RESUMEN
Super-enhancer (SE) plays a vital role in the determination of cell identity and fate. Up-regulated expression of coding genes is frequently associated with SE. However, the transcription dysregulation driven by SE, from the viewpoint of long non-coding RNA (lncRNA), remains unclear. Here, SE-associated lncRNAs in HCC are comprehensively outlined for the first time. This study integrally screens and identifies several novel SE-associated lncRNAs that are highly abundant and sensitive to JQ1. Especially, HSAL3 is identified as an uncharacterized SE-driven oncogenic lncRNA, which is activated by transcription factors HCFC1 and HSF1 via its super-enhancer. HSAL3 interference negatively regulates NOTCH signaling, implying the potential mechanism of its tumor-promoting role. The expression of HSAL3 is increased in HCC samples, and higher HSAL3 expression indicates an inferior overall survival of HCC patients. Furthermore, siHSAL3 loaded nanoparticles exert anti-tumor effect on HCC in vitro and in vivo. In conclusion, this is the first comprehensive survey of SE-associated lncRNAs in HCC. HSAL3 is a novel SE-driven oncogenic lncRNA, and siHSAL3 loaded nanoparticles are therapeutic candidates for HCC. This work sheds lights on the merit of anchoring SE-driven oncogenic lncRNAs for HCC treatment.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Hemodialysis patients are prone to gastrointestinal bleeding, and Mallory-Weiss syndrome (MWS) is one of the causes. Mallory-Weiss syndrome is often induced by severe vomiting, manifests as upper gastrointestinal bleeding, and is self-limited with a good prognosis. However, mild vomiting in hemodialysis patients can lead to the occurrence of MWS, and the mild early symptoms are easy to misdiagnose, leading to the aggravation of the disease. CASE PRESENTATION: In this paper, we report four hemodialysis patients with MWS. All patients displayed symptoms of upper gastrointestinal bleeding. The diagnosis of MWS was confirmed by gastroscopy. One patient had a history of severe vomiting; however, the other three reported histories of mild vomiting. Three patients received the conservative hemostasis treatment, and the gastrointestinal bleeding stopped. One patient underwent the gastroscopic and interventional hemostasis treatments. The conditions of three of the patients improved. Unfortunately, one of the patients died due to the cardia insufficiency. CONCLUSIONS: We think that the mild symptoms of MWS are easily covered up by other symptoms. This may lead to delays in diagnosis and treatment. For patients with severe symptoms, gastroscopic hemostasis is still the first choice, and interventional hemostasis can also be considered. For patients with mild symptoms, drug hemostasis is the first consideration.
Asunto(s)
Síndrome de Mallory-Weiss , Humanos , Tratamiento Conservador/efectos adversos , Muerte , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/terapia , Síndrome de Mallory-Weiss/complicaciones , Síndrome de Mallory-Weiss/diagnóstico , Vómitos , Adolescente , Persona de Mediana Edad , Anciano , Masculino , FemeninoRESUMEN
A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of â¼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter â¼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.
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Antineoplásicos/uso terapéutico , Nanopartículas , Neoplasias/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Apoptosis , Línea Celular Tumoral , Humanos , Metástasis de la Neoplasia , Neoplasias/patología , Esferoides CelularesRESUMEN
Chemoimmunotherapy, which combines chemotherapeutics with immune-modulating agents, represents an appealing approach for improving cancer therapy. To optimize its therapeutic efficacy, differentially delivering multiple therapeutic drugs to target cells is desirable. Here we developed an immunostimulatory nanocarrier (denoted as BLZ-945SCNs/Pt) that could spatially target tumor-associated macrophages (TAMs) and tumor cells for cancer chemoimmunotherapy. BLZ-945SCNs/Pt undergo supersensitive structure collapse in the prevascular regions of tumor tissues and enable the simultaneous release of platinum (Pt)-prodrug conjugated small particles and BLZ-945, a small molecule inhibitor of colony stimulating factor 1 receptor (CSF-1R) of TAMs. The released BLZ-945 can be preferentially taken up by TAMs to cause TAMs depletion from tumor tissues, while the small particles carrying Pt-prodrug enable deep tumor penetration as well as intracellularly specific drug release to kill more cancer cells. Our studies demonstrate that BLZ-945SCNs/Pt outperform their monotherapy counterparts in multiple tumor models. The underlying mechanism studies suggest that the designer pH-sensitive codelivery nanocarrier not only induces apoptosis of tumor cells but also modulates the tumor immune environment to eventually augment the antitumor effect of CD8+ cytotoxic T cells through TAMs depletion.
