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1.
J Nanobiotechnology ; 22(1): 297, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38812019

RESUMO

Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer.


Assuntos
Neoplasias Colorretais , Ferritinas , Lasers , Mitoxantrona , Terapia Fototérmica , Animais , Neoplasias Colorretais/terapia , Neoplasias Colorretais/tratamento farmacológico , Camundongos , Ferritinas/química , Ferritinas/metabolismo , Terapia Fototérmica/métodos , Humanos , Mitoxantrona/farmacologia , Mitoxantrona/química , Mitoxantrona/uso terapêutico , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos BALB C , Antineoplásicos/farmacologia , Antineoplásicos/química , Camundongos Nus , Feminino
2.
J Nanobiotechnology ; 20(1): 87, 2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35183191

RESUMO

BACKGROUND: UV exposure continues to induce many health issues, though commercial sunscreens are available. Novel UV filters with high safety and efficacy are urgently needed. Metal-organic frameworks (MOFs) could be a suitable platform for UV filter development, due to their tunable optical, electrical, and photoelectric properties by precise controlled synthesis. RESULTS: Herein, four zinc-based MOFs with various bandgap energies were chose to investigate their optical behaviors and evaluate their possibility as sunscreens. Zeolitic imidazolate framework-8 (ZIF-8) was found to possess the highest and widest UV reflectance, thereby protecting against sunburn and DNA damage on mouse skin and even achieving a comparable or higher anti-UV efficacy relative to the commercially available UV filters, TiO2 or ZnO, on pig skin, a model that correlates well with human skin. Also, ZIF-8 exerted appealing characteristics for topical skin use with low radical production, low skin penetration, low toxicity, high transparency, and high stability. CONCLUSION: These results confirmed ZIF-8 could potentially be a safe and effective sunscreen surrogate for human, and MOFs could be a novel source to develop more effective and safe UV filters.


Assuntos
Estruturas Metalorgânicas , Óxido de Zinco , Animais , Camundongos , Protetores Solares/farmacologia , Suínos , Raios Ultravioleta , Zinco
3.
J Nanobiotechnology ; 20(1): 3, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983531

RESUMO

BACKGROUND AND AIMS: Renal fibrosis is the common outcome in all progressive forms of chronic kidney disease. Unfortunately, the pathogenesis of renal fibrosis remains largely unexplored, among which metabolic reprogramming plays an extremely crucial role in the evolution of renal fibrosis. Ceria nanoparticles (CeNP-PEG) with strong ROS scavenging and anti-inflammatory activities have been applied for mitochondrial oxidative stress and inflammatory diseases. The present study aims to determine whether CeNP-PEG has therapeutic value for renal fibrosis. METHODS: The unilateral ureteral obstructive fibrosis model was used to assess the therapeutic effects in vivo. Transforming growth factor beta1-induced epithelial-to-mesenchymal transition in HK-2 cells was used as the in vitro cell model. The seahorse bioscience X96 extracellular flux analyzer was used to measure the oxygen consumption rate and extracellular acidification rate. RESULTS: In the present study, CeNP-PEG treatment significantly ameliorated renal fibrosis by increased E-cadherin protein expression, and decreased α-SMA, Vimentin and Fibronectin expression both in vitro and in vivo. Additionally, CeNP-PEG significantly reduced the ROS formation and improved the levels of mitochondrial ATP. The seahorse analyzer assay demonstrated that the extracellular acidification rate markedly decreased, whereas the oxygen consumption rate markedly increased, in the presence of CeNP-PEG. Furthermore, the mitochondrial membrane potential markedly enhanced, hexokinase 1 and hexokinase 2 expression significantly decreased after treatment with CeNP-PEG. CONCLUSIONS: CeNP-PEG can block the dysregulated metabolic status and exert protective function on renal fibrosis. This may provide another therapeutic option for renal fibrosis.


