Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.273
Filtrar
1.
ACS Appl Mater Interfaces ; 11(38): 34707-34716, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31482705

RESUMO

It is of great significance to develop biocompatible and degradable gene carriers with stimuli-enhanced gene therapy and imaging function. In this work, low-cytotoxic polycation PGEA (ethanolamine-functionalized poly(glycidyl methacrylate))-functionalized dextran-quantum dot (QD) nanohybrids (DQ-PGEA) were proposed as safe and efficient gene carriers via a facile and feasible method. The highly water-soluble dextran gives the carrier good stability, biocompatibility, and abundant modification sites, while QDs allow fluorescence (FL) imaging. Taking advantage of the pH-responsive self-destruction characteristic introduced by Schiff base linkages, DQ-PGEA nanohybrids could not only result in enhanced gene release but also contribute to the elimination of the carriers. Reduced (nondegradable) DQ-PGEA-R nanohybrids were also synthesized as counterparts to reveal the superiority of the responsive DQ-PGEA carriers. The effectiveness of the as-prepared gene delivery systems was verified adopting the antioncogene p53 in the mouse model of breast cancer. As expected, DQ-PGEA nanohybrids demonstrated a superior gene transfection performance and antitumor inhibition compared with their counterparts. Meanwhile, the gene delivery processes could be tracked in real time to visualize the therapeutic processes and realize FL imaging-guided gene therapy. The current multifunctional stimuli-responsive nanoplatforms with the self-destruction feature are intriguing candidates to achieve enhanced gene therapy for tumor treatment.


Assuntos
Dextranos , Técnicas de Transferência de Genes , Terapia Genética , Neoplasias Mamárias Experimentais , Nanocompostos , Pontos Quânticos , Proteína Supressora de Tumor p53 , Animais , Linhagem Celular Tumoral , Dextranos/química , Dextranos/farmacologia , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Nanocompostos/química , Nanocompostos/uso terapêutico , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacologia , Pontos Quânticos/química , Pontos Quânticos/uso terapêutico , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética
3.
Biomater Sci ; 7(8): 3158-3164, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232421

RESUMO

Indocyanine green (ICG) is a clinically-approved near infrared (NIR) dye used for optical imaging. The dye is only slightly soluble in water and is prone to aggregation in saline solutions, so that alternative formulations can improve photophysical performance. Numerous nanoscale formulations of ICG have been described in the literature, but we sought to develop an approach that does not require additional purification steps. Pre-formed liposomes incorporating 45 mol% of the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) rapidly bind ICG, resulting in enhanced NIR optical properties. ICG binding is dependent on the amount of DOTAP incorporated in the liposomes. A dye-to-lipid mass ratio of [0.5 : 25] is sufficient for full complexation, without additional purification steps following mixing. NIR absorption, fluorescence intensity, and photoacoustic signals are increased for the liposome-bound dye. Not only is the optical character enhanced by simple mixing of ICG with liposomes, but retention in 4T1 mammary tumors is observed following intratumor injection, as assessed by fluorescence and photoacoustic imaging. Subsequent photothermal therapy with 808 nm laser irradiation is effective and results in tumor ablation without regrowth for at least 30 days. Thus, ICG optical properties and photothermal ablation outcomes can be improved by mixing the dye with pre-formed DOTAP liposomes in conditions that result in full dye-binding to the liposomes.


Assuntos
Técnicas de Ablação/métodos , Ácidos Graxos Monoinsaturados/química , Verde de Indocianina/química , Lipossomos/química , Neoplasias Mamárias Experimentais/terapia , Fenômenos Ópticos , Compostos de Amônio Quaternário/química , Animais , Feminino , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Camundongos , Imagem Óptica , Fototerapia
4.
Nat Commun ; 10(1): 2839, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253798

RESUMO

Immunomodulatory therapies are becoming a paradigm-shifting treatment modality for cancer. Despite promising clinical results, cancer immunotherapy is accompanied with off-tumor toxicity and autoimmune adverse effects. Thus, the development of smarter systems to regulate immune responses with superior spatiotemporal precision and enhanced safety is urgently needed. Here we report an activatable engineered immunodevice that enables remote control over the antitumor immunity in vitro and in vivo with near-infrared (NIR) light. The immunodevice is composed of a rationally designed UV light-activatable immunostimulatory agent and upconversion nanoparticle, which acts as a transducer to shift the light sensitivity of the device to the NIR window. The controlled immune regulation allows the generation of effective immune response within tumor without disturbing immunity elsewhere in the body, thereby maintaining the antitumor efficacy while mitigating systemic toxicity. The present work illustrates the potential of the remote-controlled immunodevice for triggering of immunoactivity at the right time and site.


