RESUMO
Ribonucleic acids (RNAs) enable disease-related gene inhibition, expression, and editing and represent promising therapeutics in various diseases. The efficacy of RNA relies heavily on the presence of a secure and effective delivery system. Herein, we found that RNA could be hydrophobized by cationic lipid and ionizable lipid and conveniently coassemble with amphiphilic polymer to achieve micelle-like nanoparticles (MNP). The results of the study indicate that MNP exhibits a high level of efficiency in delivering RNA. Besides, the MNP encapsulating siRNA that targets CD47 and PD-L1 remarkably blocked these immune checkpoints in a melanoma tumor model and elicited a robust immune response. Moreover, the MNP encapsulating the mRNA of OVA achieved antigen translation and presentation, leading to an effective antitumor immunoprophylaxis outcome against OVA-expressing melanoma model. Our findings suggest that RNA hydrophobization could serve as a viable approach for delivering RNA, thereby facilitating the exploration of RNA therapy in disease treatment.
Assuntos
Melanoma , Nanopartículas , Neoplasias , Humanos , Imunoterapia , Nanopartículas/uso terapêutico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Micelas , Lipídeos , Neoplasias/terapiaRESUMO
The development of in situ tumor vaccines offers promising prospects for cancer treatment. Nonetheless, the generation of plenary autologous antigens in vivo and their codelivery to DC cells along with adjuvants remains a significant challenge. Herein, we developed an in situ tumor vaccine using a supramolecular nanoparticle/hydrogel composite (ANPMTO/ALCD) and a deformable nanoadjuvant (PPER848). The ANPMTO/ALCD composite consisted of ß-cyclodextrin-decorated alginate (Alg-g-CD) and MTO-encapsulated adamantane-decorated nanoparticles (ANPMTO) through supramolecular interaction, facilitating the long-term and sustained production of plenary autologous antigens, particularly under a 660 nm laser. Simultaneously, the produced autologous antigens were effectively captured by nanoadjuvant PPER848 and subsequently transported to lymph nodes and DC cells, benefiting from its optimized size and deformability. This in situ tumor vaccine can trigger a robust antitumor immune response and demonstrate significant therapeutic efficacy in inhibiting tumor growth, suppressing tumor metastasis, and preventing postoperative recurrence, offering a straightforward approach to programming in situ tumor vaccines.
Assuntos
Adjuvantes Imunológicos , Vacinas Anticâncer , Imunoterapia , Nanopartículas , Vacinas Anticâncer/química , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Animais , Camundongos , Imunoterapia/métodos , Nanopartículas/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Adjuvantes Imunológicos/farmacologia , Hidrogéis/química , Humanos , Linhagem Celular Tumoral , Células Dendríticas/imunologia , beta-Ciclodextrinas/química , Neoplasias/terapia , Neoplasias/imunologia , Alginatos/química , Adamantano/química , Adamantano/uso terapêuticoRESUMO
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.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genéticaRESUMO
Acute kidney injury (AKI) is closely associated with the overproduction of reactive oxygen species (ROS), which can cause multiple organ dysfunctions without timely treatment. However, only supportive treatments are currently available for AKI in clinics. Here, we developed nanomaterials of hyperbranched polyphosphoester (PPE) containing abundant thioether (S-PPE NP) and thioketal bonds (TK-PPE NP). Our data demonstrates that S-PPE NP exhibits an excellent capability of absorbing and scavenging multiple types of ROS, including H2O2, â¢OH, and â¢O2-, via thioether oxidation to sulfone or sulfoxide; it was also determined that S-PPE NP efficiently eliminates intracellular ROS, thus preventing cellular damage. Moreover, S-PPE NP was able to efficiently accumulate in the injured kidneys of AKI-bearing mice. As a result, the administration of S-PPE NP provided a superior therapeutic effect in AKI-bearing mice by downregulating ROS- and inflammation-related signaling pathways, thus reducing cell apoptosis. This thioether-containing polymer represents a promising broad-spectrum ROS scavenger that can be used for effective AKI treatments.
