RESUMO
Up to now, chemotherapy is still the main strategy for cancer treatment. However, the emergence of chemo-resistance and systemic side effects often seriously affects the treatment and prognosis. Herein, an intelligent nanoplatform based on dendritic mesoporous organosilica nanoparticles (DMON) is constructed. The encapsulated phase-change material, 1-tetradecanol (TD) can serve as a "doorkeeper" and enable the responsive release of drugs based on the temperature changes. Meanwhile, polyethylene glycol (PEG) is used to improve the dispersibility and biocompatibility. Cisplatin is chosen as the model of chemotherapy drug, which is co-loaded with indocyanine green (ICG) in DMON to produce DMON-PEG-cisplatin/ICG-TD (DPCIT). Exciting, the hyperthermia and reactive oxygen species induced by ICG under the NIR-laser irradiation will initiate a phase transition of TD to release cisplatin, thus leading a combined therapy (chemo/photothermal/photodynamic therapy). The results indicated that under laser irradiation, DPCIT can kill cancer cells and inhibit tumor growth efficiently. In addition, the designed nanoplatform reveals minimal systemic toxicity in vivo, in contrast, the distinct liver damage can be observed by the direct treatment of cisplatin. Overall, this research may provide a general approach for the targeted delivery and controlled release of chemotherapy drugs to realize a cooperatively enhanced multimodal tumor therapy.
Assuntos
Hipertermia Induzida , Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Fototerapia/métodos , Cisplatino/farmacologia , Polietilenoglicóis , Verde de Indocianina/farmacologia , Neoplasias/tratamento farmacológico , Doxorrubicina/farmacologia , Linhagem Celular TumoralRESUMO
In biomedical applications, polyethylene glycol (PEG) functionalization has been a major approach to modify nanocarriers such as nano-graphene oxide for particular biological requirements. However, incorporation of a PEG shell poses a significant diffusion barrier that adversely affects the release of the loaded drugs. This study addresses this critical issue by employing a redox-responsive PEG detachment mechanism. A PEGylated nano-graphene oxide (NGO-SS-mPEG) with redox-responsive detachable PEG shell is developed that can rapidly release an encapsulated payload at tumor-relevant glutathione (GSH) levels. The PEG shell grafted onto NGO sheets gives the nanocomposite high physiological solubility and stability in circulation. It can selectively detach from NGO upon intracellular GSH stimulation. The surface-engineered structures are shown to accelerate the release of doxorubicin hydrochloride (DXR) from NGO-SS-mPEG 1.55 times faster than in the absence of GSH. Confocal microscopy shows clear evidence of NGO-SS-mPEG endocytosis in HeLa cells, mainly accumulated in cytoplasm. Furthermore, upon internalization of DXR-loaded NGO with a disulfide-linked PEG shell into HeLa cells, DXR is effectively released in the presence of an elevated GSH reducing environment, as observed in confocal microscopy and flow cytometric experiments. Importantly, inhibition of cell proliferation is directly correlated with increased intracellular GSH concentrations due to rapid DXR release.
Assuntos
Doxorrubicina/administração & dosagem , Doxorrubicina/química , Portadores de Fármacos/química , Grafite/química , Polietilenoglicóis/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Citometria de Fluxo , Glutationa/metabolismo , Células HeLa , Humanos , Microscopia Confocal , Oxirredução/efeitos dos fármacosRESUMO
A dual stimulus-responsive mPEG-SS-PLL(15)-glutaraldehyde star (mPEG-SS-PLL(15)-star) catiomer is developed and biologically evaluated. The catiomer system combines redox-sensitive removal of an external PEG shell with acid-induced escape from the endosomal compartment. The design rationale for PEG shell removal is to augment intracellular uptake of mPEG-SS-PLL(15)-star/DNA complexes in the presence of tumor-relevant glutathione (GSH) concentration, while the acid-induced dissociation is to accelerate the release of genetic payload following successful internalization into targeted cells. Size alterations of complexes in the presence of 10 mM GSH suggest stimulus-induced shedding of external PEG layers under redox conditions that intracellularly present in the tumor microenvironment. Dynamic laser light scattering experiments under endosomal pH conditions show rapid destabilization of mPEG-SS-PLL(15)-star/DNA complexes that is followed by facilitating efficient release of encapsulated DNA, as demonstrated by agarose gel electrophoresis. Biological efficacy assessment using pEGFP-C1 plasmid DNA encoding green fluorescence protein and pGL-3 plasmid DNA encoding luciferase as reporter genes indicate comparable transfection efficiency of 293T cells of the catiomer with a conventional polyethyleneimine (bPEI-25k)-based gene delivery system. These experimental results show that mPEG-SS-PLL(15)-star represents a promising design for future nonviral gene delivery applications with high DNA binding ability, low cytotoxicity, and high transfection efficiency.