Assuntos
Raios Infravermelhos , Nanopartículas/efeitos da radiação , Fototerapia/métodos , Animais , Linhagem Celular Tumoral , Feminino , Imunomodulação , Macrófagos , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Raios Ultravioleta
5.
Cancer Immunol Immunother ; 68(7): 1143-1155, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177328

RESUMO

Enhancement of endogenous immunity to tumor-associated self-antigens and neoantigens is the goal of preventive vaccination. Toward this goal, we compared the efficacy of the following HER2 DNA vaccine constructs: vaccines encoding wild-type HER2, hybrid HER2 vaccines consisting of human HER2 and rat Neu, HER2 vaccines with single residue substitutions and a novel human HER2 DNA vaccine, ph(es)E2TM. ph(es)E2TM was designed to contain five evolution-selected substitutions: M198V, Q398R, F425L, H473R and A622T that occur frequently in 12 primate HER2 sequences. These ph(es)E2TM substitutions score 0 to 1 in blocks substitutions matrix (BLOSUM), indicating minimal biochemical alterations. h(es)E2TM recombinant protein is recognized by a panel of anti-HER2 mAbs, demonstrating the preservation of HER2 protein structure. Compared to native human HER2, electrovaccination of HER2 transgenic mice with ph(es)E2TM induced a threefold increase in HER2-binding antibody (Ab) and elevated levels of IFNγ-producing T cells. ph(es)E2TM, but not pE2TM immune serum, recognized HER2 peptide p95 355LPESFDGDPASNTAP369, suggesting a broadening of epitope recognition induced by the minimally modified HER2 vaccine. ph(es)E2TM vaccination reduced tumor growth more effectively than wild-type HER2 or HER2 vaccines with more extensive modifications. The elevation of tumor immunity by ph(es)E2TM vaccination would create a favorable tumor microenvironment for neoantigen priming, further enhancing the protective immunity. The fundamental principle of exploiting evolution-selected amino acid substitutions is novel, effective and applicable to vaccine development in general.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Neoplasias Mamárias Experimentais/terapia , Receptor ErbB-2/imunologia , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/imunologia , Animais , Antígenos de Neoplasias/genética , Vacinas Anticâncer/genética , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral/transplante , Células Dendríticas/imunologia , Evolução Molecular , Feminino , Imunogenicidade da Vacina/genética , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptor ErbB-2/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Tolerância a Antígenos Próprios/genética , Microambiente Tumoral/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico
6.
Nanoscale ; 11(24): 11470-11483, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31124554

RESUMO

Sonochemotherapy is a promising strategy for inhibiting tumor growth. However, achieving highly targeted and effective sonochemotherapy is still an enormous challenge. In this study, a novel chemotherapeutic-carrying nanocomposite (HPCID) was developed, which can effectively target metastatic cancer cells and provide an enhanced therapeutic effect. In detail, HPCID was composed of hyaluronic acid (HA), carboxyl-terminated PAMAM dendrimer, fluorochrome indocyanine green (ICG), and doxorubicin hydrochloride (Dox). The efficacy of this drug delivery system (DDS) in sonochemotherapy was assessed on the CD44-overexpressing metastatic breast cancer cell line 4T1 both in vitro and in vivo. The HA modification significantly improved the cellular internalization of HPCID, and the degradation of the HA shell by hyaluronidase that is abundant in the 4T1 cells resulted in enzyme-responsive drug release. Under ultrasound (US) stimulation, HPCID produced a high amount of reactive oxidant species (ROS), which induced significant cell apoptosis when combined with chemotherapy. In addition, the administration of HPCID in 4T1 xenograft-bearing mice combined with ultrasonic exposure significantly inhibited tumor growth and pulmonary metastasis, with no systemic toxicity. Taken together, the proposed HPCID-mediated sonodynamic therapy (SDT) is a novel strategy against breast cancer progression and metastasis.


