RESUMEN
BACKGROUND: Esophageal cancer is the fifth most common cancer affecting men in China. The primary treatment options are surgery and traditional radio-chemotherapy; no effective targeted therapy exists yet. Self-assembled RNA nanocarriers are highly stable, easily functionally modified, and have weak off-tumor targeting effects. Thus, they are among the most preferred carriers for mediating the targeted delivery of anti-tumor drugs. miR-375 was found to be significantly down-regulated in esophageal squamous cell carcinoma (ESCC) tissues and its overexpression effectively inhibits the proliferation, migration, and invasion of ESCC cells. Moreover, epidermal growth factor receptor (EGFR) was overexpressed in ESCC cells, and accumulation of RNA nanoparticles in ESCC tumors was enhanced by EGFR-specific aptamer (EGFRapt) modification. RESULTS: Herein, a novel four-way junction RNA nanocarrier, 4WJ-EGFRapt-miR-375-PTX simultaneously loaded with miR-375, PTX and decorated with EGFRapt, was developed. In vitro analysis demonstrated that 4WJ-EGFRapt-miR-375-PTX possesses strong thermal and pH stabilities. EGFRapt decoration facilitated tumor cell endocytosis and promoted deep penetration into 3D-ESCC spheroids. Xenograft mouse model for ESCC confirmed that 4WJ-EGFRapt-miR-375-PTX was selectively distributed in tumor sites via EGFRapt-mediating active targeting and targeted co-delivery of miR-375 and PTX exhibited more effective therapeutic efficacy with low systemic toxicity. CONCLUSION: This strategy may provide a practical approach for targeted therapy of ESCC.
Asunto(s)
Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , MicroARNs , Terapia Molecular Dirigida/métodos , Nanopartículas , Animales , Apoptosis/efectos de los fármacos , Aptámeros de Péptidos/metabolismo , Aptámeros de Péptidos/farmacocinética , Línea Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/farmacocinética , Femenino , Humanos , Ratones , Ratones Desnudos , MicroARNs/química , MicroARNs/farmacocinética , MicroARNs/farmacología , Sistema de Administración de Fármacos con Nanopartículas/química , Sistema de Administración de Fármacos con Nanopartículas/farmacocinética , Sistema de Administración de Fármacos con Nanopartículas/farmacologíaRESUMEN
Tumor-specific therapeutic platforms with improved targeting efficacy and minimized side effect are crucial in cancer therapy. Capitalizing on the recognition capability and biocompatibility of aptamers, we herein designed a multistage targeted drug-delivery system using multiple biodegradable molecules-enveloped nanovehicle that can be employed to efficiently treat human epithelial growth factor receptor (HER2)-overexpressing breast cancer. In this nanovehicle, two aptamers respectively specific to HER2 and ATP were organized in a hierarchical manner. The outmost HER2 aptamer (HB5) governs the recognition to HER2 protein overexpressed in SK-BR-3 cell lines, while the ATP aptamer incorporated with anticancer drug (-)-epigallocatechin gallate (EGCG) and protamine sulfate in the inner core functions as a switch of drug release in response to abundant intracellular ATP. The targeting and drug locker aptamers were cascaded for active targeting effect and stimuli responsiveness, guaranteeing the site-specific drug transportation and endogenous species-triggered drug release inside the tumor cells. Moreover, nanostructured lipid carriers (NLCs) were constructed to wrap and stabilize the loosely bounded ternary complex, minimizing premature drug leakage potentially encountered by the biomolecule assembled nanocarriers. This multiple biomolecules-enveloped nanovehicle demonstrated improved inhibitory actions on tumor growth and minimum side effect to normal organs and tissues both in vitro and in vivo. The presented nanovehicle built from recognition and therapeutic components in a nontoxic framework offered a promising drug-delivery platform with transport precision and biological safety.
