RESUMEN
Over the past decades, many drugs based on the use of nanotechnology and nucleic acids have been developed. However, until recently, most of them remained at the stage of pre-clinical development and testing and did not find their way to the clinic. In our opinion, the main reason for this situation lies in the enormous complexity of the development and industrial production of such formulations leading to their high cost. The development of nanotechnology-based drugs requires the participation of scientists from many and completely different specialties including Pharmaceutical Sciences, Medicine, Engineering, Drug Delivery, Chemistry, Molecular Biology, Physiology and so on. Nevertheless, emergence of coronavirus and new vaccines based on nanotechnology has shown the high efficiency of this approach. Effective development of vaccines based on the use of nucleic acids and nanomedicine requires an understanding of a wide range of principles including mechanisms of immune responses, nucleic acid functions, nanotechnology and vaccinations. In this regard, the purpose of the current review is to recall the basic principles of the work of the immune system, vaccination, nanotechnology and drug delivery in terms of the development and production of vaccines based on both nanotechnology and the use of nucleic acids.
RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal form of interstitial lung disease. We hypothesized that the local pulmonary delivery of prostaglandin E2 (PGE2) by liposomes can be used for the effective treatment of IPF. To test this hypothesis, we used a murine model of bleomycin-induced IPF to evaluate liposomal delivery of PGE2 topically to the lungs. Animal survival, body weight, hydroxyproline content in the lungs, lung histology, mRNA, and protein expression were studied. After inhalation delivery, liposomes accumulated predominately in the lungs. In contrast, intravenous administration led to the accumulation of liposomes mainly in kidney, liver, and spleen. Liposomal PGE2 prevented the disturbances in the expression of many genes associated with the development of IPF, substantially restricted inflammation and fibrotic injury in the lung tissues, prevented decrease in body weight, limited hydroxyproline accumulation in the lungs, and virtually eliminated mortality of animals after intratracheal instillation of bleomycin. In summary, our data provide evidence that pulmonary fibrosis can be effectively treated by the inhalation administration of liposomal form of PGE2 into the lungs. The results of the present investigations make the liposomal form of PGE2 an attractive drug for the effective inhalation treatment of idiopathic pulmonary fibrosis.
Asunto(s)
Dinoprostona/administración & dosificación , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Administración Intravenosa , Animales , Bleomicina/toxicidad , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Hidroxiprolina/metabolismo , Fibrosis Pulmonar Idiopática/inducido químicamente , Inmunohistoquímica , Riñón/efectos de los fármacos , Liposomas/administración & dosificación , Liposomas/metabolismo , Hígado/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , ARN Mensajero/metabolismo , Bazo/efectos de los fármacos , Factores de Tiempo , Distribución TisularRESUMEN
Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.
Asunto(s)
Doxorrubicina/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Oligonucleótidos/farmacología , Administración por Inhalación , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Ratones , Ratones Desnudos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Oligonucleótidos/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-2RESUMEN
Low penetration ability of Small Interfering RNA (siRNA) through the cellular plasma membrane combined with its limited stability in blood, limits the effectiveness of the systemic delivery of siRNA. In order to overcome such difficulties, we constructed a nanocarrier-based delivery system by taking advantage of the lessons learned from the problems in the delivery of DNA. In the present study, siRNA nanoparticles were first formulated with Poly(Propyleneimine) (PPI) dendrimers. To provide lateral and steric stability to withstand the aggressive environment in the blood stream, the formed siRNA nanoparticles were caged with a dithiol containing cross-linker molecules followed by coating them with Poly(Ethylene Glycol) (PEG) polymer. A synthetic analog of Luteinizing Hormone-Releasing Hormone (LHRH) peptide was conjugated to the distal end of PEG polymer to direct the siRNA nanoparticles specifically to the cancer cells. Our results demonstrated that this layer-by-layer modification and targeting approach confers the siRNA nanoparticles stability in plasma and intracellular bioavailability, provides for their specific uptake by tumor cells, accumulation of siRNA in the cytoplasm of cancer cells, and efficient gene silencing. In addition, in vivo body distribution data confirmed high specificity of the proposed targeting delivery approach which created the basis for the prevention of adverse side effects of the treatment on healthy organs.
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Polipropilenos/química , ARN Interferente Pequeño/administración & dosificación , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Membrana Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Dendrímeros/química , Sistemas de Liberación de Medicamentos , Expresión Génica/efectos de los fármacos , Genes bcl-2/genética , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Indicadores y Reactivos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Nanopartículas , Trasplante de Neoplasias , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Interferente Pequeño/sangre , Propiedades de Superficie , Distribución Tisular , Tolueno/análogos & derivadosRESUMEN
PURPOSE: To compare systemic intravenous and local intratracheal delivery of doxorubicin (DOX), antisense oligonucleotides (ASO) and small interfering RNA (siRNA). METHODS: "Neutral" and cationic liposomes were used to deliver DOX, ASO, and siRNA. Liposomes were characterized by dynamic light scattering, zeta-potential, and atomic force microscopy. Cellular internalization of DOX, ASO and siRNA was studied by confocal microscopy on human lung carcinoma cells. In vivo experiments were carried out on nude mice with an orthotopic model of human lung cancer. RESULTS: Liposomes provided for an efficient intracellular delivery of DOX, ASO, and siRNA in vitro. Intratracheal delivery of both types of liposomes in vivo led to higher peak concentrations and much longer retention of liposomes, DOX, ASO and siRNA in the lungs when compared with systemic administration. It was found that local intratracheal treatment of lung cancer with liposomal DOX was more efficient when compared with free and liposomal DOX delivered intravenously. CONCLUSIONS: The present study outlined the clear advantages of local intratracheal delivery of liposomal drugs for the treatment of lung cancer when compared with systemic administration of the same drug.