Assuntos
Doxorrubicina , Sistemas de Liberação de Medicamentos , Ácido Hialurônico , Neoplasias Mamárias Experimentais/terapia , Nanocompostos , Terapia por Ultrassom , Animais , Doxorrubicina/química , Doxorrubicina/farmacologia , Feminino , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nanocompostos/química , Nanocompostos/uso terapêutico , Metástase Neoplásica
7.
Gene ; 701: 32-40, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898703

RESUMO

Treatment of breast cancer by delivering important tumor suppressor plasmids is a promising approach in the field of clinical medicine. We transfected p21 and p53 tumor suppressor plasmids, into different breast cancer cell lines using inorganic nanoparticles (NPs) of carbonate apatite to evaluate the effect of gene expression on reducing breast cancer cell growth. In triple negative MDA-MB-231 breast cancer cell line, the cytotoxicity assay upon combined delivery of p21 and p53 plasmid loaded NPs showed significant decrease in cell growth compared to distinct p21 or p53 treatments. Also, in MCF-7 and 4T1 cell lines, significant reduction in cellular growth was observed following p21 or p53 plasmid transfection. The Western blot data showed that NP loaded p21 and p53 transgene delivery in MDA-MB-231 cell line resulted in a noteworthy decrease in phosphorylated form of MAPK protein of MAPK/ERK pathway. The in vivo studies in syngeneic breast cancer mouse model demonstrated that the rate of growth and final tumor volume were reduced to a greater extent in mice that received intravenous injection of p21 + NP and p53 + NP therapeutics.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21 , Neoplasias Mamárias Experimentais , Plasmídeos , Transfecção , Proteína Supressora de Tumor p53 , Animais , Apatitas/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/genética , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Nanopartículas , Plasmídeos/genética , Plasmídeos/farmacologia , Transplante Isogênico , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética
8.
Int J Cancer ; 145(8): 2267-2281, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30860605

RESUMO

Triple-negative breast cancer (TNBC), an aggressive, metastatic and recurrent breast cancer (BC) subtype, currently suffers from a lack of adequately described spontaneously metastatic preclinical models that faithfully reproduce the clinical scenario. We describe two preclinical spontaneously metastatic TNBC orthotopic murine models for the development of advanced therapeutics: an immunodeficient human MDA-MB-231-Luc model and an immunocompetent mouse 4T1 model. Furthermore, we provide a broad range of multifactorial analysis for both models that could provide relevant information for the development of new therapies and diagnostic tools. Our comparisons uncovered differential growth rates, stromal arrangements and metabolic profiles in primary tumors, and the presence of cancer-associated adipocyte infiltration in the MDA-MB-231-Luc model. Histopathological studies highlighted the more rapid metastatic spread to the lungs in the 4T1 model following a lymphatic route, while we observed both homogeneous (MDA-MB-231-Luc) and heterogeneous (4T1) metastatic spread to axillary lymph nodes. We encountered unique metabolomic signatures in each model, including crucial amino acids and cell membrane components. Hematological analysis demonstrated severe leukemoid and lymphoid reactions in the 4T1 model with the partial reestablishment of immune responses in the immunocompromised MDA-MB-231-Luc model. Additionally, we discovered ß-immunoglobulinemia and increased basal levels of G-CSF correlating with a metastatic switch, with G-CSF also promoting extramedullary hematopoiesis (both models) and causing hepatosplenomegaly (4T1 model). Overall, we believe that the characterization of these preclinical models will foster the development of advanced therapeutic strategies for TNBC treatment, especially for the treatment of patients presenting both, primary tumors and metastatic spread.


Assuntos
Modelos Animais de Doenças , Neoplasias Mamárias Experimentais/terapia , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Metástase Linfática , Neoplasias Mamárias Experimentais/diagnóstico , Neoplasias Mamárias Experimentais/metabolismo , Metabolômica/métodos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Reprodutibilidade dos Testes , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/metabolismo
9.
Nat Commun ; 10(1): 1114, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846699