Asunto(s)
Antineoplásicos/química , Portadores de Fármacos/química , Macrófagos/efectos de los fármacos , Nanopartículas/química , Animales , Antineoplásicos/administración & dosificación , Apoptosis , Benzotiazoles/administración & dosificación , Benzotiazoles/química , Línea Celular Tumoral , Terapia Combinada , Liberación de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Inmunoterapia/métodos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Tamaño de la Partícula , Ácidos Picolínicos/administración & dosificación , Ácidos Picolínicos/química , Platino (Metal)/química , Polímeros/química , Profármacos/administración & dosificación , Profármacos/química , Propiedades de Superficie , Microambiente TumoralRESUMEN
Although surface PEGylation of siRNA vectors is effective for preventing protein adsorption and thereby helps these vectors to evade the reticuloendothelial system (RES) in vivo, it also suppresses the cellular uptake of these vectors by target cells. This dilemma could be overcome by employing stimuli-responsive shell-detachable nanovectors to achieve enhanced cellular internalization while maintaining prolonged blood circulation. Among the possible stimuli, dysregulated pH in tumor (pHe) is the most universal and practical. However, the design of pHe-sensitive system is problematic because of the subtle differences between the pHe and pH in other tissues. Here, a simple acid-sensitive bridged copolymer is developed and used for tumor-targeted systemic delivery of siRNA. After forming the micelleplex delivery system, the corresponding nanoparticles (Dm-NP) might undergo several modifications as follows: (i) a poly(ethylene glycol) (PEG) corona, which is stable in the circulatory system and protects nanovectors from RES clearance; (ii) a pHe responsive linkage breakage, which induces PEG detachment at tumor sites and thereby facilitates cell targeting; and (iii) a cell-penetration peptide, which is exposed upon the removal of PEG and further enhances cellular uptake. Thus, Dm-NP achieved both prolonged circulation and effective accumulation in tumor cells and resulted in the safe and enhanced inhibition of non-small cell lung cancer growth.
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Neoplasias/metabolismo , Polímeros/química , ARN Interferente Pequeño/administración & dosificación , Micelas , ARN Interferente Pequeño/farmacocinética , Distribución TisularRESUMEN
The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Quinasa 4 Dependiente de la Ciclina/genética , Terapia Genética , Proteínas Proto-Oncogénicas/genética , ARN Interferente Pequeño/genética , Proteínas ras/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/terapia , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Técnicas de Transferencia de Gen , Humanos , Ratones , Nanopartículas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras) , ARN Interferente Pequeño/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Synthetic lethal interaction provides a conceptual framework for the development of wiser cancer therapeutics. In this study, we exploited a therapeutic strategy based on the interaction between GATA binding protein 2 (GATA2) downregulation and the KRAS mutation status by delivering small interfering RNA targeting GATA2 (siGATA2) with cationic lipid-assisted polymeric nanoparticles for treatment of non-small-cell lung carcinoma (NSCLC) harboring oncogenic KRAS mutations. Nanoparticles carrying siGATA2 (NPsiGATA2) were effectively taken up by NSCLC cells and resulted in targeted gene suppression. NPsiGATA2 selectively inhibited cell proliferation and induced cell apoptosis in KRAS mutant NSCLC cells. However, this intervention was harmless to normal KRAS wild-type NSCLC cells and HL7702 hepatocytes, confirming the advantage of synthetic lethality-based therapy. Moreover, systemic delivery of NPsiGATA2 significantly inhibited tumor growth in the KRAS mutant A549 NSCLC xenograft murine model, suggesting the therapeutic promise of NPsiGATA2 delivery in KRAS mutant NSCLC therapy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Factor