Assuntos
Cério , Glicólise/efeitos dos fármacos , Rim , Nanopartículas Metálicas/química , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Cério/química , Cério/farmacologia , Fibrose/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
Angew Chem Int Ed Engl ; 61(8): e202115956, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-34931436

RESUMO

Wearable personal protective equipment that is decorated with photoactive self-cleaning materials capable of actively neutralizing biological pathogens is in high demand. Here, we developed a series of solution-processable, crystalline porous materials capable of addressing this challenge. Textiles coated with these materials exhibit a broad range of functionalities, including spontaneous reactive oxygen species (ROS) generation upon absorption of daylight, and long-term ROS storage in dark conditions. The ROS generation and storage abilities of these materials can be further improved through chemical engineering of the precursors without altering the three-dimensional assembled superstructures. In comparison with traditional TiO2 or C3 N4 self-cleaning materials, the fluorinated molecular coating material HOF-101-F shows a 10- to 60-fold enhancement of ROS generation and 10- to 20-fold greater ROS storage ability. Our results pave the way for further developing self-cleaning textile coatings for the rapid deactivation of highly infectious pathogenic bacteria under both daylight and light-free conditions.


Assuntos
Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Escherichia coli/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Têxteis , Dispositivos Eletrônicos Vestíveis , Antibacterianos/síntese química , Antibacterianos/química , Materiais Revestidos Biocompatíveis/síntese química , Materiais Revestidos Biocompatíveis/química , Escherichia coli/metabolismo , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Porosidade , Propriedades de Superfície
5.
Adv Funct Mater ; 27(1)2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28729818

RESUMO

Chronic non-healing wounds remain a major clinical challenge that would benefit from the development of advanced, regenerative dressings that promote wound closure within a clinically relevant time frame. The use of copper ions has shown promise in wound healing applications possibly by promoting angiogenesis. However, reported treatments that use copper ions require multiple applications of copper salts or oxides to the wound bed, exposing the patient to potentially toxic levels of copper ions and resulting in variable outcomes. Herein we set out to assess whether copper metal organic framework nanoparticles (HKUST-1 NPs) embedded within an antioxidant thermoresponsive citrate-based hydrogel would decrease copper ion toxicity and accelerate wound healing in diabetic mice. HKUST-1 and poly-(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) were synthesized and characterized. HKUST-1 NP stability in a protein solution with and without embedding them in PPCN hydrogel was determined. Copper ion release, cytotoxicity, apoptosis, and in vitro migration processes were measured. Wound closure rates and wound blood perfusion were assessed in vivo using the splinted excisional dermal wound diabetic mouse model. HKUST-1 NP disintegrated in protein solution while HKUST-1 NPs embedded in PPCN (H-HKUST-1) were protected from degradation and copper ions were slowly released. Cytotoxicity and apoptosis due to copper ion release were significantly reduced while dermal cell migration in vitro and wound closure rates in vivo were significantly enhanced. In vivo, H-HKUST-1 induced angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. These results suggest that a cooperatively stabilized, copper ion-releasing H-HKUST-1 hydrogel is a promising innovative dressing for the treatment of chronic wounds.

6.
Nanotechnology ; 25(12): 125102, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24576956

RESUMO

Metastasis, the main cause of cancer related deaths, remains the greatest challenge in cancer treatment. Disulfiram (DSF), which has multi-targeted anti-tumor activity, was encapsulated into redox-sensitive shell crosslinked micelles to achieve intracellular targeted delivery and finally inhibit tumor growth and metastasis. The crosslinked micelles demonstrated good stability in circulation and specifically released DSF under a reductive environment that mimicked the intracellular conditions of tumor cells. As a result, the DSF-loaded redox-sensitive shell crosslinked micelles (DCMs) dramatically inhibited cell proliferation, induced cell apoptosis and suppressed cell invasion, as well as impairing tube formation of HMEC-1 cells. In addition, the DCMs could accumulate in tumor tissue and stay there for a long time, thereby causing significant inhibition of 4T1 tumor growth and marked prevention in lung metastasis of 4T1 tumors. These results suggested that DCMs could be a promising delivery system in inhibiting the growth and metastasis of breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Dissulfiram/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Maleatos/administração & dosagem , Oxirredução/efeitos dos fármacos , Poliestirenos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Micelas
7.
Artigo em Inglês | MEDLINE | ID: mdl-36897565