Assuntos
Reagentes de Ligações Cruzadas/química , Dissulfetos/química , Técnicas de Transferência de Genes , Vetores Genéticos/química , Iminas/química , Polilisina/química , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Reagentes de Ligações Cruzadas/síntese química , Reagentes de Ligações Cruzadas/farmacologia , Dissulfetos/farmacologia , Vetores Genéticos/síntese química , Vetores Genéticos/farmacologia , Glutaral/química , Glutaral/farmacologia , Células HEK293 , Células HeLa , Humanos , Iminas/farmacologia , Estrutura Molecular , Oxirredução , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Polilisina/genética , Propriedades de SuperfícieRESUMO
Herein, a multi-functional nanoplatform (PDA-DTC/Cu-MnO2) was established, which has been employed for MR imaging-guided multi-therapy (CDT, PTT and chemotherapy) for cancer treatment. The in vitro and in vivo results confirmed that the biocompatible nanoplatform could significantly induce tumor cell death and inhibit tumor growth.
Assuntos
Antineoplásicos/farmacologia , Imageamento por Ressonância Magnética , Nanopartículas/química , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Cobre/farmacologia , Ditiocarb/química , Ditiocarb/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/química , Indóis/farmacologia , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Camundongos , Estrutura Molecular , Imagem Óptica , Óxidos/química , Óxidos/farmacologia , Tamanho da Partícula , Polímeros/química , Polímeros/farmacologiaRESUMO
Based on the Pt nanozyme modified mesoporous polydopamine in situ, a multi-functional nanoplatform was established, which could overcome tumour hypoxia by catalyzing overexpressed H2O2 in tumour cells to enhance photodynamic therapy. In vivo results confirmed that the tumour growth was inhibited efficiently by synergetic therapy.
Assuntos
Antineoplásicos/química , Indóis/química , Nanopartículas Metálicas/química , Polímeros/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Clorofilídeos , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Peróxido de Hidrogênio/metabolismo , Lasers , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia , Platina/química , Porosidade , Porfirinas/química , Soroalbumina Bovina/químicaRESUMO
Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non-small-cell lung cancer because of its limited expression of PD-L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid-derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA-CuS/DTX@PEI-PpIX-CpG nanocomposites, denoted as FA-CD@PP-CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)-enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA-CD@PP-CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1-tumor-bearing mice modal. A low dosage of loaded DTX in FA-CD@PP-CpG can promote infiltration of CTLs to improve efficacy of anti-PD-L1 antibody (aPD-L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA-CD@PP-CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel-enhanced immunotherapy for clinical application of breast cancer.
Assuntos
Docetaxel/química , Oligonucleotídeos/química , Linfócitos T Citotóxicos/imunologia , Animais , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Portadores de Fármacos/química , Ácido Fólico/química , Humanos , Imunoterapia , Lasers , Camundongos , Nanocompostos/química , Fototerapia , Polietilenoimina/química , Protoporfirinas/química , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
Apatinib is an oral tyrosine kinase inhibitor, which selectively targets vascular endothelial growth factor receptor 2 and has the potential to treat many tumors therapeutically. Cyclic arginylglycylaspartic acid (cRGD)- and polyethylene glycol (PEG)-modified liposomes (cRGD-Lipo-PEG) were constructed to act as a targeted delivery system for the delivery of apatinib to the human colonic cancer cell line, HCT116. These cRGD-modified liposomes specifically recognized integrin αvß3 and exhibited greater uptake efficiency with respect to delivering liposomes into HCT116 cells when compared to nontargeted liposomes (Lipo-PEG), as well as greater death of tumor cells and apoptosis. The mechanism by which cRGD-Lipo-PEG targets cells was elucidated further with competition assays. To determine the anticancer efficacy in vivo, nude mice were implanted with HCT116 xenografts and treated with apatinib-loaded liposomes or free apatinib intravenously or via intragastric administration. The active and passive targeting of cRGD-Lipo-PEG led to significant tumor treatment targeting ability, better inhibition of tumor growth, and less toxicity when compared with treatments using uncombined apatinib. The results presented strongly support the case for cRGD-Lipo-PEG representing a targeted delivery system for apatinib in the treatment of colonic cancer.