RESUMO
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.
Assuntos
Síndrome de Mallory-Weiss , Humanos , Tratamento Conservador/efeitos adversos , Morte , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Síndrome de Mallory-Weiss/complicações , Síndrome de Mallory-Weiss/diagnóstico , Vômito , Adolescente , Pessoa de Meia-Idade , Idoso , Masculino , FemininoRESUMO
Blocking immune checkpoint pathways with an antibody or small interfering RNA (siRNA) has become a promising method to reactivate antitumor responses for cancer treatment. However, both blockade strategies achieve only temporary inhibition of these immune checkpoints. Herein, a photoswitched CRISPR/Cas9 system for genomic disruption of the PD-L1 gene is developed to achieve permanent blockade of the PD-1/PD-L1 pathway; this system is constructed by using a photoactivated self-degradable polyethyleneimine derivative and the plasmid pX330/sgPD-L1 (expression of the Cas9 protein and single-guide RNA targeting PD-L1). Under light irradiation, this photoswitched CRISPR/Cas9 system efficiently genetically disrupts the PD-L1 gene in not only bulk cancer cells but also cancer stem-like cells. As a result, the photoswitched CRISPR/Cas9 system significantly increases the infiltration of CD8+ T cells into tumor tissue, leading to effective activation of a T cell-mediated antitumor response against cancer cells and cancer stem-like cells. This study provides an alternative strategy to block the PD-1/PD-L1 pathway for efficacious immune checkpoint therapy.
RESUMO
The inherent features of small interfering RNA (siRNA), including a relatively high molecular weight, negative charge, and hydrophilic nature, lead to the widespread use of cationic polymers and lipid-based nanocarriers, which might induce potential cytotoxicity, thus limiting their clinical application. Here, we report a facile strategy for changing the inherent features of siRNA molecules by achieving hydrophobization. We found that the simple mixing of siRNA and doxorubicin hydrochloride (DOX·HCl) could form a hydrophobic complex, which was readily encapsulated into noncationic PEG- b-PLA micelles for systemic delivery. In addition to delivering DOX·HCl, this strategy could be extended to deliver other hydrochloride forms of anticancer drugs with large hydrophobic domains. This facile strategy efficiently avoids the use of cationic nanocarriers, providing a new avenue for siRNA delivery.
Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , RNA Interferente Pequeno/farmacologia , Antineoplásicos/química , Cátions/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lactatos/química , Micelas , Nanopartículas/administração & dosagem , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , RNA Interferente Pequeno/químicaRESUMO
The cell nucleus-targeted delivery of therapeutic agents plays a critical role in cancer therapy, since the biological target of many anticancer therapeutics is the cell nucleus. However, multiple physiological barriers limit the delivery efficiency of free drugs, resulting in unsatisfactory therapeutic effects. Herein, thioketal crosslinked polyphosphoester-based nanoparticles with a tumor acidity (pHe )-sensitive transactivator of transcription (TAT) peptide (DA-masked TAT-decorating reactive oxygen species (ROS)-sensitive Ce6/DOX-loaded hyperbranched nanoparticles (D TRCD)) are explored for cascade nucleus-targeted drug delivery. Following administration, D TRCD experiences prolonged circulation by masking the targeting effect of its TAT peptide and then achieves enhanced tumor cell uptake and improved translocation into the perinuclear region by reactivating the TAT targeting capability in tumor tissue. Subsequently, ROS generated by D TRCD under 660 nm laser not only disrupts the nuclear membrane to allow entry into the nuclei but also triggers intracellular release of the payload in the nuclei. As evidenced by in vivo experiments, such pHe /photo dual-sensitive polymeric nanocarriers offer remarkable therapeutic effects, efficiently suppressing tumor growth. This multistage cascade nucleus-targeted drug delivery concept provides new avenues to develop nucleus-targeted drug delivery systems.