Asunto(s)
Aptámeros de Péptidos , Neoplasias de la Mama/tratamiento farmacológico , Catequina/análogos & derivados , Materiales Biocompatibles Revestidos , Sistemas de Liberación de Medicamentos/métodos , Regulación Neoplásica de la Expresión Génica , Nanoestructuras , Receptor ErbB-2/biosíntesis , Aptámeros de Péptidos/química , Aptámeros de Péptidos/farmacocinética , Aptámeros de Péptidos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Catequina/química , Catequina/farmacocinética , Catequina/farmacología , Línea Celular Tumoral , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacocinética , Materiales Biocompatibles Revestidos/farmacología , Femenino , Humanos , Nanoestructuras/química , Nanoestructuras/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: We will describe recently discovered smart aptamers with tumor specificity, with an emphasis on targeted delivery of novel therapeutic molecules, cancer-specific biomarkers, and immunotherapy. RECENT FINDINGS: The development of cancer-specific aptamers has facilitated targeted delivery of potent therapeutic molecules to cancer cells without harming nontumoral cells. This specificity also makes it possible to discover novel cancer biomarkers. Furthermore, alternative immune-checkpoint blockade aptamers have been developed for combinational immunotherapy. SUMMARY: Aptamers selected against cancer cells show cancer specificity, which has great potential for targeting. First, functionalizing targeted aptamers with therapeutic molecule payloads (e.g., small activating RNAs, antimitotic drugs, therapeutic antibodies, and peptides) facilitates successful delivery into cancer cells. This approach greatly improves the therapeutic index by minimizing side-effects in nontumoral cells. Second, cancer-specific proteins have been identified as cancer biomarkers through in-vitro and in-vivo selection, aptamer pull-down assays, and mass spectrometry. These newly discovered biomarkers improve therapeutic intervention and diagnostic specificity. In addition, the development of alternative immune-checkpoint blockade aptamers is suggested for use in combinational immunotherapeutic with current immune blockade regimens, to reduce the resistance and exhaustion of T cells in clinical trials. VIDEO ABSTRACT: http://links.lww.com/COON/A21.
Asunto(s)
Aptámeros de Nucleótidos/uso terapéutico , Aptámeros de Péptidos/uso terapéutico , Neoplasias/tratamiento farmacológico , Aptámeros de Nucleótidos/genética , Aptámeros de Nucleótidos/farmacocinética , Aptámeros de Péptidos/genética , Aptámeros de Péptidos/farmacocinética , Humanos , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
The use of monoclonal antibodies and aptamers is growing every single day, as the use of nanoparticle systems. Although most of the products are under investigation, there are a few commercialized products available at the market, for human consume. In this study, we have compared three formulations (aptamer anti-MUC1, monoclonal antibody - Trastuzumab and monoclonal antibodies nanoparticles - PLA/PVA/MMT trastuzumab) to identify their profile as also to understand their behavior into an alive biological system. In this direction the radiolabeling of the products were done and they were all tested in animals (in vivo) in two conditions: healthy rats and breast cancer induced animals. The results showed that the nanoparticle has the better biodistribution profile, followed by the aptamer. We conclude that more studies and a global effort to elucidate the biological behavior of drugs and especially nano-drugs are necessary.
Asunto(s)
Antineoplásicos/farmacocinética , Aptámeros de Péptidos/farmacocinética , Glándulas Mamarias Animales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Cintigrafía/métodos , Trastuzumab/farmacocinética , Animales , Antineoplásicos/química , Aptámeros de Péptidos/química , Femenino , Humanos , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Mucina-1/química , Mucina-1/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Poliésteres/química , Alcohol Polivinílico/química , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas , Ratas Wistar , Coloración y Etiquetado/métodos , Tecnecio/química , Tecnecio/farmacocinética , Distribución Tisular , Trastuzumab/químicaRESUMEN
Aptamers represent the novel class of oligonucleotides holding multiple applications in the area of biomedicine. The advancements introduced with the Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach further eased the scope of producing modified aptamers within a short span yet retaining the properties of stability and applicability. In the recent times, aptamers were identified to have the potential for penetrating into the deep human crevices and thus can be utilized in addressing the issues of complex neurological disorders. Considering the specificity and stability enhancement by chemical modifications, aptamer-based nanotechnologies may have great potential for future therapeutics and diagnostics (theranostics). The research community has already witnessed success with the approval of macugen (an anti-vascular endothelial growth factor aptamer) for treating degenerating eye disease, and hopefully those that are in the clinical trials will soon be translated for human application. Herein, we have summarized the aptamer chemistry, aptamer-nanoconjugates and their applications against neurological diseases.
