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Aim: To evaluate a liposome complex conjugated with anti-epidermal growth factor receptor (EGFR) antibodies for the treatment of pre-eclampsia (PE).Methods: In in vitro experiments, the transfection rate, silencing effect and cytotoxicity were determined. In the in vivo PE model, the siRNA distribution, mean arterial pressure, 24-h urine protein concentration, serum sFlt1 concentration, number of viable fetuses and placental weight were measured.Results: The nanomedicine effectively reduced the expression of sFIt1 and had a strong ability to target placental tissues. It could significantly reduce the symptoms of pre-eclampsia and improve pregnancy outcomes in PE model rats.Conclusion: The constructed nanomedicine can improve pregnancy outcomes in a rat model of pre-eclampsia and provides a new strategy for the treatment of pre-eclampsia.
[Box: see text].
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Silenciador del Gen , Liposomas , Preeclampsia , ARN Interferente Pequeño , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Preeclampsia/genética , Embarazo , Femenino , Animales , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , ARN Interferente Pequeño/genética , Ratas , Humanos , Liposomas/química , Resultado del Embarazo , Placenta/metabolismo , Ratas Sprague-Dawley , Receptores ErbB/genética , Receptores ErbB/metabolismo , Modelos Animales de EnfermedadRESUMEN
Introduction: The toxic side effects of systemic high-dose chemotherapy and poor sensitivity to radiotherapy hinder the survival rate of patients with osteosarcoma (OS). Nanotechnology offers new solutions for OS treatment; however, conventional nanocarriers suffer from inadequate targeting of tumors and short in vivo circulation time. Methods: Here, we designed a novel drug delivery system, [Dbait-ADM@ZIF-8]OPM, which uses OS-platelet hybrid membranes to encapsulate nanocarriers, to enhance the targeting and circulation time of nanocarriers, thereby enabling high enrichment of the nanocarriers in OS sites. Results: In the tumor microenvironment, the pH-sensitive nanocarrier, which is the metal-organic framework ZIF-8, dissociates to release radiosensitizer Dbait and the classical chemotherapeutic agent Adriamycin for the integrated treatment of OS via radiotherapy and chemotherapy. Benefiting from the excellent targeting ability of the hybrid membrane and the outstanding drug loading capacity of the nanocarrier, [Dbait-ADM@ZIF-8]OPM showed potent anti-tumor effects in tumor-bearing mice with almost no significant biotoxicity. Conclusion: Overall, this project is a successful exploration of the combination of radiotherapy and chemotherapy of OS treatment. Our findings solve the problems of the insensitivity of OS to radiotherapy and the toxic side effects of chemotherapy. Furthermore, this study is an expansion of the research of OS nanocarriers and provides new potential treatments for OS.
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The health risks of exposure to 'eco-friendly' biodegradable plastics of anthropogenic origin and their effects on the gastrointestinal tract are largely unknown. Here we demonstrate that the enzymatic hydrolysis of polylactic acid microplastics generated nanoplastic particles by competing for triglyceride-degrading lipase during gastrointestinal processes. Nanoparticle oligomers were formed by hydrophobically driven self-aggregation. In a mouse model, polylactic acid oligomers and their nanoparticles bioaccumulated in the liver, intestine and brain. Hydrolysed oligomers caused intestinal damage and acute inflammation. A large-scale pharmacophore model revealed that oligomers interacted with matrix metallopeptidase 12. Mechanistically, high binding affinity (Kd = 13.3 µmol l-1) of oligomers to the catalytic zinc-ion finger domain led to matrix metallopeptidase 12 inactivation, which might mediate the adverse bowel inflammatory effects after exposure to polylactic acid oligomers. Biodegradable plastics are considered to be a solution to address environmental plastic pollution. Thus, understanding the gastrointestinal fates and toxicities of bioplastics will provide insights into potential health risks.