Assuntos
Núcleo Celular/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polímeros/química , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Concentração de Íons de Hidrogênio , Espécies Reativas de OxigênioRESUMO
Nucleic acid-based macromolecules have paved new avenues for the development of therapeutic interventions against a spectrum of diseases; however, their clinical translation is limited by successful delivery to the target site and cells. Therefore, numerous systems have been developed to overcome delivery challenges to nucleic acids. From the viewpoint of clinical translation, it is highly desirable to develop systems with clinically validated materials and controllability in synthesis. With this in mind, a cationic lipid assisted PEG-b-PLA nanoparticle (CLAN) is designed that is capable of protecting nucleic acids via encapsulation inside the aqueous core, and delivers them to target cells, while maintaining or improving nucleic acid function. The system is formulated from clinically validated components (PEG-b-PLA and its derivatives) and can be scaled-up for large scale manufacturing, offering potential for its future use in clinical applications. Here, the development and working mechanisms of CLANs, the ways to improve its delivery efficacy, and its application in various disease treatments are summarized. Finally, a prospective for the further development of CLAN is also discussed.
Assuntos
Lactatos/química , Nanomedicina/métodos , Nanopartículas/química , Neoplasias/terapia , Ácidos Nucleicos/uso terapêutico , Polietilenoglicóis/química , Animais , Sistemas CRISPR-Cas , Edição de Genes , Coração/fisiologia , Humanos , Sistema Imunitário , Células de Kupffer/metabolismo , Lipídeos/química , Substâncias Macromoleculares , Neoplasias/metabolismo , Células-Tronco Neoplásicas/citologia , Ácidos Nucleicos/química , Peixe-ZebraRESUMO
In this work, novel amphiphilic diblock copolymers of polyethylene glycol and polyphosphoester with pendant thioether groups, denoted as mPEG- b-PMSPEP, were synthesized through the ring-opening polymerization of functionalized cyclic phosphoester monomer using methoxy poly(ethylene glycol) and Sn(Oct)2 as the macroinitiator and catalyst, respectively. The successful synthesis was confirmed by 1H, 13C, 31P nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC). These amphiphilic block copolymers self-assembled spontaneously in the aqueous solution, and the formed nanoparticles were sensitive to the oxidation that induced the hydrophobic to hydrophilic transition for its PMSPEP core under triggering of H2O2 and the subsequent dissociation of the nanoparticles. In addition, the reactive oxygen species (ROS) generated by light and the photosensitizer were also capable of carrying out the oxidation of these nanoparticles. Their oxidation profiles were systemically evaluated by 1H NMR. Finally, the mPEG- b-PMSPEP nanoparticles were used to coencapsulate the photosensitizer chlorin e6 (Ce6) and anticancer drug paclitaxel (PTX), achieving the photoaccelerated PTX release via oxidation of the nanoparticles by the generated ROS under light irradiation. Meanwhile, the in vitro cytotoxicity assays indicated that these nanoparticles coencapsulated with PTX and Ce6 showed a combined cell-killing effect toward MDA-MB-231 tumor cells, exhibiting great potential for drug delivery systems that realize the synergistic chemo-photodynamic therapy for cancer treatment.