de Transcripción GATA2/metabolismo , Genes ras , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas/química , ARN Interferente Pequeño/metabolismo , Animales , Apoptosis , Transporte Biológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Cationes , Línea Celular Tumoral , Proliferación Celular , Factor de Transcripción GATA2/uso terapéutico , Silenciador del Gen , Hepatocitos/metabolismo , Humanos , Neoplasias Pulmonares/genética , Ratones Desnudos , Microscopía Confocal , Mutación , Nanomedicina/métodos , Polímeros/química , Interferencia de ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin (SN38), has demonstrated potent anticancer activity. However, its clinical application is hindered by its low solubility and high crystallization propensity, which further complicates its encapsulation into nanoparticles for systemic delivery. Herein, we explore the utilization of lipid-assisted poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) nanoparticles to achieve ultrahigh loading capability for SN38. Through the introduction of cationic, anionic, or neutral lipids, the SN38 loading efficiency and loading capacity is elevated to >90% and >10% respectively. These lipids efficiently attenuate the intermolecular π-π stacking of SN38, thereby disrupting its crystalline structure. Moreover, we assess the therapeutic activity of SN38-loaded formulations in various tumor models and identify an anionic lipid 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) sodium salt (DOPG)-assisted formulation that exhibits the highest anticancer activity and has favorable biosafety. Overall, our findings present a simple and robust strategy to achieve ultrahigh loading efficiency of SN38 using commonly employed PEG-b-PLA nanoparticles, opening up a new avenue for the systemic delivery of SN38.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Polietilenglicoles/química , Nanopartículas/química , Alcoholes Grasos , Poliésteres , Línea Celular TumoralRESUMEN
We report a new strategy for differential delivery of antimicrobials to bacterial infection sites with a lipase-sensitive polymeric triple-layered nanogel (TLN) as the drug carrier. The TLN was synthesized by a convenient arm-first procedure using an amphiphilic diblock copolymer, namely, monomethoxy poly(ethylene glycol)-b-poly(ε-caprolactone), to initiate the ring-opening polymerization of the difunctional monomer 3-oxapentane-1,5-diyl bis(ethylene phosphate). The hydrophobic poly(ε-caprolactone) (PCL) segments collapsed and surrounded the polyphosphoester core, forming a hydrophobic and compact molecular fence in aqueous solution which prevented antibiotic release from the polyphosphoester core prior to reaching bacterial infection sites. However, once the TLN sensed the lipase-secreting bacteria, the PCL fence of the TLN degraded to release the antibiotic. Using Staphylococcus aureus (S. aureus) as the model bacterium and vancomycin as the model antimicrobial, we demonstrated that the TLN released almost all the encapsulated vancomycin within 24 h only in the presence of S. aureus, significantly inhibiting S. aureus growth. The TLN further delivered the drug into bacteria-infected cells and efficiently released the drug to kill intracellular bacteria. This technique can be generalized to selectively deliver a variety of antibiotics for the treatment of various infections caused by lipase-secreting bacteria and thus provides a new, safe, effective, and universal approach for the treatment of extracellular and intracellular bacterial infections.
Asunto(s)
Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Lipasa/metabolismo , Polietilenglicoles/química , Polietileneimina/química , Polímeros/química , Antibacterianos/farmacología , Portadores de Fármacos/metabolismo , Lipasa/química , Pruebas de Sensibilidad Microbiana , Nanogeles , Polietilenglicoles/metabolismo , Polietileneimina/metabolismo , Polímeros/metabolismo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Relación Estructura-Actividad , Vancomicina/farmacologíaRESUMEN
Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.