RESUMO

Advances in genetic engineering have enabled the use of bacterial outer membrane vesicles (OMVs) to deliver vaccines, drugs and immunotherapy agents, as a strategy to circumvent biocompatibility and large-scale production issues associated with synthetic nanomaterials. We investigate bioengineered OMVs for contrast enhancement in optoacoustic (photoacoustic) imaging. We produce OMVs encapsulating biopolymer-melanin (OMVMel) using a bacterial strain expressing a tyrosinase transgene. Our results show that upon near-infrared light irradiation, OMVMel generates strong optoacoustic signals appropriate for imaging applications. In addition, we show that OMVMel builds up intense heat from the absorbed laser energy and mediates photothermal effects both in vitro and in vivo. Using multispectral optoacoustic tomography, we noninvasively monitor the spatio-temporal, tumour-associated OMVMel distribution in vivo. This work points to the use of bioengineered vesicles as potent alternatives to synthetic particles more commonly employed for optoacoustic imaging, with the potential to enable both image enhancement and photothermal applications.


Assuntos
Nanopartículas , Técnicas Fotoacústicas/métodos , Animais , Proteínas da Membrana Bacteriana Externa/química , Bioengenharia , Biopolímeros/química , Feminino , Temperatura Alta/uso terapêutico , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/terapia , Melaninas/química , Camundongos , Camundongos Nus , Nanopartículas/química , Nanotecnologia , Nanomedicina Teranóstica
10.
Exp Mol Med ; 51(1): 2, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617282

RESUMO

Growth hormone receptor (GHR) plays a vital role in breast cancer chemoresistance and metastasis but the mechanism is not fully understood. We determined if GHR could be a potential therapeutic target for estrogen receptor negative (ER-ve) breast cancer, which are highly chemoresistant and metastatic. GHR was stably knocked down in ER-ve breast cancer cells and its effect on cell proliferation, metastatic behavior, and chemosensitivity to docetaxel (DT) was assessed. Microarray analysis was performed to identify potential GHR downstream targets involved in chemoresistance. GHR and ATP-binding cassette sub-family G member 2 (ABCG2) overexpression and knockdown studies were performed to investigate the mechanism of GHR-induced chemoresistance. Patient-derived xenografts was used to study the effect of GHR and ABCG2. Immunohistochemical data was used to determine the correlation between GHR, pAKT, pmTOR, and ABCG2 expressions. GHR silencing drastically reduced the chemoresistant and metastatic behavior of ER-ve breast cancer cells and also inhibited AKT/mTOR pathway. In contrast, activation, or overexpression of GHR increased chemoresistance and metastasis by increasing the expression and promoter activity, of ABCG2. Inhibition of JAK2/STAT5 signaling repressed GHR-induced ABCG2 promoter activity and expression. Further, ABCG2 knockdown significantly increased the chemosensitivity. Finally, patient-derived xenograft studies revealed the role of GHR in chemoresistance. Overall, these findings demonstrate that targeting GHR could be a novel therapeutic approach to overcome chemoresistance and associated metastasis in aggressive ER-ve breast cancers.


Assuntos
Inativação Gênica , Neoplasias Mamárias Experimentais/terapia , Terapêutica com RNAi/métodos , Receptores da Somatotropina/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Feminino , Humanos , Janus Quinase 2/metabolismo , Células MCF-7 , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Estrogênicos/genética , Receptores da Somatotropina/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
11.
Cancer Immunol Immunother ; 68(1): 131-141, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29947961

RESUMO

Tumor relapse and metastatic spreading act as major hindrances to achieve complete cure of breast cancer. Evidence suggests that cancer stem cells (CSC) would function as a reservoir for the local and distant recurrence of the disease, due to their resistance to radio- and chemotherapy and their ability to regenerate the tumor. Therefore, the identification of appropriate molecular targets expressed by CSC may be critical in the development of more effective therapies. Our studies focused on the identification of mammary CSC antigens and on the development of CSC-targeting vaccines. We compared the transcriptional profile of CSC-enriched tumorspheres from an Her2+ breast cancer cell line with that of the more differentiated parental cells. Among the molecules strongly upregulated in tumorspheres we selected the transmembrane amino-acid antiporter xCT. In this review, we summarize the results we obtained with different xCT-targeting vaccines. We show that, despite xCT being a self-antigen, vaccination was able to induce a humoral immune response that delayed primary tumor growth and strongly impaired pulmonary metastasis formation in mice challenged with tumorsphere-derived cells. Moreover, immunotargeting of xCT was able to increase CSC chemosensitivity to doxorubicin, suggesting that it may act as an adjuvant to chemotherapy. In conclusion, our approach based on the comparison of the transcriptome of tumorspheres and parental cells allowed us to identify a novel CSC-related target and to develop preclinical therapeutic approaches able to impact on CSC biology, and therefore, hampering tumor growth and dissemination.