RESUMO

The internalization of antigens by dendritic cells (DCs) is the initial critical step for vaccines to activate the immune response; however, the systemic delivery of antigens into DCs is hampered by various technical challenges. Here we show that a virus-like gold nanostructure (AuNV) can effectively bind to and be internalized by DCs due to its biomimetic topological morphology, thereby significantly promoting the maturation of DCs and the cross-presentation of the model antigen ovalbumin (OVA). In vivo experiments demonstrate that AuNV efficiently delivers OVA to draining lymph nodes and significantly inhibits the growth of MC38-OVA tumors, generating a ∼80% decrease in tumor volume. Mechanistic studies reveal that the AuNV-OVA vaccine induces a remarkable increase in the rate of maturation of DCs, OVA presentation, and CD4+ and CD8+ T lymphocyte populations in both lymph node and tumor and an obvious decrease in myeloid-derived suppressor cells and regulatory T cell populations in spleen. The good biocompatibility, strong adjuvant activity, enhanced uptake of DCs, and improved T cell activation make AuNV a promising antigen delivery platform for vaccine development.

8.
Adv Mater ; 35(52): e2307193, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37951210

RESUMO

The immune response in cancer reflects a series of carefully regulated events; however, current tumor immunotherapies typically address a single key aspect to enhance anti-tumor immunity. In the present study, a nanoplatform (Fe3 O4 @IR820@CpG)-based immunotherapy strategy that targets the multiple key steps in cancer-immunity cycle is developed: 1) promotes the release of tumor-derived proteins (TDPs), including tumor-associated antigens and pro-immunostimulatory factors), in addition to the direct killing effect, by photothermal (PTT) and photodynamic therapy (PDT); 2) captures the released TDPs and delivers them, together with CpG (a Toll-like receptor 9 agonist) to antigen-presenting cells (APCs) to promote antigen presentation and T cell activation; 3) enhances the tumor-killing ability of T cells by combining with anti-programmed death ligand 1 antibody (α-PD-L1), which collectively advances the outstanding of the anti-tumor effects on colorectal, liver and breast cancers. The broad-spectrum anti-tumor activity of Fe3 O4 @IR820@CpG with α-PD-L1 demonstrates that optimally manipulating anti-cancer immunity not singly but as a group provides promising clinical strategies.


Assuntos
Neoplasias da Mama , Vacinas , Humanos , Feminino , Antígeno B7-H1/metabolismo , Linfócitos T , Imunoterapia/métodos , Lasers , Linhagem Celular Tumoral
9.
Bioconjug Chem ; 23(2): 222-31, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22168476

RESUMO

The development of safe and efficient gene delivery systems is still a challenge for successful gene therapy. In this work, low molecular weight polyethylenimine (PEI 2K) was modified by Tween 85, which bears three oleate chains. Tween 85 modified PEI 2K (TP) could condense DNA efficiently, and TP/DNA complexes (TPCs) showed high resistance to salt-induced aggregation and enzymatic degradation. In addition, TP did not show the obvious cytotoxicity. The introduction of Tween 85 led to a significant increase in the cellular uptake of complexes with higher transfection efficiency, which was strongly inhibited by the addition of free Tween 85 in MCF-7/ADR cells, but not in MCF-7 cells. These results indicated that TP could be a potentially safe and effective copolymer for gene delivery, and TPCs could be taken up mainly by Tween 85-mediated endocytosis in MCF-7/ADR cells.