Asunto(s)
Aptámeros de Nucleótidos/uso terapéutico , Aptámeros de Péptidos/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Terapia Molecular Dirigida/métodos , Técnica SELEX de Producción de Aptámeros/métodos , Nanomedicina Teranóstica/métodos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/terapia , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/farmacocinética , Aptámeros de Péptidos/química , Aptámeros de Péptidos/farmacocinética , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Humanos , Degeneración Macular/metabolismo , Degeneración Macular/patología , Degeneración Macular/terapia , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Miastenia Gravis/metabolismo , Miastenia Gravis/patología , Miastenia Gravis/terapia , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/terapia , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/terapiaRESUMEN
Hyperbranched polymers conjugated to a peptide-aptamer were prepared using a combination of RAFT polymerisation and click chemistry for targeting tumour cells in vivo. The polymers showed enhanced cell-uptake in vitro (compared to unconjugated polymer) while excellent specificity for solid tumours was observed in vivo using a mouse model of melanoma.
Asunto(s)
Aptámeros de Péptidos/síntesis química , Sistemas de Liberación de Medicamentos , Melanoma Experimental/patología , Metacrilatos/síntesis química , Polietilenglicoles/síntesis química , Neoplasias Cutáneas/patología , Animales , Aptámeros de Péptidos/farmacocinética , Colorantes Fluorescentes , Inyecciones Intravenosas , Inyecciones Subcutáneas , Metacrilatos/farmacocinética , Ratones , Ratones Endogámicos C57BL , Imagen Molecular/métodos , Polietilenglicoles/farmacocinética , Rodaminas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: We investigated the stability, pharmacokinetic, and pharmacodynamic profile of the 2(nd) generation anti-von Willeband factor aptamer ARC15105. METHODS AND RESULTS: Platelet plug formation was measured by collagen/adenosine diphosphate-induced closure time with the platelet function analyzer-100 and platelet aggregation by multiple electrode aggregometry. Platelet adhesion was measured on denuded porcine aortas and in a flow chamber. Aptamer stability was assessed by incubation in nuclease rich human, monkey, and rat serum for up to 72 hours. Pharmacokinetic and pharmacodynamic profiles were tested in cynomolgus monkeys after IV and SC administration. The median IC(100) and IC(50) to prolong collagen/adenosine diphosphate-induced closure timewere 27 nmol/L and 12 nmol/L, respectively. ARC15105 (1.3 µmol/L) completely inhibited ristocetin-induced platelet aggregation in whole blood (P<0.001), but also diminished collagen, ADP, arachidonic acid, and thrombin receptor activating peptide-induced platelet aggregation to some extent (P<0.05). ARC15105 (40 nmol/L) decreased platelet adhesion by >90% on denuded porcine aortas (P<0.001), which was comparable to the degree of inhibition obtained with abciximab. ARC15105 (100 nmol/L) also inhibited platelet adhesion to collagen under arterial shear in a flow chamber by >90% (P<0.001). The IV and SC terminal half-lives in cynomolgus monkeys were 67 and 65 hours, respectively, and the SC bioavailability was ≈98%. Allometric scaling estimates the human T(1/2) would be ≈217 hours. Pharmacodynamic analysis confirms that ARC15105 inhibits von Willeband factor activity >90% in blood samples taken 300 hours after a 20 mg/kg IV or SC dose in monkeys. CONCLUSIONS: The potency, pharmacokinetic profile, and SC bioavailability of ARC15105 support its clinical investigation for chronic inhibition of von Willeband factor -mediated platelet activation.