Assuntos
Sistema y+ de Transporte de Aminoácidos/imunologia , Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Células-Tronco Neoplásicas/imunologia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos Endogâmicos BALB C
12.
Acta Biomater ; 84: 328-338, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30500447

RESUMO

In this work, we developed a novel multifunctional nanoplatform based on hyaluronic acid modified Au nanocages (AuNCs-HA). The rational design of AuNCs-HA renders the nanoplatform three functionalities: (1) AuNCs-HA with excellent LSPR peak in the NIR region act as contrast agent for enhanced photoacoustic (PA) imaging and photothermal therapy (PTT); (2) the nanoplatform with high-energy rays (X-ray) absorption and auger electrons generation acts as a radiosensitizer for radiotherapy; (3) good photocatalytic property and large surface area make AuNCs-HA a photosensitive agent for photodynamic therapy (PDT). In vivo results demonstrated that AuNCs-HA presented excellent PA imaging performance after intravenous injection, which provided contour, size, and location information of the tumor. Moreover, because AuNCs-HA could combine radiotherapy and phototherapy together, the tumors treated with AuNCs-HA showed complete growth inhibition, comparing to that with each therapy alone. Taken together, our present study demonstrates that AuNCs-HA is of great potential as a multifunctional nanoplatform for PA imaging-guided radio- and photo-therapy of tumor. STATEMENT OF SIGNIFICANCE: In this study, a commendable theranostic nanoplatform based on hyaluronic acid modified AuNCs (AuNCs-HA) was developed. In our approach, the dilute solution of Gold(III) chloride is slowly dripped into Ag nanocubes solution, then the Au nanocages were obtained by redox reaction, and followed by HA modification. We explored them, simultaneously, as radiosensitizers for RT, photosensitizers for PDT, and therapeutic agents for PTT. Compared to that of each therapies alone, the combination of radio-therapy and photo-therapy results in a considerably improved tumor eliminating effect and efficiently inhibited tumor growth. In addition, AuNCs-HA exhibited remarkably strong PA signals for precise identification of the location, size, and boundary of the tumor, thereby facilitating imaging-guided therapy. In brief, our design of AuNCs-HA represents a general and versatile strategy for building up cancer-targeted nanotheranostics with desired synergistic imaging and therapy functionalities.


Assuntos
Ouro , Hipertermia Induzida , Neoplasias Mamárias Experimentais , Nanopartículas Metálicas , Técnicas Fotoacústicas , Fotoquimioterapia , Animais , Feminino , Ouro/química , Ouro/farmacologia , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/terapia , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Nanomedicina Teranóstica
13.
ACS Appl Mater Interfaces ; 11(1): 417-429, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30537815

RESUMO

Environmental stimuli, including pH, light, and temperature, have been utilized for activating controlled drug delivery to achieve efficient antitumor therapeutics while minimizing undesirable side effects. In this study, a multifunctional nanoplatform based on hollow mesoporous copper sulfide nanoparticles (H-CuS NPs) was developed by loading the interior cavity of the NPs with a drug-loaded phase-change material (PCM, 1-tetradecanol). Doxorubicin (DOX) and chlorin e6 (Ce6) were selected as the model chemotherapeutic drug and photosensitizer, respectively, which were encapsulated in H-CuS NPs via the PCM to form H-CuS@PCM/DOX/Ce6 (HPDC) NPs. When exposed to near infrared laser irradiation, this nanocomplex could produce a strong photothermic effect and thus induce the controlled release of DOX and Ce6 from the melting PCM. Subsequently, the DOX-mediated chemotherapeutic effect and Ce6-mediated photodynamic effect further contributed to enhanced tumor eradication. The efficacy of this multimodal cancer treatment combining chemo-, photothermal, and photodynamic therapies was systematically evaluated both in vitro and in vivo using a 4T1 mouse mammary tumor cell line and a mouse model bearing breast cancer. Moreover, this nanoplatform exhibited minimal systemic toxicity and good hemocompatibility and may provide an effective strategy for the delivery of multiple therapeutic agents and application of multimodal cancer treatments.