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Anticuerpos Monoclonales/metabolismo , Inmunomodulación , Inmunoterapia , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/terapia , Animales , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica , Femenino , Proteínas Inmovilizadas/metabolismo , Inmunidad , Células Asesinas Naturales/inmunología , Masculino , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Linfocitos T/inmunologíaRESUMEN
Surface modification is often needed in tissue engineering to enhance the interaction between cells and synthetic materials and improve the cytocompatibility and cellular functions. In this study, block copolymers of poly(L-lactic acid) and poly(ethyl ethylene phosphate) (PLLA-b-PEEP) were synthesized and used to modify the PLLA surface via a spin-coating process, to understand whether surface modification with polyphosphoester-based polymer will be osteoinductive for potential bone tissue engineering applications. X-ray photoelectron spectra measurements revealed that phosphorus atomic compositions after surface modification increased from 2.09% to 4.39% with increasing PEEP length of PLLA-b-PEEP from 58 to 224 units, which also led to a more hydrophilic surface property compared with unmodified PLLA. The initial osteoblast attachment and proliferation on the modified surfaces were significantly enhanced. Moreover, cellular alkaline phosphatase activity and mineral calcium depositions were also promoted by PEEP modification. The gene expression determined by reverse transcription polymerase chain reaction further revealed that type I collagen and osteocalcin expression were upregulated in osteoblasts cultured on the modified surfaces, indicating that PEEP modification might be potentially osteoinductive and favorable for further application in bone tissue engineering.
Asunto(s)
Materiales Biocompatibles/química , Proliferación Celular , Ésteres/química , Osteoblastos/citología , Osteoblastos/metabolismo , Polímeros/química , Fosfatasa Alcalina/metabolismo , Animales , Animales Recién Nacidos , Materiales Biocompatibles/síntesis química , Calcio/metabolismo , Adhesión Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Polímeros/síntesis química , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ingeniería de TejidosRESUMEN
The CRISPR/Cas9 gene editing technology holds promise for the treatment of multiple diseases. However, the inability to perform specific gene editing in targeted tissues and cells, which may cause off-target effects, is one of the critical bottlenecks for therapeutic application of CRISPR/Cas9. Herein, macrophage-specific promoter-driven Cas9 expression plasmids (pM458 and pM330) were constructed and encapsulated in cationic lipid-assisted PEG-b-PLGA nanoparticles (CLAN). The obtained nanoparticles encapsulating the CRISPR/Cas9 plasmids were able to specifically express Cas9 in macrophages as well as their precursor monocytes both in vitro and in vivo. More importantly, after further encoding a guide RNA targeting Ntn1 (sgNtn1) into the plasmid, the resultant CLANpM330/sgNtn1 successfully disrupted the Ntn1 gene in macrophages and their precursor monocytes in vivo, which reduced expression of netrin-1 (encoded by Ntn1) and subsequently improved type 2 diabetes (T2D) symptoms. Meanwhile, the Ntn1 gene was not disrupted in other cells due to specific expression of Cas9 by the CD68 promoter. This strategy provides alternative avenues for specific in vivo gene editing with the CRISPR/Cas9 system.
Asunto(s)
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Edición Génica , Macrófagos/química , Nanopartículas/química , Netrina-1/genética , Animales , Sistemas CRISPR-Cas/genética , Cationes/química , Células Cultivadas , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Células HEK293 , Humanos , Lípidos/química , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Netrina-1/metabolismo , Polímeros/química , Células RAW 264.7RESUMEN
Cascades of systemic and intracellular obstacles, including low stability in blood, little tumor accumulation, weak tumor penetration, poor cellular uptake, inefficient endosomal escape and deficient disassembly in the cytoplasm, must be overcome in order to deliver nucleic acid drugs for cancer therapy. Nanocarriers that are sensitive to a variety of physiological stimuli, such as pH, redox status, and cell enzymes, are substantially changing the landscape of nucleic acid drug delivery by helping to overcome cascaded systemic and intracellular barriers. This review discusses nucleic acid-based therapeutics, systemic and intracellular barriers to efficient nucleic acid delivery, and nanocarriers responsive to extracellular and intracellular biological stimuli to overcome individual barriers. In particular, responsive nanocarriers for the cascaded delivery of nucleic acids in vivo are highlighted. Developing novel cascaded nanocarriers that transform their physicochemical properties in response to various stimuli in a timely and spatially controlled manner for nucleic acid drug delivery holds great potential for translating the promise of nucleic acid drugs and achieving clinically successful cancer therapy.