Asunto(s)
Aptámeros de Nucleótidos/uso terapéutico , Aptámeros de Péptidos/farmacología , Plaquetas/efectos de los fármacos , Infarto del Miocardio/sangre , Activación Plaquetaria/efectos de los fármacos , Adhesividad Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Factor de von Willebrand/antagonistas & inhibidores , Anciano , Animales , Aptámeros de Nucleótidos/administración & dosificación , Aptámeros de Nucleótidos/farmacocinética , Aptámeros de Péptidos/administración & dosificación , Aptámeros de Péptidos/farmacocinética , Austria , Disponibilidad Biológica , Plaquetas/metabolismo , Boston , Estudios de Casos y Controles , Colágeno/metabolismo , Estudios Transversales , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Macaca fascicularis , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacocinética , Pruebas de Función Plaquetaria , Unión Proteica , Quebec , Ratas , Porcinos , Factor de von Willebrand/metabolismoRESUMEN
The repression of the androgen receptor (AR) activity is a major objective to inhibit prostate cancer growth. One underlying mechanism for efficient hormone therapy is based on corepressors that inactivate the AR. In line with this, castration-resistant prostate cancer is associated with malfunction or reduced corepressor action. To overcome this, the overexpression of endogenous corepressors, however, affects many other transcription factors. Therefore, an AR-specific corepressor could be of advantage. Using a yeast peptide aptamer two-hybrid screen with the full-length human AR, we identified a short amino acid-stretch that binds specifically to the human AR in yeast and in mammalian cells and not to the closely related progesterone or glucocorticoid receptors. Furthermore, fused to a silencing domain, this aptamer-based corepressor (AB-CoR) exhibits corepressor activity by inhibiting both the AR-mediated transactivation and expression of the AR target gene PSA. Furthermore, stable expression of the AB-CoR inhibits growth of human LNCaP prostate cancer cells. Moreover, we generated a cell-permeable AB-CoR by fusing a protein transduction domain to establish a vector-free transport system. Treatment of LNCaP cells with the bacterially expressed and affinity-purified cell-permeable AB-CoR peptide resulted in a significant inhibition of both AR-mediated transactivation and prostate cancer cell proliferation. Thus, generation of a novel AR-specific aptamer-based corepressor may present a vector-free inhibition of AR-dependent prostate cancer growth as a novel approach.
Asunto(s)
Aptámeros de Péptidos/farmacocinética , Proliferación Celular , Proteínas Co-Represoras/metabolismo , Regulación hacia Abajo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/fisiopatología , Receptores Androgénicos/metabolismo , Aptámeros de Péptidos/síntesis química , Aptámeros de Péptidos/genética , Aptámeros de Péptidos/metabolismo , Línea Celular Tumoral , Proteínas Co-Represoras/síntesis química , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/farmacocinética , Regulación hacia Abajo/efectos de los fármacos , Humanos , Masculino , Permeabilidad , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Unión Proteica , Receptores Androgénicos/genética , Especificidad de la Especie , Activación Transcripcional/efectos de los fármacosRESUMEN
BACKGROUND: Inhibitors of DNA-binding proteins (Id1-4), lacking the basic DNA-binding domain, function as dominant inhibitors of cell-cycle regulators. Overexpression of Id proteins promotes cancer cell proliferation and resistance against apoptosis. Level of Id protein expression, especially of Id1, correlates with poor differentiation, enhanced malignant potential and more aggressive clinical behaviour of ovarian tumours. Although overexpression of Ids has been found and shown to correlate with poor clinical outcome, their inhibition at protein level has never been studied. METHODS: A peptide aptamer, Id1/3-PA7, targeting Id1 and Id3, was isolated from a randomised combinatorial expression library using yeast and mammalian two-hybrid