Assuntos
Neoplasias da Mama , Doxorrubicina , Sistemas de Liberação de Medicamentos , Hipertermia Induzida , Neoplasias Mamárias Experimentais , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Cobre/química , Cobre/farmacocinética , Cobre/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Raios Infravermelhos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia , Sulfetos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
ACS Nano ; 13(1): 274-283, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30566319

RESUMO

Multidrug resistance (MDR) is the key cause that accounts for the failure of clinical cancer chemotherapy. To address the problem, herein, we presented an alternative strategy to conquer drug-resistant breast cancer through the combinatorial delivery of Ca2+ channel siRNA with cytotoxic drugs. Mesoporous silica nanocapsules (MSNCs) with mesoporous and hollow structure were fabricated for co-delivery of T-type Ca2+ channel siRNA and doxorubicin (DOX) with high drug loading efficiency. The DOX/siRNA co-loaded MSNCs showed a synergistic therapeutic effect on drug-resistant breast cancer cells MCF-7/ADR, while had only an additive effect on the drug-sensitive MCF-7 counterpart. It was found that the combination of T-type Ca2+ channel siRNA and DOX had a similar effect on MCF-7 and MCF-7/ADR in the knockdown of overexpressed T-type Ca2+ channels and decrease in cytosolic Ca2+ concentration ([Ca2+]i), but it specifically induced G0/G1 phase cell-cycle arrest and intracellular drug accumulation enhancement in MCF-7/ADR. The in vitro and in vivo results demonstrated that the MSNCs with good biocompatibility had a high efficiency for conquering the drug-resistant breast cancer with the DOX/calcium channel siRNA cocktail co-delivery. It provides a biological target for drug/gene delivery enhanced cancer therapy with nanoformulations.


Assuntos
Antineoplásicos/administração & dosagem , Sinalização do Cálcio , Doxorrubicina/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanocápsulas/química , Terapêutica com RNAi/métodos , Animais , Antineoplásicos/uso terapêutico , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Células MCF-7 , Masculino , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Nanocápsulas/efeitos adversos , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Dióxido de Silício/química
15.
PLoS One ; 13(11): e0207255, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30500835

RESUMO

Matrix metalloproteinase-9 (MMP-9), whose expression is frequently dysregulated in cancer, promotes tumor growth, invasion, and metastasis by multiple mechanisms, including extracellular matrix remodeling and growth-factor and cytokine activation. We developed a monoclonal antibody against murine MMP-9, which we found decreased growth of established primary tumors in an orthotopic model of HER2-driven breast cancer (HC11-NeuT) in immunocompetent mice. RNA sequencing (RNAseq) profiling of NeuT tumors and additional mouse model tumors revealed that anti-MMP-9 treatment resulted in upregulation of immune signature pathways associated with cytotoxic T-cell response. As there is a need to boost the low response rates observed with anti-PDL1 antibody treatment in the clinical setting, we assessed the potential of anti-MMP-9 to improve T-cell response to immune checkpoint inhibitor anti-PDL1 in NeuT tumors. Anti-MMP-9 and anti-PDL1 cotreatment reduced T-cell receptor (TCR) clonality and increased TCR diversity, as detected by TCR sequencing of NeuT tumors. Flow cytometry analyses of tumors showed that the combination treatment increased the frequency of CD3+ T cells, including memory/effector CD4 and CD8 T cells, but not regulatory T cells, among tumor-infiltrating leukocytes. Moreover, in vitro enzymatic assays corroborated that MMP-9 cleaves key T-cell chemoattractant CXC receptor 3 ligands (CXC ligand [CXCL] 9, CXCL10, and CXCL11) and renders them inactive in T-cell migration assays. Consistent with our in vitro experiments, analysis of NeuT tumor protein lysates showed that anti-MMP-9 treatment increases expression of CXCL10 and other T cell-stimulating factors, such as interleukin (IL)-12p70 and IL-18. We show that inhibition of MMP-9, a key component of the tumor-promoting and immune-suppressive myeloid inflammatory milieu, increases T-helper cell 1 type cytokines, trafficking of effector/memory T cells into tumors, and intratumoral T-cell diversity.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Metaloproteinase 9 da Matriz/imunologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Quimiocinas/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos do Interstício Tumoral/patologia , Neoplasias Mamárias Experimentais/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia
16.
Biomed Microdevices ; 20(4): 105, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30535532