Assuntos
Técnicas de Transferência de Genes , Polietilenoimina/farmacocinética , Polissorbatos/farmacocinética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Endocitose/efeitos dos fármacos , Humanos , Estrutura Molecular , Peso Molecular , Polietilenoimina/química , Polissorbatos/síntese química , Polissorbatos/química
10.
Nanomedicine ; 8(5): 740-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21930110

RESUMO

Candesartan cilexetil (CC) is widely used for the treatment of hypertension and heart failure, but it shows very poor aqueous solubility and very low oral absorption. In this work, CC-loaded solid lipid nanoparticles (CLNs) were successfully developed to improve the oral bioavailability. The physicochemical properties of CLNs were characterized, and the pharmacokinetic behavior of CLNs was evaluated in rats. CLNs exhibited nanometer-sized spherical particles with high entrapment efficiency (91.33%). The absorption of CLNs in the stomach was only 2.8% of that in intestine. Moreover, CLNs could be internalized into the enterocytes and then transported into the systemic circulation via the portal circulation and intestinal lymphatic pathway. The pharmacokinetic results indicated that the oral bioavailability of candesartan was obviously improved over 12-fold after incorporation into solid lipid nanoparticles. These results demonstrated that solid lipid nanoparticles have great potential for increasing oral bioavailability of lipophilic drugs such as CC. FROM THE CLINICAL EDITOR: Candesartan cilexetil is a potent angiotensin receptor inhibitor with low bioavailability due to poor aqueous solubility. In this work, solid lipid nanoparticles were used to improve the oral bioavailability 12-fold compared to standard preparation in rats, suggesting that a similar approach might be effective in future human applications.


Assuntos
Anti-Hipertensivos , Benzimidazóis , Disponibilidade Biológica , Compostos de Bifenilo , Nanopartículas , Tetrazóis , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/química , Benzimidazóis/farmacocinética , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Células CACO-2 , Trato Gastrointestinal/metabolismo , Humanos , Absorção Intestinal/efeitos dos fármacos , Lipídeos/química , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Ratos , Ratos Sprague-Dawley , Tetrazóis/administração & dosagem , Tetrazóis/química , Tetrazóis/farmacocinética
11.
Nanoscale ; 13(15): 7389-7402, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33889904

RESUMO

Metal-organic frameworks (MOFs) as promising materials have been widely used in drug delivery, disease diagnosis and therapy; however, their effects on the reproductive system remain unknown, which hinders their further clinical applications. Here we show that repeated subcutaneous injections of copper MOFs (HKUST-1) induce higher toxicity into the male reproductive system relative to the female reproductive system, with disrupted seminiferous tubule histology, sperm generation disorder, irreversible sperm morphological abnormities and reduced pregnancy rate but only slight follicle dysfunction and pregnancy complications in female mice. Interestingly, the modification of HKUST-1 with folic acid attenuates the reproductive toxicity and even improves pregnancy and fetus development. This study confirms the gender-dependent toxicity of HKUST-1 to the reproductive system, and that folic acid modification could relieve the reproductive toxicity, thus providing us a deep understanding of reproductive toxicity of copper MOFs, and also a guideline and feasible way to improve the biocompatibility of copper MOFs for potential medical use.


Assuntos
Estruturas Metalorgânicas , Animais , Cobre , Sistemas de Liberação de Medicamentos , Feminino , Ácido Fólico , Masculino , Camundongos
12.
ACS Nano ; 12(2): 1023-1032, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29406741

RESUMO

The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. We hypothesized that copper-based metal-organic framework nanoparticles (Cu-MOF NPs), referred to as HKUST-1, which are rapidly degraded in protein solutions, can be modified to slowly release Cu2+, resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic-acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addition, cytotoxicity and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu2+ release, thus enabling the direct application of Cu-MOF NPs to wounds.