systems. Id1/3-PA7 was fused, expressed and purified with a cell-penetrating protein transduction domain. RESULTS: Intracellular-delivered Id1/3-PA7 colocalised to Id1 and Id3. It induced cell-cycle arrest and apoptosis in ovarian cancer cells ES-2 and PA-1. It activated the E-box promoter and increased the expression level of cyclin-dependent kinase inhibitor (CDKN2A) in a dose-dependent manner that is paralleled by the cleavage of poly-ADP ribose polymerase. These effects were counteracted by ectopically overexpressed Id1 and Id3. CONCLUSION: Id1/3-PA7 could represent an exogenous anti-tumour agent that can significantly trigger cell-cycle arrest and apoptosis in ovarian cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Aptámeros de Péptidos/farmacología , Carcinoma/patología , Ciclo Celular/efectos de los fármacos , Proteínas Inhibidoras de la Diferenciación/antagonistas & inhibidores , Neoplasias Ováricas/patología , Antineoplásicos/farmacología , Aptámeros de Péptidos/metabolismo , Aptámeros de Péptidos/farmacocinética , Carcinoma/genética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes p16/efectos de los fármacos , Humanos , Proteína 1 Inhibidora de la Diferenciación/antagonistas & inhibidores , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Proteínas Inhibidoras de la Diferenciación/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/genética , Distribución Tisular , Células Tumorales CultivadasRESUMEN
Commercially pure titanium (cp-Ti) is widely used in the field of long-term clinical oral implantology owing to its ability to allow close bone-implant apposition. The optimization of its function based on artificial proteins has become a key issue in the development of improved cp-Ti implants. Here, we set out to identify peptide aptamers with preferential adsorption towards titanium-based implants through the phage display methodology. Fifteen sequences were selected in the third round of biopanning. One sequence, ATWVSPY (named TBP1), had a 40% repetition rate and exhibited the strongest binding affinity to cp-Ti disks. Ten sequences were selected in the fourth round, among which the repetition rate is 80% for TBP1 and 20% for TBP2 (GVGLPHT). The peptide aptamers against cp-Ti disks can provide an alternative method of functional coating for biomaterial surfaces.
Asunto(s)
Aptámeros de Péptidos/aislamiento & purificación , Aptámeros de Péptidos/metabolismo , Biblioteca de Péptidos , Prótesis e Implantes , Titanio/metabolismo , Adsorción , Secuencia de Aminoácidos , Aptámeros de Péptidos/farmacocinética , Materiales Biocompatibles Revestidos/síntesis química , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Ensayo de Materiales , Unión Proteica , Especificidad por Sustrato , Propiedades de Superficie , Andamios del Tejido/química , Titanio/químicaRESUMEN
Assured dispersibility is a prerequisite for clinical application of nanomaterials. Carbon nanomaterials have hydrophobic surfaces and thus readily agglomerate under aqueous conditions. Various conjugates composed of a carbon surface-binding moiety and polyethylene glycol (PEG) have been examined as dispersants for carbon nanomaterials. Here we synthesized a conjugate composed of a comb-shaped PEG (cPEG) and carbon nanomaterial-binding peptide (NHBP-1). The resultant cPEG-NHBP3 conjugate displayed multiple units (2.4 on average) of NHBP-1 on a single cPEG molecule whose average molecular weight was 15-20 kDa. cPEG-NHBP3 endowed single-walled carbon nanohorns (SWNHs) with good dispersibility in vitro, which could not be achieved with 20PEG-NHBP, a conjugate composed of linear 20 kDa PEG and a single NHBP-1 peptide. Notably, cPEG-NHBP1, which was similar to 20PEG-NHBP but had a comb-shaped PEG backbone, functioned better as a dispersant than 20PEG-NHBP, suggesting a graft-type PEG formula is better-suited for dispersing nanomaterials. Finally, cPEG-NHBP3 treatment substantially suppressed formation of SWNH agglomerates in mouse lung, suggesting the potential utility of SWNHs as a carrier in drug delivery systems.