RESUMO

Beyond heterogeneous cancer cells, the tumor microenvironment includes stromal and immune cells, blood vessels, extracellular matrix and biologically active molecules. Abnormal signaling, uncontrolled proliferation and high interstitial pressure all contribute to a chaotic, non-hierarchical vascular organization. Using an immune competent 4T1 breast adenocarcinoma murine model, this study fully characterizes the architecture and immunocyte milieu of the tumor microenvironment. Heterogeneous vessel distribution, chaotic connectivity, limited perfusion, cancer cell density, immune phenotype, and biological responses to immune therapy are presented. Cancer cell density mirrored the distribution of large, perfusable vessels, both predominately in the tumor periphery. Intratumoral administration of the proinflammatory cytokine IL-12 led to an increase in CD45+ leukocytes, with a specific increase in CD4+ and CD8+ T cells, and a decrease in the percentage of Gr-llo myeloid-derived suppressor cells. Concomitantly, serum G-CSF, IL-10 and VEGF decreased, while CXCR9 and interferon gamma increased. The distribution pattern of infiltrating monocytes/macrophages, visualized using a fluorescent perfluorocarbon emulsion, indicated that macrophages predominately localize in the vicinity of large blood vessels. Electron microscopy supports the presence of dense tumor cell masses throughout the tumor, with the largest vessels present in the surrounding mammary fat pad. Overall, large vessels in the 4T1 tumor periphery support high, localized vascular perfusion and myeloid accumulation. The pro-inflammatory cytokine IL-12 stimulated a transition towards T helper 1 cytokines in serum, supporting suppression of tumor growth and angiostatic conditions.


Assuntos
Imunoterapia , Imagem Multimodal , Microambiente Tumoral/imunologia , Animais , Interleucina-12/metabolismo , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Resultado do Tratamento
17.
ACS Appl Mater Interfaces ; 10(49): 42102-42114, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30431261

RESUMO

Current nanodrug-based cancer therapy is susceptible to the problems of rapid clearance from circulation and limited therapeutic efficacy. Herein, we report a magnetically targeted and photothermal-triggered drug release nanotheranostics system based on superparamagnetic iron oxide (Fe3O4), IR780, doxorubicin (DOX), and perfluoropentane (PFP) entrapped poly-lactide- co-glycolide (PLGA) nanoparticles (IR780/Fe3O4@PLGA/PFP/DOX NPs) for triple-modal imaging-guided synergistic therapy of breast cancer. In this work, IR780 and Fe3O4 convert light into heat, which triggers DOX release from IR780/Fe3O4@PLGA/PFP/DOX NPs and a phase-shift thermoelastic expansion of PFP; this procedure further accelerates the DOX release and tissue extrusion deformation. Fe3O4 NPs also serve as the target moiety by an external magnet directed to the tumor. Specifically, the IR780/Fe3O4@PLGA/PFP/DOX NPs can be used for triple-modal imaging, including near infrared fluorescence, magnetic resonance, and ultrasound. Furthermore, the antitumor therapy studies reveal the extraordinary performance of IR780/Fe3O4@PLGA/PFP/DOX NPs in magnetically targeted synergistic chemo-photothermal therapy of cancer. Therefore, the multifunctional IR780/Fe3O4@PLGA/PFP/DOX NPs guided by the magnetic field show a great potential for cancer theranostics.


Assuntos
Doxorrubicina , Sistemas de Liberação de Medicamentos , Imagem por Ressonância Magnética , Nanopartículas de Magnetita , Neoplasias Mamárias Experimentais , Imagem Óptica , Fototerapia , Animais , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Hipertermia Induzida , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Ultrassonografia
18.
ACS Nano ; 12(11): 11041-11061, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30481959