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Plásticos Biodegradables , Animales , Ratones , Poliésteres , Metaloproteasas , Inflamación/inducido químicamenteRESUMEN
Necrosis induces strong inflammation with undesirable implications in clinics compared with apoptosis. Fortunately, the switch between necrosis and apoptosis could be realized by tailoring the appropriate structural properties of gold nano rods (GNRs) that could precisely modulate cell death pathways. Herein, the intracellular interaction between GNRs and organelles is monitored and it is found that lysosomes dominates necrosis/apoptosis evoking. Then the surface molecule density of GNRs, which is first defined as ρsurf. molecule (Nsurf. molecules /(a × π × Diameter × Length)), mediates lysosome activities as the membrane permeabilization (LMP), the Cathepsin B and D release, the cross-talk between lysosome and different organelles, which selectively evokes apoptosis or necrosis and the production of TNF-α from macrophages. GNRs with small ρsurf. molecule mainly induce apoptosis, while with large ρsurf. molecule they greatly contribute to necrosis. Interestingly, necrosis can be suppressed by GNRs with higher ρsurf. molecule due to the overexpression of key protease caspase 8, which cleaves the RIP1-RIP3 complex and activates caspase 3 followed by necrosis to apoptosis transition. This investigation indicates that the ρsurf. molecule greatly affects the utility of nanomaterials and different structural properties of nanomaterials have different implications in clinics.
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Apoptosis , Oro/química , Nanotubos/química , Neoplasias/metabolismo , Neoplasias/patología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Desnudos , NecrosisRESUMEN
BACKGROUND: Diabetic retinopathy (DR) is a complication of diabetes that affects the eyes and vision. It is a leading cause of visual impairment and blindness in working-age people. Vascular endothelial growth factor-A (VEGF-A) is a primary initiator and potential mediator of DR. Matrix metalloproteinase-9 (MMP-9) plays a progressive role in the onset and severity of DR. Interleukin-12 (IL-12) is a cytokine of the chemokine family that could reduce the levels of MMP-9 and VEGF-A and suppress tumor angiogenesis. We hypothesize that IL-12 may also have superior therapeutic efficacy against DR. However, protein drugs are prone to degradation by various proteases after drug injection. Therefore, they have short half-lives and low blood concentrations. The objective of this study was to develop IL-12-loaded nanoparticles for long-term and sustained DR treatment. METHODS: IL-12-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IL-12-PNP) were developed by double emulsion. The characteristics, anti-DR activity, and mechanisms of IL-12-PNP were examined in vitro and in vivo. RESULTS: The nanoparticles had suitable particle size (~132.8 nm), drug encapsulation efficiency (~34.7%), and sustained drug release profile. Compared with IL-12 and blank nanoparticles, IL-12-PNP showed better inhibitory efficacy against VEGF-A and MMP-9 expression in rat endothelial cells and DR mouse retina. Intraocular IL-12-PNP administration significantly reduced retinal damage in DR mice as they presented with increased thickness and decreased neovascularization after treatment. CONCLUSION: These data indicate that IL-12-PNP is an effective drug delivery platform for DR therapy. It restores the thickness and reduces neovascularization of the retinas of DR mice.
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Retinopatía Diabética/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Interleucina-12/administración & dosificación , Interleucina-12/uso terapéutico , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Animales , Preparaciones de Acción Retardada/farmacología , Retinopatía Diabética/patología , Células Endoteliales/metabolismo , Inyecciones Intravítreas , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Nanopartículas/ultraestructura , Neovascularización Patológica/tratamiento farmacológico , Ratas Sprague-Dawley , Retina/efectos de los fármacos , Retina/metabolismo , Retina/patología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
As the leading cause of cancer-associated mortality worldwide, lung cancer is often associated with therapy failure and decreases in survival; these factors are often attributed to lung cancer-initiating cells (CICs). In addition, sufficient evidence has suggested that simultaneous targeting of CICs, together with cancer cells, is critical for the achievement of preferable therapeutic efficacy, due to the spontaneous conversion between CICs and cancer cells. Salinomycin sodium (SS) is an antibacterial therapeutic agent that exerts potent activity against CICs in various types of cancer, including lung cancer. The present study generated SS lipid-polymer hybrid nanoparticles (NPs) with cluster of differentiation (CD)133 and epidermal growth factor receptor (EGFR) antibodies (CD133/EGFR SS NPs) for the simultaneous treatment of lung CICs and cancer cells. The activity of CD133/EGFR SS NPs was analyzed using cytotoxicity and tumorsphere formation assays, flow cytometry, and an in vivo anticancer assay in mice bearing lung cancer xenografts. The results revealed that CD133/EGFR SS NPs effectively promoted SS delivery to lung CICs and cancer cells, achieving superior therapeutic effects compared with non-targeted NPs or NPs with a single antibody. Furthermore, CD133/EGFR SS NPs exhibited the best efficacy in inhibiting tumor growth compared with the control agents in lung cancer-bearing mice. In conclusion, CD133/EGFR SS NPs may be capable of efficiently targeting and treating lung CICs together with cancer cells, and may represent an effective treatment for lung cancer.