Assuntos
Cobre/química , Diabetes Mellitus Experimental/tratamento farmacológico , Ácido Fólico/farmacologia , Estruturas Metalorgânicas/química , Nanopartículas/química , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular , Ácido Fólico/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL
13.
Acta Biomater ; 10(6): 2674-83, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24525035

RESUMO

To maximize the interference efficacy of pGPU6/Neo-p65 shRNA-expressing pDNA (p65 shRNA) and subsequently more effectively inhibit tumor growth and lymphatic metastasis through blocking the nuclear factor-kappa B (NF-κB) signaling pathway, seven Tween 85-polyethyleneimine (PEI) conjugates (TnPs, n=2, 3, 4, 5, 6, 7 and 8), which differed in the length of the polymethylene [-(CH2)n-] spacer between Tween 85 and PEI, were synthesized and investigated. The results showed that the transfection efficiency and cytotoxicity both increased with the spacer chain length. Then, TnPs with a [-(CH2)6-] spacer (T6P) were chosen to deliver p65 shRNA to a tumor and subsequently inhibit tumor growth and lymphatic metastasis. The T6P/p65 shRNA complex nanoparticles (T6Ns) could significantly down-regulate p65 expression in breast cancer cells, and consequently inhibit cell invasion and disrupt the tube formation. Most importantly, T6Ns accumulated greatly in tumor tissue, and as a result, significantly inhibited the growth and lymphatic metastasis of breast cancer xenograft. All these results indicated that the transfection efficacies of cationic amphiphiles could be significantly modulated by minor structural variations, and that T6P was promising for the effective delivery of p65 shRNA to knock down the expression of the key metastasis-driving genes and inhibit tumor growth and metastasis.


Assuntos
Metástase Linfática , Neoplasias/patologia , Polietilenoimina/química , Polissorbatos/química , RNA Interferente Pequeno/administração & dosagem , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias/metabolismo
14.
Biomaterials ; 34(37): 9648-56, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24016858

RESUMO

Lung metastasis is one of the greatest challenges for breast cancer treatment. Here, a nanodiamonds (NDs)-mediated doxorubicin (DOX) delivery system was first designed to inhibit the lung metastasis of breast cancer effectively. DOX was non-covalently bound to NDs via physical adsorption in an aqueous solution, then DSPE-PEG 2K was coated to the NDs-DOX complex (NDX) to increase the dispersibility and prolong the circulation time. DSPE-PEG 2K coating NDX (DNX) displayed high drug loading and excellent ability to deliver DOX to the nucleus, thereby significantly enhancing cytotoxicity and inducing cell apoptosis. Furthermore, DNX showed good histocompatibility and could improve drug accumulation in lung, as a result, markedly inhibited the lung metastasis of breast cancer. The high anti-metastasis efficacy with the decreased systemic toxicity suggested that DNX could be a promising drug delivery system for the therapy of lung metastasis of breast cancer.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias da Mama/patologia , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Nanodiamantes/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley
15.
ACS Nano ; 7(7): 5858-69, 2013 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-23734880