Assuntos
Portadores de Fármacos , Nanopartículas , Neoplasias/tratamento farmacológico , Paclitaxel , Polietilenoglicóis , Linhagem Celular Tumoral , Clorofilídeos , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Peróxido de Hidrogênio/química , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Apoptose , Linhagem Celular Tumoral , Humanos , Metástase Neoplásica , Neoplasias/patologia , Esferoides CelularesRESUMO
Precisely controlling the interaction of nanoparticles with biological systems (nanobio interactions) from the injection site to biological targets shows great potential for biomedical applications. Inspired by the ability of nanoparticles to alter their physicochemical properties according to different stimuli, we explored the tumor acidity and near-infrared (NIR) light activated transformable nanoparticle DATAT-NPIR&DOX. This nanoparticle consists of a tumor acidity-activated TAT [the TAT lysine residues' amines was modified with 2,3-dimethylmaleic anhydride (DA)], a flexible chain polyphosphoester core coencapsulated a NIR dye IR-780, and DOX (doxorubicin). The physicochemical properties of the nanoparticle can be controlled in a stepwise fashion using tumor acidity and NIR light, resulting in adjustable nanobio interactions. The resulting transformable nanoparticle DATAT-NPIR&DOX efficiently avoids the interaction with mononuclear phagocyte system (MPS) ("stealth" state) due to the masking of the TAT peptide during blood circulation. Once it has accumulated in the tumor tissues, DATAT-NPIR&DOX is reactivated by tumor acidity and transformed into the "recognize" state in order to promote interaction with tumor cells and enhance cellular internalization. Then, this nanoparticle is transformed into "attack" state under NIR irradiation, achieving the supersensitive DOX release from the flexible chain polyphosphoester core in order to increase the DOX-DNA interaction. This concept provides new avenues for the creation of transformable drug delivery systems that have the ability to control nanobio interactions.
Assuntos
Antineoplásicos/química , Adutos de DNA/química , Doxorrubicina/química , Corantes Fluorescentes/química , Produtos do Gene tat/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Oligopeptídeos/química , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Corantes/química , Adutos de DNA/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Produtos do Gene tat/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Indóis/química , Raios Infravermelhos , Camundongos , Nanopartículas/efeitos da radiação , Neoplasias/química , Neoplasias/diagnóstico por imagem , Tamanho da Partícula , Células RAW 264.7RESUMO
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.
Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Macrófagos/efeitos dos fármacos , Nanopartículas/química , Animais , Antineoplásicos/administração & dosagem , Apoptose , Benzotiazóis/administração & dosagem , Benzotiazóis/química , Linhagem Celular Tumoral , Terapia Combinada , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Imunoterapia/métodos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Ácidos Picolínicos/administração & dosagem , Ácidos Picolínicos/química , Platina/química , Polímeros/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Propriedades de Superfície , Microambiente TumoralRESUMO
Benefiting from its strong oxidizing properties, the singlet oxygen has garnered serious attentions in physical, chemical, as well as biological studies. However, the photosensitizers for the generation of singlet oxygen bear in low quantum yields, lack of long wavelength absorption band, poor biocompatibility, undegradable in living tissues, and so on. Here we first demonstrate the exfoliated black phosphorus nanosheets to be effective photosensitizers for the generation of singlet oxygen with a high quantum yield of about 0.91, rendering their attractive applications in catalysis and photodynamic therapy. Through in vitro and in vivo studies, the water dispersible black phosphorus nanosheets show notable cancer therapy ability. In addition, the photodegradable character of black phosphorus from element to biocompatible phosphorus oxides further highlights its therapeutic potential against cancer. This study will not only expand the breadth of study in black phosphorus but also offer an efficient catalyst and photodynamic therapy agent.
RESUMO
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.
Assuntos
Neoplasias/metabolismo , Polímeros/química , RNA Interferente Pequeno/administração & dosagem , Micelas , RNA Interferente Pequeno/farmacocinética , Distribuição TecidualRESUMO
UNLABELLED: Infection with hepatitis B virus (HBV) is the most common cause of liver disease worldwide. However, because the current interferon (IFN)-based treatments have toxic side effects and marginal efficacy, improved antivirals are essential. Here we report that unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) from the HBV genome (HBV-CpG) induced robust expression of IFN-α by plasmacytoid dendritic cells (pDCs) in a Toll-like receptor 9 (TLR9)-dependent manner. We also identified inhibitory guanosine-rich ODNs in the HBV genome (HBV-ODN) that are capable of inhibiting HBV-CpG-induced IFN-α production. Furthermore, nanoparticles containing HBV-CpG, termed NP(HBV-CpG), reversed the HBV-ODN-mediated suppression of IFN-α production and also exerted a strong immunostimulatory effect on lymphocytes. Our results suggest that NP(HBV-CpG) can enhance the immune response to hepatitis B surface antigen (HBsAg) and skew this response toward the Th1 pathway in mice immunized with rHBsAg and NP(HBV-CpG). Moreover, NP(HBV-CpG)-based therapy led to the efficient clearance of HBV and induced an anti-HBsAg response in HBV carrier mice. CONCLUSION: Endogenous HBV-CpG ODNs from the HBV genome induce IFN-α production so that nanoparticle-encapsulated HBV-CpG may act as an HBsAg vaccine adjuvant and may also represent a potent therapeutic agent for the treatment of chronic HBV infection.