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Antibióticos Antineoplásicos/farmacología , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Piranos/farmacología , Antígeno AC133/antagonistas & inhibidores , Animales , Antibióticos Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Humanos , Ácido Láctico/química , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Desnudos , Nanopartículas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Piranos/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We previously developed salinomycin (sali)-entrapped nanoparticles labeled with CD133 aptamers which could efficiently eliminate CD133+ osteosarcoma cancer stem cells (CSCs). However, sufficient evidences suggest that the simultaneous targeting both CSCs and cancer cells is pivotal in achieving preferable cancer therapeutic efficacy, due to the spontaneous conversion between cancer cells and CSCs. We hereby constructed sali-entrapped lipid-polymer nanoparticles labeled with CD133 and EGFR aptamers (CESP) to target both osteosarcoma cells and CSCs. The cytotoxicity of CESP in osteosarcoma cells and CSCs was superior to that of single targeting or nontargeted sali-loaded nanoparticles. Administration of CESP in vivo showed the best efficacy in inhibiting tumor growth than other controls in osteosarcoma-bearing mice. Thus, CESP was demonstrated to be capable of efficiently targeting both osteosarcoma CSCs and cancer cells, and it represents an effective potential approach to treat osteosarcoma.
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Aptámeros de Nucleótidos/química , Neoplasias Óseas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Células Madre Neoplásicas/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Piranos/administración & dosificación , Antígeno AC133/química , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Proliferación Celular/efectos de los fármacos , Receptores ErbB/química , Femenino , Humanos , Lípidos/química , Ratones , Ratones Desnudos , Nanopartículas/química , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Osteosarcoma/metabolismo , Osteosarcoma/patología , Polímeros/química , Piranos/farmacología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Melanoma is the deadliest type of skin cancer. CD20+ melanoma stem cells (CSCs) are pivotal for metastasis and initiation of melanoma. Therefore, selective elimination of CD20+ melanoma CSCs represents an effective treatment to eradicate melanoma. Salinomycin has emerged as an effective drug toward various CSCs. Due to its poor solubility, its therapeutic efficacy against melanoma CSCs has never been evaluated. In order to target CD20+ melanoma CSCs, we designed salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers (CD20-SA-NPs). Using a single-step nanoprecipitation method, salinomycin-loaded lipid-polymer nanoparticles (SA-NPs) were prepared, then CD20-SA-NPs were obtained through conjugation of thiolated anti-CD20 aptamers to SA-NPs via a maleimide-thiol reaction. CD20-SA-NPs displayed a small size of 96.3 nm, encapsulation efficiency higher than 60% and sustained drug release ability. The uptake of CD20-SA-NPs by CD20+ melanoma CSCs was significantly higher than that of SA-NPs and salinomycin, leading to greatly enhanced cytotoxic effects in vitro, thus the IC50 values of CD20-SA-NPs were reduced to 5.7 and 2.6 µg/mL in A375 CD+20 cells and WM266-4 CD+ cells, respectively. CD20-SA-NPs showed a selective cytotoxicity toward CD20+ melanoma CSCs, as evidenced by the best therapeutic efficacy in suppressing the formation of tumor spheres and the proportion of CD20+ cells in melanoma cell lines. In mice bearing melanoma xenografts, administration of CD20-SA-NPs (salinomycin 5 mg·kg-1·d-1, iv, for 60 d) showed a superior efficacy in inhibition of melanoma growth compared with SA-NPs and salinomycin. In conclusion, CD20 is a superior target for delivering drugs to melanoma CSCs. CD20-SA-NPs display effective delivery of salinomycin to CD20+ melanoma CSCs and represent a promising treatment for melanoma.
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Antineoplásicos/uso terapéutico , Portadores de Fármacos/uso terapéutico , Melanoma/tratamiento farmacológico , Nanopartículas/uso terapéutico , Células Madre Neoplásicas/efectos de los fármacos , Piranos/uso terapéutico , Animales , Antígenos CD20/química , Antineoplásicos/farmacología , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/metabolismo , Aptámeros de Nucleótidos/uso terapéutico , Aptámeros de Nucleótidos/toxicidad , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidad , Humanos , Lecitinas/química , Lecitinas/metabolismo , Lecitinas/uso terapéutico , Lecitinas/toxicidad , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/metabolismo , Nanopartículas/toxicidad , Tamaño de la Partícula , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Polietilenglicoles/uso terapéutico , Polietilenglicoles/toxicidad , Piranos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Breast cancer stem cells (CSCs) are responsible for the initiation, recurrence, and metastasis of breast cancer. Sufficient evidence has established that breast cancer cells can spontaneously turn into breast CSCs. Thus, it is essential to simultaneously target breast CSCs and cancer cells to maximize the efficacy of breast cancer therapy. HER2 has been found to be overexpressed in both breast CSCs and cancer cells. We developed salinomycin-loaded polymer-lipid hybrid anti-HER2 nanoparticles (Sali-NP-HER2) to target both HER2-positive breast CSCs and cancer cells. METHODS: The antitumor activity of Sali-NP-HER2 constructed by conjugating anti-HER2 antibodies to polymer-lipid salinomycin nanoparticles was evaluated in vitro and in vivo. RESULTS: Sali-NP-HER2 efficiently bound to HER2-positive breast CSCs and cancer cells, resulting in enhanced cytotoxic effects compared with non-targeted nanoparticles or salinomycin. In mice bearing breast cancer xenografts, administration of Sali-NP-HER2 exhibited superior efficacy in inhibiting tumor growth. Sali-NP-HER2 reduced the breast tumorsphere formation rate and the proportion of breast CSCs more effectively than non-targeted nanoparticles or salinomycin alone. CONCLUSION: Sali-NP-HER2 represents a promising approach in treating HER2-positive breast cancer by targeting both breast CSCs and cancer cells.
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Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/administración & dosificación , Piranos/administración & dosificación , Receptor ErbB-2/metabolismo , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Lípidos/química , Ratones , Nanopartículas/química , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Polímeros/química , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This manuscript describes a synergistic therapy for mastocarcinoma by pH and temperature dual-sensitive nanogel, and effects of microstructure, composition and properties of nanogel on the cellular response mechanism. The extracellular internalization of nanogels was obviously enhanced, due to the passive targeting function at T>VPTT. Interestingly, the increased cytotoxicity was further synergistically enhanced by an unexpected apoptosis as evoked by the 5-fluorouracil loaded nanogel (FLNG). The systemically evaluation of the effectors generated from different sub-cellular organelles including endosome, lysosome, autophagosome confirmed that it was a lysomal dependent apoptosis. Such specific apoptosis was mainly attributed to its activatable protonated PEI at low pH, which caused lysosomal membrane destruction and lysosomal enzyme cathepsin B (Cat B) leakage. This Cat B was then translocated to the mitochondria resulting in mitochondrial membrane permeability increase and mitochondrial membrane potential (MMP) decrease, followed by cytochrome c (Cyt C) release. Cyt C was the main molecule that evoked apoptosis as reflected by overexpression of caspase 9. Additionally, such lysosome dependent, apoptosis was further enhanced by the passive cellular targeting at T>VPTT. Thus, the tumor growth inhibition was synergistically enhanced by the extracellular temperature dependent passive targeting and intracellular pH activatable lysosomal dependent apoptosis.