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Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Oligonucleótidos Antisentido/administración & dosificación , Interferencia de ARN , ARN Interferente Pequeño/administración & dosificación , Administración por Inhalación , Animales , Antibióticos Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacocinética , Portadores de Fármacos , Ácidos Grasos Monoinsaturados/química , Humanos , Inyecciones Intravenosas , Luz , Liposomas , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Microscopía de Fuerza Atómica , Microscopía Confocal , Oligonucleótidos Antisentido/farmacocinética , Tamaño de la Partícula , Compuestos de Amonio Cuaternario/química , ARN Interferente Pequeño/farmacocinética , Dispersión de Radiación , Propiedades de Superficie , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To enhance the efficacy of cancer treatment, we propose a complex approach: simultaneous delivery to the tumor of a chemotherapeutic agent and a suppressor of hypoxia-inducible factor 1 alpha (HIF1A). EXPERIMENTAL DESIGN: The novel complex liposomal drug delivery system was developed and evaluated in vitro and in vivo on nude mice bearing xenografts of multidrug-resistant human ovarian carcinoma. The proposed novel complex drug delivery system consists of liposomes as a nanocarrier, a traditional anticancer drug (doxorubicin) as a cell death inducer, and antisense oligonucleotides targeted to HIF1A mRNA as a suppressor of cellular resistance and angiogenesis. RESULTS: The system effectively delivers active ingredients into tumor cells, multiplies the cell death signal initiated by doxorubicin, and inhibits cellular defensive mechanisms and angiogenesis by down-regulating BCL2, HSP90, and vascular endothelial growth factor proteins. This, in turn, activates caspases, promotes apoptosis, necrosis, and tumor shrinkage. The proposed novel complex multipronged approach enhances the efficiency of chemotherapy. CONCLUSIONS: The proposed combination therapy prevents the development of resistance in cancer cells, and thus, increases the efficacy of chemotherapy to an extent that cannot be achieved by individual components applied separately. It could form the foundation for a novel type of cancer therapy based on simultaneous delivery of an anticancer drug and a suppressor of HIF1A.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Subunidad alfa del Factor 1 Inducible por Hipoxia/efectos de los fármacos , Oligonucleótidos Antisentido/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Animales , Western Blotting , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos , Femenino , Humanos , Ratones , Microscopía de Fuerza Atómica , Microscopía Electrónica de Transmisión , Nanopartículas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To compare the influence of different characteristics of nanocarriers on the efficacy of chemotherapy and imaging, we designed, characterized, and evaluated three widely used nanocarriers: linear polymer, dendrimer and liposome in vitro and in vivo. These nanocarriers delivered the same anticancer drug (paclitaxel) and/or imaging agent (Cy5.5). A synthetic analog of LHRH peptide targeted to receptors overexpressed on the membrane of cancer cells was attached to the nanocarriers as a tumor targeting moiety. Significant differences were found between various studied non-targeted carriers in their cellular internalization, cytotoxicity, tumor and organ distribution and anticancer efficacy. LHRH peptide substantially enhanced intratumoral accumulation and anticancer efficacy of all delivery systems and minimized their adverse side effects. For the first time, the present study revealed that the targeting of nanocarriers to tumor-specific receptors minimizes the influence of the architecture, composition, size and molecular mass of nanocarriers on the efficacy of imaging and cancer treatment.
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Antineoplásicos/administración & dosificación , Medios de Contraste/administración & dosificación , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias , Polímeros/química , Receptores LHRH/metabolismo , Animales , Antineoplásicos/uso terapéutico , Carbocianinas/administración & dosificación , Línea Celular Tumoral , Dendrímeros/química , Diagnóstico por Imagen , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Liposomas , Ratones , Ratones Desnudos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We designed, synthesized, and evaluated in vitro and in vivo a novel targeted anticancer polymeric prodrug containing multiple copies of tumor targeting moiety [synthetic luteinizing hormone-releasing hormone (LHRH) peptide, analog of LHRH] and anticancer drug (camptothecin). One, two, or three molecules of the targeting peptide and anticancer drug were covalently conjugated with bis(2-carboxyethyl) polyethylene glycol polymer using citric acid as a multivalent spacer. We showed that LHRH peptide was bound to extracellular receptors and localized in plasma membrane of cancer cells. The designed tumor-targeted prodrug increased the solubility of anticancer drug and offered cytoplasmic and/or nuclear delivery of drug to cancer cells expressing LHRH receptors. The multicomponent prodrug containing three copies of the targeting peptide and drug was almost 100 times more cytotoxic and substantially had enhanced antitumor activity compared with the analogous nontargeted prodrug and prodrugs containing one or two copies of active components.