RESUMO

Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX). Intravenous injection of the encapsulated two-drug combination dramatically improved the pharmacokinetics and tumor drug concentrations of DOX and IND in an orthotopic 4T1 tumor model in syngeneic mice. Delivery of a threshold ICD stimulus resulted in the uptake of dying BC cells by dendritic cells, tumor antigen presentation and the activation/recruitment of naïve T-cells. The subsequent activation of perforin- and IFN-γ releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. Immune phenotyping of the tumor tissues confirmed the recruitment of CD8+ cytotoxic T lymphocytes (CTLs), disappearance of Tregs, and an increase in CD8+/FOXP3+ T-cell ratios. Not only does the DOX/IND-Liposome provide a synergistic antitumor response that is superior to a DOX-only liposome, but it also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. All considered, an innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/terapia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Triptofano/análogos & derivados , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Lipossomos/química , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Triptofano/administração & dosagem , Triptofano/química , Triptofano/farmacologia
19.
ACS Nano ; 12(12): 12169-12180, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30418734

RESUMO

Protein-assisted biomimetic synthesis has been an emerging offshoot of nanofabrication in recent years owing to its features of green chemistry, facile process, and ease of multi-integration. As a result, many proteins have been used for biomimetic synthesis of varying kinds of nanostructures. Although the efforts on exploring new proteins and investigating their roles in biomimetic chemistry are increasing, the most essential intrinsic properties of proteins are largely neglected. Herein we report a frequently used enzyme (horseradish peroxidase, HRP) to demonstrate the possibility of enzymatic activity retaining after accomplishing the roles in biomimetic synthesis of ultrasmall gadolinium (Gd) nanodots and stowing its substrate 2,2'-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid ammonium salt) (ABTS), denoted as Gd@HRPABTS. It was found that ca. 70% of the enzymatic activity of HRP was preserved. The associated changes of protein structure with chemical treatments were studied by spectroscopic analysis. Leveraging on the highly retained catalytic activity, Gd@HRPABTS exerts strong catalytic oxidation of peroxidase substrate ABTS into photoactive counterparts in the presence of intrinsic H2O2 inside the tumor, therefore enabling tumor-selective catalytic photoacoustic (PA) imaging and photothermal therapy (PTT). In addition, the MR moiety of Gd@HRPABTS provides guidance for PTT and further diagrams that Gd@HRPABTS is clearable from the body via kidneys. Preliminary toxicity studies show no observed adverse effects by administration of them. This study demonstrates beyond the well-known roles in biomimetic chemistry that HRP can also preserve its enzymatic activity for tumor catalytic theranostics.


Assuntos
Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Neoplasias da Mama/terapia , Peroxidase do Rábano Silvestre/metabolismo , Fototerapia , Nanomedicina Teranóstica , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Materiais Biomiméticos/química , Materiais Biomiméticos/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Gadolínio/administração & dosagem , Gadolínio/química , Gadolínio/farmacologia , Peroxidase do Rábano Silvestre/administração & dosagem , Peroxidase do Rábano Silvestre/química , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/terapia , Camundongos , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Técnicas Fotoacústicas
20.
Int J Pharm ; 553(1-2): 363-374, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30385372

RESUMO

Gold nanoclusters (AuNCs) have been considered to be a promising candidate for hyperthermia-based anticancer therapy. Herein, we introduce albumin-assisted AuNCs composed of small gold nanoparticles (AuNPs, <6 nm) assembled with strands of polyallylamine (PAH), which exhibited strong surface plasmon resonance upon near-infrared (NIR, ∼808 nm) laser irradiation and good in vivo stability. Our albumin-assisted PAH-AuNCs (BSA/PAH-AuNCs) were facilely fabricated as a top-down process by a simple ultrasonication after the preparation of large nano-aggregates of PAH-AuNPs. Albumin played a critical role as a stabilizer and surfactant in making loosely associated large aggregates and thereby producing small gold nanoclusters (∼60 nm) of slightly negative charge upon ultrasonication. The prepared BSA/PAH-AuNCs displayed excellent hyperthermal effects (∼60 °C) in response to ∼808-nm NIR laser irradiation in a 4T1 cell system in vitro and in 4T1 cell tumor xenograft mice in vivo, indicating their remarkable potential to suppress breast cancer growth, without almost no significant toxicity in histology. Consequently, our gold nanoclusters should be considered as a promising photothermal agent that are easy to manufacture and exhibit marked anticancer effects in terms of tumor ablation.


Assuntos
Hipertermia Induzida/métodos , Terapia a Laser/métodos , Neoplasias Mamárias Experimentais/terapia , Nanopartículas Metálicas , Albuminas/química , Animais , Feminino , Ouro , Masculino , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Poliaminas/química , Ressonância de Plasmônio de Superfície , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA