Humanos , Camundongos , Nanopartículas , Microtomografia por Raio-X
20.
Biomacromolecules ; 19(7): 2957-2968, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29617556

RESUMO

One of critical steps in genome editing by CRISPR-Cas9 is to deliver the CRISPR-Cas9 system into targeted cells. In this study, we developed a dual-targeting delivery system based on polymer/inorganic hybrid nanoparticles to realize highly efficient genome editing in targeted tumor cells as well as in situ detection on the related protein expression in edited cells. The CRISPR-Cas9 plasmid for CDK11 knockout was encapsulated in the core of the delivery system composed of protamine sulfate, calcium carbonate, and calcium phosphate by coprecipitation, and functional derivatives of carboxymethyl chitosan (biotinylated carboxymethyl chitosan with biotin ligands and aptamer-incorporated carboxymethyl chitosan with AS1411 ligands) were decorated on the nanovector surface by electrostatic interactions to form the dual-targeting delivery system. On the basis of the tumor cell targeting capability of biotin and AS1411 ligands as well as the nuclear targeting of AS1411, the dual-targeting system can deliver the CRISPR-Cas9 plasmid into the nuclei of tumor cells to realize highly efficient genome editing, resulting in a dramatic decrease (>90%) in CDK11 protein together with the significant downregulation of other proteins involved in tumor development, including an ∼90% decrease in MMP-9, >40% decrease in VEGF, and ∼70% decrease in survivin. Using the same vector, molecular beacons can be easily delivered to edited cell nuclei to in situ detect the mRNA level of related proteins (p53 and survivin as typical examples) and mRNA distribution in subcellular organelles. Our strategy can realize effective genome editing and in situ detection on related protein expression simultaneously.


Assuntos
Edição de Genes/métodos , Inativação Gênica , Transfecção/métodos , Biotina/química , Carbonato de Cálcio/química , Quitosana/análogos & derivados , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Humanos , Células MCF-7 , Nanopartículas/química , Protaminas/química
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