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Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Lisosomas/metabolismo , Nanoestructuras/química , Animales , Caspasa 9/metabolismo , Catepsina B/metabolismo , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Citocromos c/metabolismo , Portadores de Fármacos , Femenino , Geles , Humanos , Concentración de Iones de Hidrógeno , Iminas/química , Potencial de la Membrana Mitocondrial , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Terapia Molecular Dirigida , Tamaño de la Partícula , Polietilenos/químicaRESUMEN
BACKGROUND: Acute pancreatitis (AP) is an acute inflammatory condition of the pancreas. The symptoms, treatment, and prognosis of mild and severe AP are different, and severe AP is a potentially life-threatening disease with a high incidence of complications and high mortality rate. Thus, it is urgent to develop an effective approach to reliably discriminate between mild and severe AP. METHODS: We have developed novel gadolinium-diethylenetriaminepentaacetic (Gd-DTPA)-loaded mannosylated liposomes (named thereafter M-Gd-NL) that preferably target macrophages in AP. The targeting ability of M-Gd-NL toward macrophages in AP and its ability to discriminate between mild and severe AP were evaluated. RESULTS: The liposomes were of desired particle size (~100 nm), Gd-DTPA encapsulation efficiency (~85%), and stability. M-Gd-NL and non-targeted Gd-DTPA-loaded liposomes (Gd-NL) exhibited increased relaxivity compared with Gd-DTPA. Compared with Gd-NL and Gd-DTPA, M-Gd-NL showed increased uptake in macrophages, resulting in increased T1 imaging ability both in vitro (macrophage cell line) and in vivo (severe AP model). Importantly, M-Gd-NL had the ability to discriminate between mild and severe AP, as reflected by a significantly higher T1 magnetic resonance imaging signal in severe AP than in mild AP. M-Gd-NL did not show severe organ toxicity in rats. CONCLUSION: Our data suggest that M-Gd-NL had enhanced magnetic resonance imaging ability by targeting macrophages in AP and good ability to discriminate between mild and severe AP. We believe that M-Gd-NL could shed new light on the diagnosis of AP in the near future.
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Modelos Animales de Enfermedad , Gadolinio DTPA/farmacocinética , Liposomas/farmacocinética , Imagen por Resonancia Magnética/métodos , Manosa/química , Pancreatitis/diagnóstico , Enfermedad Aguda , Animales , Medios de Contraste , Citometría de Flujo , Gadolinio DTPA/administración & dosificación , Liposomas/administración & dosificación , Masculino , Pancreatitis/diagnóstico por imagen , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
AIM: To target both head and neck squamous cell carcinoma (HNSCC) cells and cancer stem cells (CSCs) by salinomycin-loaded DSPE-PEG-MTX (synthesized using DSPE-PEG2000-NH2 and methotrexate) nanomicelles (M-SAL-MTX). MATERIALS & METHODS: The characterization, antitumor activity and mechanism of M-SAL-MTX were evaluated. RESULTS & CONCLUSION: M-SAL-MTX showed enhanced inhibitory effect toward both HNSCC CSCs and non-CSCs compared with a single treatment of methotrexate and salinomycin. In nude mice-bearing HNSCC xenografts, M-SAL-MTX suppressed tumor growth more effectively than other controls including combination of methotrexate and salinomycin. Therefore, M-SAL-MTX may provide a strategy for treating HNSCC by targeting both HNSCC CSCs and HNSCC cells.
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Antibacterianos/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Portadores de Fármacos/química , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Metotrexato/administración & dosificación , Células Madre Neoplásicas/efectos de los fármacos , Piranos/administración & dosificación , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Metotrexato/farmacología , Metotrexato/uso terapéutico , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Células Madre Neoplásicas/patología , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Piranos/farmacología , Piranos/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Magnetic resonance imaging (MRI) combined with ultrasmall superparamagnetic iron oxide (USPIO) is effective for the detection of atherosclerotic (AS) plaque, and paclitaxel is effective for the treatment of AS. C11 is a polypeptide with high affinity and specificity for collagen IV. It is abundantly expressed in the outer layer of AS plaque. This study aimed to develop USPIO + paclitaxel-loaded polymer-lipid hybrid theranostic nanoparticles conjugated with C11 (UP-NP-C11) for simultaneous imaging and treatment AS plaque. UP-NP-C11 was developed by the nanoprecipitation method, and the theranostics of AS plaque by UP-NP-C11 were evaluated both in vitro and in the rabbit AS model. UP-NP-C11 was of desired particle size (140.2 nm), showed encapsulation efficiency of 35.5% and 55.2% for USPIO and paclitaxel, respectively, and had drug release profile. The accumulation of USPIO in Matrigel (containing abundant collagen IV) and macrophages coated on the Matrigel was significantly higher in the UP-NP-C11-treated group than in the group treated by UP-NP (USPIO + paclitaxel-loaded nanoparticles). Thus, UP-NP-C11 exerted better growth inhibitory effect and MRI ability in macrophages than UP-NP. Significantly, UP-NP-C11 showed better in vivo MRI ability and therapeutic effect in rabbit AS plaque than UP-NP and commercial USPIO + paclitaxel, and Prussian blue staining revealed significantly greater accumulation of USPIOs in the UP-NP-C11-treated group than in the control group. Furthermore, UP-NP-C11 did not cause severe toxicity to the rabbits. UP-NP-C11 represents a potential approach for targeted MRI and therapy in AS plaque.