RESUMO

The combination of a chemotherapeutic drug with a multidrug resistance (MDR) modulator has emerged as a promising strategy for treating MDR cancer. To ensure two drugs could be simultaneously delivered to tumor region at the optimum ratio, and the MDR modulator could be released earlier and faster than the chemotherapeutic drug to inactivate P-glycoprotein (P-gp) and subsequently inhibit the pumping out of the chemotherapeutic drug, a smart pH-sensitive polymeric micelles system with high drug loading and precise drug ratio was designed and prepared by conjugating doxorubicin (DOX) to poly(styrene-co-maleic anhydride) (SMA) derivative with adipic dihydrazide (ADH) through a acid-cleavable hydrazone bond, and then encapsulating disulfiram (DSF), a P-gp inhibitor as well as an apoptosis inducer, into the micelles formed by the self-assembly of SMA-ADH-DOX (SAD) conjugate. The pH-sensitive polymeric micelles system enabled a temporal release of two drugs: encapsulated DSF was released fast to inhibit the activity of P-gp and restore cell apoptotic signaling pathways, while conjugated DOX was released in a sustained and pH-dependent manner and highly accumulated in drug resistant cells to exert therapeutic effect, due to the inactivation of P-gp by DSF. The smart co-delivery system was very effective in enhancing the cytotoxicity by increasing the intracellular accumulation of DOX and promoting the apoptotic response, and showed the most effective inhibitory effect on the growth of drug-resistant breast cancer xenografts as compared to other combinations of both drugs. In a word, this smart co-delivery system has significant promise for the clinical therapy of MDR cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Preparações de Ação Retardada/administração & dosagem , Nanocápsulas/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Difusão , Dissulfiram/administração & dosagem , Dissulfiram/química , Feminino , Concentração de Íons de Hidrogênio , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Nanocápsulas/química , Polímeros/química , Resultado do Tratamento
16.
Biomaterials ; 34(21): 5381-90, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23591394

RESUMO

Metastasis is one of the greatest challenges in cancer treatment. In this study, a bioreducible polymer, Tween 85-s-s-polyethyleneimine 2K (TSP), was synthesized and used as a non-viral gene vector for p65 shRNA to block NF-κB signaling pathway, thereby inhibiting the growth and metastasis of breast cancer. The TSP/p65 shRNA complex nanoparticles (TSNs) could significantly down-regulate p65 expression in breast cancer cells due to the rapid degradation of TSP with prompt shRNA release, and consequently not only inhibit cell proliferation and invasion, but also induce cell apoptosis and disrupt the tube formation. Most importantly, TSNs showed high accumulation in tumor and almost completely inhibited the growth and metastasis of the breast cancer xenograft in nude mice induced by MDA-MB-435 cells. All these results indicated the promising of TSP as a non-viral gene vector to knock down p65 expression and inhibit the growth and metastasis of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Nanopartículas/química , Polietilenoimina/química , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/enzimologia , Linhagem Celular , Núcleo Celular/metabolismo , Proliferação de Células , Forma Celular , Ciclina D1/metabolismo , Feminino , Humanos , Linfonodos/patologia , Espectroscopia de Ressonância Magnética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Nanopartículas/ultraestrutura , Invasividade Neoplásica , Metástase Neoplásica , Neovascularização Patológica/patologia , Polietilenoimina/síntese química , Polissorbatos , Distribuição Tecidual , Fator de Transcrição RelA/metabolismo
17.
Int J Nanomedicine ; 7: 4961-72, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23028224

RESUMO

BACKGROUND AND METHODS: A new amphiphilic comb-shaped copolymer (SP) was synthesized by conjugating poly(styrene-co-maleic anhydride) with low molecular weight polyethyleneimine for gene delivery. Fourier transform infrared spectrum, (1)H nuclear magnetic resonance, and gel permeation chromatography were used to characterize the graft copolymer. RESULTS: The buffering capability of SP was similar to that of polyethyleneimine within the endosomal pH range. The copolymer could condense DNA effectively to form complexes with a positive charge (13-30 mV) and a small particle size (130-200 nm) at N/P ratios between 5 and 20, and protect DNA from degradation by DNase I. In addition, SP showed much lower cytotoxicity than polyethyleneimine 25,000. Importantly, the gene transfection activity and cellular uptake of SP-DNA complexes were all markedly higher than that of complexes of polyethyleneimine 25,000 and DNA in MCF-7 and MCF-7/ADR cell lines. CONCLUSION: This work highlights the promise of SP as a safe and efficient synthetic vector for DNA delivery.


Assuntos
DNA/química , DNA/genética , Anidridos Maleicos/química , Nanocápsulas/química , Polietilenoimina/química , Poliestirenos/química , Transfecção/métodos , DNA/administração & dosagem , Difusão , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Peso Molecular , Nanocápsulas/ultraestrutura
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