Assuntos
Sistemas de Liberação de Medicamentos , Endocitose , Peptídeos Cíclicos/química , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Citometria de Fluxo , Fluorescência , Células HCT116 , Humanos , Integrina alfaVbeta3/metabolismo , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Espectroscopia de Prótons por Ressonância Magnética , Piridinas/farmacologia , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacosRESUMO
In this study, long-circulating Arg-Gly-Asp (RGD)-modified aclacinomycin A (ACM) liposomes were prepared by thin film hydration method. Their morphology, particle size, encapsulation efficiency, and in vitro release were investigated. The RGD-ACM liposomes was about 160 nm in size and had the visual appearance of a yellowish suspension. The zeta potential was -22.2 mV and the encapsulation efficiency was more than 93%. The drug-release behavior of the RGD-ACM liposomes showed a biphasic pattern, with an initial burst release and followed by sustained release at a constant rate. After being dissolved in phosphate-buffered saline (pH 7.4) and kept at 4°C for one month, the liposomes did not aggregate and still had the appearance of a milky white colloidal solution. In a pharmacokinetic study, rats treated with RGD-ACM liposomes showed slightly higher plasma concentrations than those treated with ACM liposomes. Maximum plasma concentrations of RGD-ACM liposomes and ACM liposomes were 4,532 and 3,425 ng/mL, respectively. RGD-ACM liposomes had a higher AUC0-∞ (1.54-fold), mean residence time (2.09-fold), and elimination half-life (1.2-fold) when compared with ACM liposomes. In an in vivo study in mice, both types of liposomes inhibited growth of human lung adenocarcinoma (A549) cells and markedly decreased tumor size when compared with the control group. There were no obvious pathological tissue changes in any of the treatment groups. Our results indicate that RGD-modified ACM liposomes have a better antitumor effect in vivo than their unmodified counterparts.
Assuntos
Aclarubicina/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Antibióticos Antineoplásicos/administração & dosagem , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Oligopeptídeos/metabolismo , Aclarubicina/sangue , Aclarubicina/química , Aclarubicina/farmacocinética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Antibióticos Antineoplásicos/sangue , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Área Sob a Curva , Linhagem Celular Tumoral , Química Farmacêutica , Preparações de Ação Retardada , Estabilidade de Medicamentos , Meia-Vida , Injeções Intravenosas , Lipossomos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/química , Tamanho da Partícula , Ratos , Solubilidade , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Polylysine with cleavable PEGylation and hydrophobic histidylation (mPEG-SS-Lysn-r-Hism) was designed and developed for efficient siRNA delivery and tumor therapy. mPEG-SS-Lysn-r-Hism was used to carry and deliver small interfering RNA (siRNA) for silencing endogenous vascular endothelial growth factor (VEGF) expression and inhibiting tumor growth in HepG2 tumor-bearing mice. In this gene vector, histidine(Bzl) was selected for hydrophobic histidylation for the proton sponge ability of the imidazole ring and hydrophobic benzyl group. Cleavable PEGylation was introduced for in vivo circulation as well as selective PEG detachment in response to intracellular reduction condition in order to release the genetic payload. PEG detachment induced gene release was supported by agarose gel electrophoresis retardation assay, undertaken in the intracellular relevant reduction condition. In vitro transfection evaluation of histidylated copolymers, using pEGFP as genetic model, indicated significantly higher GFP expression than unmodified counterparts, comparable to the gold standard PEI. The efficacy of hydrophobic histidylation was found to be pronounced in mesenchymal stem cells (MSCs). In vivo application of the VEGF-siRNA package by tailored mPEG-SS-Lysn-r-Hism showed distinct tumor suppression in terms of macroscopic tumor volume and molecular analysis.