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Dextranos/química , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita/química , Paclitaxel/química , Placa Aterosclerótica/metabolismo , Nanomedicina Teranóstica/métodos , Animales , Dextranos/farmacocinética , Lípidos/química , Masculino , Paclitaxel/farmacocinética , Paclitaxel/farmacología , Polímeros/química , ConejosRESUMEN
Cancer initiating cells (CIC) are tumorigenic cancer cells that have properties similar to normal stem cells. CD20 is a phenotype of melanoma CIC that is responsible for melanoma drug resistance. Vincristine (VCR) is commonly used in melanoma therapy; however, it has been found ineffective against CIC. To target CD20+ melanoma CIC, we prepared VCR-containing immunoliposomes that were conjugated to CD20 antibodies (VCR-Lip-CD20). The drug release profile and the antibody-mediated targeting of the immunoliposomes were optimized to target CD20+ melanoma CIC. The immunoliposomes had desirable particle size (163 nm), drug encapsulation efficiency (91.8%), and drug release profile. We demonstrated that these immunoliposomes could successfully target more than 55% of CD20+ Chinese Hamster Ovary cells (CHO-CD20) even when the CHO-CD20 cells accounted for only 0.1% of a mixed population of CHO-CD20 and CHO cells. After treating WM266-4 melanoma mammospheres for 96 h, the ICo values of the drug delivered in VCR-Lip-CD20, VCR-Lip (VCR liposomes), and VCR were found to be 53.42, 98.99, and 99.09 µg/mL, respectively, suggesting that VCR-Lip-CD20 was 1.85 times more effective than VCR-Lip and VCR. VCR-Lip-CD20 could almost completely remove the tumorigenic ability of WM266-4 mammospheres in vivo, and showed the best therapeutic effect in WM266-4 melanoma xenograft mice. Significantly, VCR-Lip-CD20 could selectively kill CD20+ melanoma CIC in populations of WM266-4 cells both in vitro and in vivo. We demonstrated that VCR-Lip-CD20 has the potential to efficiently target and kill CD20+ melanoma CIC.
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Antígenos CD20/inmunología , Antineoplásicos/química , Liposomas/química , Melanoma/metabolismo , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Peso Corporal/efectos de los fármacos , Células CHO , Línea Celular , Proliferación Celular/efectos de los fármacos , Cricetinae , Cricetulus , Humanos , Liposomas/metabolismo , Liposomas/farmacocinética , Liposomas/farmacología , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIMS: To develop salinomycin-loaded poly(lactic-co-glycolic acid) nanoparticles conjugated with both CD133 aptamers A15 and EGFR aptamers CL4 (CESN), to target hepatocellular carcinoma (HCC) cells simultaneously expressing EGFR and CD133. MATERIALS & METHODS: The antitumor activity and mechanism of CESN were investigated. RESULTS & CONCLUSION: The cytotoxicity of CESN in HCC cells and CD133(+) HCC cells was superior to that of A15 or CL4-conjugted or nontargeted salinomycin-loaded nanoparticles. The antitumor assay in mice bearing HCC xenograft tumors confirmed the superior antitumor activity of CESN over other controls. We speculated that the improved therapeutic effect of CESN may be attributed to both targeting a higher percentage of HCC cells and increased delivery of salinomycin to HCC cells.