Asunto(s)
Preparaciones de Acción Retardada/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Ácidos Nucleicos/administración & dosificación , Animales , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/química , Portadores de Fármacos/química , Humanos , Nanopartículas/químicaRESUMEN
Synergistic photodynamic and photothermal therapy of cancer cells is of considerable scientific and technological interest. In this work, we demonstrate a sacrificial template strategy to fabricate yolk-shell nanoparticles combining upconversion nanoparticles (UCNPs) and CuS nanoparticles. Lanthanide-doped upconversion nanoparticles of NaYF4:30% Yb,1% Nd,0.5% Er@NaYF4:20% Nd (also denoted as UCNPs) have been prepared as 808 nm light excited remote-controlled nanotransducers for in vitro cancer cell treatment. The upconversion fluorescence of the as-prepared UCNPs@CuS yolk-shell nanoparticles is completely quenched under the excitation of an 808 nm laser, which demonstrates that the energy transfer between the UCNPs and CuS is very efficient. In addition, the as-prepared UCNPs@CuS nanoparticles show higher production ability for hydroxyl radicals (ËOH) and singlet oxygen (1O2) compared to CuS hollow nanospheres of similar size. In particular, the excited shell layer (CuS) showed an enhanced photothermal effect while producing reactive oxygen species (ROS) including singlet oxygen (1O2) and hydroxyl radicals (ËOH) after being exposed to near infrared (NIR) light. Thus, the as-prepared UCNPs@CuS yolk-shell nanoparticles exhibited the synergistic effect of photothermal and photodynamic therapy of cancer cells, which resulted in significant cell death after exposure to an 808 nm laser. The synthetic strategy will provide an alternative method to fabricate other UCNP based core-shell nanoparticles for potential and important applications in bionanotechnology including theranostics, multimodal treatment, magnetic resonance imaging-guided photodynamic therapy, etc.
RESUMEN
It is a significant challenge to develop nanoscale magnetic resonance imaging (MRI) contrast agents with high performance of relaxation. In this work, Gd3+-doped CaF2-based core-shell nanoparticles (CaF2:Yb,Er@CaF2:Gd) of sub-10 nm size were controllably synthesized by a facile sequential growth method. The as-prepared hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles modified using PEG-PAA di-block copolymer benefited from the presence of Gd only in the outer CaF2 layer of the nanoparticles, which exhibited r1 as high as 21.86 mM-1 s-1 under 3.0 T, seven times as high as that of commercially used gadopentetate dimeglumine (Gd-DTPA). Low cytotoxicity, no hemolysis phenomenon and no potential gadolinium ion leakage phenomenon of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles have been observed and confirmed. Clear vascular details can be observed in magnetic resonance angiography and obvious MR signal of 4T1 tumor area could be significantly improved by intravenous injection of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles at a low dosage in mice. A series of in vivo biological safety evaluations confirmed the good biocompatibility of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles, which might be employed in clinical blood pool imaging and tumor diagnosis as a safe and efficient MRI probe.