Assuntos
Citosina , Guanosina , Vírus da Hepatite B/genética , Hepatite B/tratamento farmacológico , Imunoterapia/métodos , Nanopartículas/uso terapêutico , Oligodesoxirribonucleotídeos/uso terapêutico , Fosfatos , Animais , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Modelos Animais de Doenças , Hepatite B/imunologia , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B/farmacologia , Antígenos de Superfície da Hepatite B/uso terapêutico , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Técnicas In Vitro , Interferon-alfa/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/farmacologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêuticoRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Quinase 4 Dependente de Ciclina/genética , Terapia Genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/genética , Proteínas ras/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Técnicas de Transferência de Genes , Humanos , Camundongos , Nanopartículas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras) , RNA Interferente Pequeno/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fator de Transcrição GATA2/metabolismo , Genes ras , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , RNA Interferente Pequeno/metabolismo , Animais , Apoptose , Transporte Biológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cátions , Linhagem Celular Tumoral , Proliferação de Células , Fator de Transcrição GATA2/uso terapêutico , Inativação Gênica , Hepatócitos/metabolismo , Humanos , Neoplasias Pulmonares/genética , Camundongos Nus , Microscopia Confocal , Mutação , Nanomedicina/métodos , Polímeros/química , Interferência de RNA , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To date, five siRNA-based medications have received clinical approval and have demonstrated remarkable therapeutic efficacy in treating various diseases. However, their application has been predominantly limited to liver-specific diseases due to constraints in siRNA delivery capabilities. In this study, we have developed a siRNA delivery system utilizing clinically approved mPEG-b-PLGA, a cationic lipid, and an ionizable lipid. We optimized this system by carefully adjusting their mass ratios, resulting in highly efficient gene silencing. Furthermore, the optimized nanoparticle formulation, which encapsulates siRNA targeting CD47, induces a robust immune response. This response effectively suppresses the progression of melanoma tumors by blocking this critical immune checkpoint.
Assuntos
Melanoma , Nanopartículas , Poliésteres , Polietilenoglicóis , Humanos , RNA Interferente Pequeno , Polímeros , Melanoma/tratamento farmacológico , Imunoterapia , LipídeosRESUMO
Immune checkpoint blockade (ICB) has shown considerable promise for treating various malignancies, but only a subset of cancer patients benefit from immune checkpoint inhibitor therapy because of immune evasion and immune-related adverse events (irAEs). The mechanisms underlying how tumor cells regulate immune cell response remain largely unknown. Here we show that hexokinase domain component 1 (HKDC1) promotes tumor immune evasion in a CD8+ T cell-dependent manner by activating STAT1/PD-L1 in tumor cells. Mechanistically, HKDC1 binds to and presents cytosolic STAT1 to IFNGR1 on the plasma membrane following IFNγ-stimulation by associating with cytoskeleton protein ACTA2, resulting in STAT1 phosphorylation and nuclear translocation. HKDC1 inhibition in combination with anti-PD-1/PD-L1 enhances in vivo T cell antitumor response in liver cancer models in male mice. Clinical sample analysis indicates a correlation among HKDC1 expression, STAT1 phosphorylation, and survival in patients with hepatocellular carcinoma treated with atezolizumab (anti-PD-L1). These findings reveal a role for HKDC1 in regulating immune evasion by coupling cytoskeleton with STAT1 activation, providing a potential combination strategy to enhance antitumor immune responses.