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Antígenos CD/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Receptores ErbB/genética , Glicoproteínas/genética , Neoplasias Hepáticas/tratamiento farmacológico , Nanocápsulas/química , Péptidos/genética , Piranos/administración & dosificación , Antígeno AC133 , Antineoplásicos/administración & dosificación , Aptámeros de Nucleótidos/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Ácido Láctico/química , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Terapia Molecular Dirigida/métodos , Nanocápsulas/administración & dosificación , Nanocápsulas/ultraestructura , Nanoconjugados/administración & dosificación , Nanoconjugados/química , Nanoconjugados/ultraestructura , Tamaño de la Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Piranos/química , Resultado del TratamientoRESUMEN
AIM: To develop novel nanoliposomes (Lip-ADR-Cer) codelivering doxorubicin (ADR) and PEGylated C16 ceramide (PEG-ceramide C16) to overcome multidrug resistance. MATERIALS & METHODS: The antitumor activity and mechanism of Lip-ADR-Cer were evaluated. RESULTS & CONCLUSION: The IC50 of Lip-ADR-Cer after 48-h treatment with the MCF-7/ADR and HL-60/ADR cancer cells, both being ADR resistant, was 2.2- and 1.4-fold effective respectively versus the general nanoliposomes with no PEG-ceramide C16 (Lip-ADR). The antitumor assay in mice bearing MCF-7/ADR or HL-60/ADR xenograft tumors confirmed the superior antitumor activity of Lip-ADR-Cer over Lip-ADR. We found that the improved therapeutic effect of Lip-ADR-Cer may be attributed to both of the cytotoxic effect of PEG-ceramide C16 and glucosylceramide synthase overexpression in multidrug resistance cells.
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Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/uso terapéutico , Ceramidas/administración & dosificación , Ceramidas/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Animales , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Ceramidas/química , Doxorrubicina/química , Combinación de Medicamentos , Sinergismo Farmacológico , Glucosiltransferasas/genética , Humanos , Liposomas , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/uso terapéutico , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Cancer stem cells (CSCs) possess the characteristics associated with normal stem cells and are responsible for cancer initiation, recurrence, and metastasis. CD133 is regarded as a CSCs marker of osteosarcoma, which is the most common primary bone malignancy in childhood and adolescence. Salinomycin, a polyether ionophore antibiotic, has been shown to kill various CSCs, including osteosarcoma CSCs. However, salinomycin displayed poor aqueous solubility that hinders its clinical application. The objective of this study was to develop salinomycin-loaded nanoparticles to eliminate CD133(+) osteosarcoma CSCs. METHODS: The salinomycin-loaded PEGylated poly(lactic-co-glycolic acid) nanoparticles (SAL-NP) conjugated with CD133 aptamers (Ap-SAL-NP) were developed by an emulsion/solvent evaporation method, and the targeting and cytotoxicity of Ap-SAL-NP to CD133(+) osteosarcoma CSCs were evaluated. RESULTS: The nanoparticles are of desired particle size (~150 nm), drug encapsulation efficiency (~50%), and drug release profile. After 48 hours treatment of the Saos-2 CD133(+) osteosarcoma cells with drugs formulated in Ap-SAL-NP, SAL-NP, and salinomycin, the concentrations needed to kill 50% of the incubated cells were found to be 2.18, 10.72, and 5.07 µg/mL, respectively, suggesting that Ap-SAL-NP could be 4.92 or 2.33 fold more effective than SAL-NP or salinomycin, respectively. In contrast, Ap-SAL-NP was as effective as SAL-NP, and less effective than salinomycin in Saos-2 CD133(-) cells, suggesting that Ap-SAL-NP possess specific cytotoxicity toward Saos-2 CD133(+) cells. Ap-SAL-NP showed the best therapeutic effect in Saos-2 osteosarcoma xenograft mice, compared with SAL-NP or salinomycin. Significantly, Ap-SAL-NP could selectively kill CD133(+) osteosarcoma CSCs both in vitro and in vivo, as reflected by the tumorsphere formation and proportion of Saos-2 CD133(+) cells. CONCLUSION: Our results suggest that CD133 is a potential target for drug delivery to osteosarcoma CSCs and that it is possible to significantly inhibit the osteosarcoma growth by killing CD133(+) osteosarcoma CSCs. We demonstrated that Ap-SAL-NP have the potential to target and kill CD133(+) osteosarcoma CSCs.