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Angiografía por Resonancia Magnética/métodos , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/diagnóstico , Animales , Medios de Contraste/química , Medios de Contraste/uso terapéutico , Gadolinio/química , Gadolinio/uso terapéutico , Células HeLa , Humanos , Imagen por Resonancia Magnética/métodos , Ratones , Nanopartículas/uso terapéutico , Neoplasias/patología , Iterbio/química , Iterbio/uso terapéuticoRESUMEN
The design of ideal nanoparticle delivery systems should be capable of meeting the requirements of several stages of drug delivery, including prolonged circulation, enhanced accumulation and penetration in the tumor, facilitated cellular internalization and rapid release of the active drug in the tumor cells. However, among the current design strategies, meeting the requirements of one stage often conflicts with the other. Herein, a tumor pH-labile linkage-bridged block copolymer of poly(ethylene glycol) with poly(lacide-co-glycolide) (PEG-Dlinkm-PLGA) was used for siRNA delivery to fulfill all aforementioned requirements of these delivery stages. The obtained siRNA-encapsulating PEG-Dlinkm-PLGA nanoparticle gained efficiently prolonged circulation in the blood and preferential accumulation in tumor sites via the PEGylation. Furthermore, the PEG surface layer was detached in response to the tumor acidic microenvironment to facilitate cellular uptake, and the siRNA was rapidly released within tumor cells due to the hydrophobic PLGA layer. Hence, PEG-Dlinkm-PLGA nanoparticles met the requirements of several stages of drug delivery, and resulted in the enhanced therapeutic effect of the nanoparticular delivery systems.
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Neoplasias de la Mama/terapia , Preparaciones de Acción Retardada/química , Ácido Láctico/química , Polietilenglicoles/química , Ácido Poliglicólico/química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/uso terapéutico , Tratamiento con ARN de Interferencia , Animales , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Femenino , Humanos , Concentración de Iones de Hidrógeno , Ratones , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacocinética , Quinasa Tipo Polo 1RESUMEN
Conjugated polymers containing alternating donor/acceptor units have strong and sharp absorbance peaks in near-infrared (NIR) region, which could be suitable for photothermal therapy. However, these polymers as photothermal transducers are rarely reported because of their water insolubility, which limits their applications for cancer therapy. Herein, we report the donor-acceptor conjugated polymer PBIBDF-BT with alternating isoindigo derivative (BIBDF) and bithiophene (BT) units as a novel photothermal transducer, which exhibited strong near-infrared (NIR) absorbance due to its low band gap (1.52 eV). To stabilize the conjugated polymer physiological environments, we utilized an amphiphilic copolymer, poly(ethylene glycol)-block-poly(hexyl ethylene phosphate) (mPEG-b-PHEP), to stabilize PBIBDF-BT-based nanoparticles (PBIBDF-BT@NPPPE) through a single emulsion method. The obtained nanoparticles PBIBDF-BT@NPPPE showed great stability in physiological environments and excellent photostability. Moreover, the PBIBDF-BT@NPPPE exhibited high photothermal conversion efficiency, reaching 46.7%, which is relatively high compared with those of commonly used materials for photothermal therapy. Accordingly, in vivo and in vitro experiments demonstrated that PBIBDF-BT@NPPPE exhibits efficient photothermal anticancer efficacy. More importantly, PBIBDF-BT@NPPPE could simultaneously encapsulate other types of therapeutic agents though hydrophobic interactions with the PHEP core and achieve NIR-triggered intracellular drug release and a synergistic combination therapy of thermo-chemotherapy for the treatment of cancer.