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Antígenos CD , Aptámeros de Nucleótidos , Glicoproteínas , Ácido Láctico/química , Nanopartículas/química , Células Madre Neoplásicas , Osteosarcoma/metabolismo , Péptidos , Ácido Poliglicólico/química , Piranos , Antígeno AC133 , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/genética , Aptámeros de Nucleótidos/farmacocinética , Aptámeros de Nucleótidos/farmacología , Línea Celular Tumoral , Glicoproteínas/genética , Glicoproteínas/metabolismo , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Péptidos/genética , Péptidos/metabolismo , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Piranos/química , Piranos/farmacocinética , Piranos/farmacología , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIMS: The aim of this study was to obtain adriamycin-loaded polymer-lipid hybrid nanoparticles conjugated with anti-EGF receptor antibody (PLNP-Mal-EGFR) for hepatocellular carcinoma (HCC) chemotherapy. MATERIALS & METHODS: The nanoparticles were characterized by dynamic light scattering and fluorescence spectroscopy. The in vitro and in vivo distribution and anti-tumor activity of the nanoparticles were evaluated. RESULTS & CONCLUSION: PLNP-Mal-EGFR showed significantly enhanced cellular cytotoxicity against HCC cells overexpressing EGFR compared with nontargeted nanoparticles (polymer-lipid hybrid nanoparticles [containing DSPE-PEG-Mal] and polymer-lipid hybrid nanoparticles [containing DSPE-mPEG] combined with anti-EGFR Fab´). PLNP-Mal-EGFR and nontargeted nanoparticles could significantly reduce the proportion of side-population cells in HCC cells. The in vivo accumulation of PLNP-Mal-EGFR was obviously higher than that of nontargeted nanoparticles in SMMC-7721 HCC cells overexpressing EGFR. Notably, PLNP-Mal-EGFR showed significantly enhanced anti-tumor activity against HCC in vivo compared with nontargeted nanoparticles and free adriamycin. Therefore, PLNP-Mal-EGFR may serve as an effective therapeutic approach for HCC chemotherapy.
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Anticuerpos/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Receptores ErbB/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas , Sistemas de Liberación de Medicamentos , Lípidos/química , Microscopía Confocal , Polímeros/químicaRESUMEN
Monoclonal antibodies (mAbs) or their derivatives are often used as the targeted ligands in the ligand targeted liposomes (LTLs). LTLs modified with mAbs or their derivatives are defined as immunoliposomes. Immunoliposomes can be designed to improve the pharmacological properties of conventional drugs. The development of immunoliposomes, which perfectly combines antibody engineering and liposomes, is becoming a possible state-of-the-art in liposome research. This review discusses the recent characterization and therapeutic effects of immunoliposomes in cancer therapy. The recent advances in the field of immunoliposomes for the treatment of cancer are summarized as follows: antibody engineering, current antibody conjugation strategies, characterization and therapeutic effects of immunoliposomes and the future perspective of immunoliposomes. Although antibody targeted immunoliposomes are being developed rapidly, there has been still a number of hot spots in research that require sustained effort for success. It is reasonable to predict that immunoliposomes will be approved for clinic use, and patients will benefit much from this cancer targeted therapy.
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Anticuerpos/química , Antineoplásicos/química , Liposomas/química , Animales , Anticuerpos/inmunología , Anticuerpos Inmovilizados/química , Antineoplásicos/administración & dosificación , Portadores de Fármacos/química , Humanos , Hidrazonas/química , Neoplasias/terapia , Ácidos Nucleicos/administración & dosificación , Ácidos Nucleicos/química , Compuestos de Sulfhidrilo/químicaRESUMEN
The chemotherapy combined with gene therapy has received great attention. We developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' co-delivering adriamycin (ADR) and ribonucleotide reductase M2 (RRM2) siRNA (ADR-RRM2-TLPD), to achieve combined therapeutic effects in human hepatocellular carcinoma (HCC) overexpressing EGFR. The antitumor activity and mechanisms of ADR-RRM2-TLPD were investigated. The results showed that RRM2 expression was higher in HCC than in non-HCC tissue, and RRM2 siRNA inhibited HCC cell proliferation, suggesting that RRM2 is a candidate target for HCC therapy. ADR-RRM2-TLPD delivered ADR and RRM2 siRNA to EGFR overexpressing HCC cells specifically and efficiently both in vitro and in vivo, resulting in enhanced therapeutic effects (cytotoxicity, apoptosis and senescence-inducing activity) compared with single-drug loaded or non-targeted controls, including ADR-NC-TLPD (targeted LPD co-delivering ADR and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and ADR-RRM2-NTLPD (non-targeted LPD co-delivering ADR and RRM2 siRNA). Mechanism studies showed that p21 is involved in the combined therapeutic effect of ADR-RRM2-TLPD. The average weight of the orthotopic HCC in mice treated with ADR-RRM2-TLPD was significantly lighter than that of mice treated with other controls. Thus, ADR-RRM2-TLPD represents a potential strategy for combined therapy of HCC overexpressing EGFR.