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Quimioterapia/métodos , Neoplasias/tratamiento farmacológico , Polímeros/química , Tiofenos/administración & dosificación , Tiofenos/farmacología , Línea Celular Tumoral , Liberación de Fármacos/efectos de los fármacos , Liberación de Fármacos/efectos de la radiación , Humanos , Indoles/administración & dosificación , Indoles/química , Indoles/farmacología , Nanopartículas/química , Fármacos Fotosensibilizantes/farmacología , Tiofenos/químicaRESUMEN
Lack of effective treatment results in the low survival for patients with pancreatic cancer, and photodynamic therapy (PDT) with photosensitizers has emerged as an effective therapeutic option for treatment of various tumors by light-generated cytotoxic reactive oxygen species (ROS) to induce cell apoptosis or necrosis. However, the poor solubility, rapid blood clearance, and weak internalization of the photosensitizer seriously inhibit its anticancer efficacy. To overcome these obstacles, a polyphosphoester-based nanocarrier (NP-PPE) is employed as the carrier of the hydrophobic photosensitizer, chlorin e6 (Ce6), for photodynamic therapy. The Ce6-encapsulated nanocarrier (NP-PPE/Ce6) significantly promoted the cellular internalization of Ce6, enhanced the generation of ROS in the tumor cells after irradiation. Therefore, the cellular phototoxicity of NP-PPE/Ce6 against BxPC-3 pancreatic cancer cells was markedly enhanced than that of free Ce6 in vitro. Furthermore, NP-PPE/Ce6 improved accumulation of Ce6 in tumor tissue and treatment with NP-PPE/Ce6 significantly enhanced antitumor efficacy in human BxPC-3 pancreatic cancer xenografts. These results suggest that using a polyphosphoester-based nanocarrier as the delivery system for a photosensitizer has great potential for PDT of pancreatic cancer.
Asunto(s)
Portadores de Fármacos/química , Nanoestructuras/química , Fármacos Fotosensibilizantes/química , Porfirinas/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clorofilidas , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/farmacocinética , Porfirinas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Distribución Tisular , Trasplante HeterólogoRESUMEN
Multidrug resistance (MDR) has been recognized as a key factor contributing to the failure of chemotherapy for cancer in the clinic, often due to insufficient delivery of anticancer drugs to target cells. For addressing this issue, a redox-responsive polyphosphoester-based micellar nanomedicine, which can be triggered to release transported drugs in tumor cells, has been developed. The micelles are composed of diblock copolymers with a hydrophilic PEG block and a hydrophobic polyphosphoester (PPE) block bearing a disulfide bond in a side group. After incubating the redox-responsive micelles with drug-resistant tumor cells, the intracellular accumulation and retention of DOX were significantly enhanced. Moreover, after internalization by MDR cancer cells, the disulfide bond in the side group was cleaved by the high intracellular glutathione levels, resulting in a hydrophobic to hydrophilic transition of the PPE block and subsequent disassembly of the micelles. Thus, the encapsulated DOX was rapidly released, and abrogation of drug resistance in the cancer cells was observed in vitro. Moreover, the DOX-loaded redox-responsive micelles exhibited significantly enhanced inhibition of tumor growth in nude mice bearing MCF-7/ADR xenograft tumors via tail vein injection, indicating that such micelles have great potential in overcoming MDR for cancer therapy.
Asunto(s)
Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Ésteres/química , Micelas , Nanomedicina/métodos , Polifosfatos/química , Animales , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Dispersión Dinámica de Luz , Femenino , Citometría de Flujo , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Oxidación-Reducción , Espectroscopía de Protones por Resonancia Magnética , Pirenos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Polymeric nanoparticles have been widely used as nano-drug delivery systems in preclinical and clinical trials for cancer therapy, and these systems usually need to be sterically stabilized by poly(ethylene glycol) (PEG) to maintain stability and avoid rapid clearance by the immune system. Recently, zwitterionic materials have been demonstrated to be potential alternatives to the classic PEG. Herein, we developed two drug delivery systems stabilized by zwitterionic polyphosphoesters. These nanoparticles showed favourable stability and anti-protein absorption ability in vitro. Meanwhile, as drug carriers, these zwitterionic polyphosphoester-stabilized nanoparticles significantly prolonged drug circulation half-lives and increased drug accumulation in tumors, which was comparable to PEG-stabilized nanoparticles. Systemic delivery of doxorubicin (DOX) by zwitterionic polyphosphoester-stabilized nanoparticles significantly inhibited tumor growth in a MDA-MB-231 tumor model, suggesting the potential of zwitterionic polyphosphoester-based nanoparticles in anticancer drug delivery.