RESUMO
SignificanceDeep profiling of the plasma proteome at scale has been a challenge for traditional approaches. We achieve superior performance across the dimensions of precision, depth, and throughput using a panel of surface-functionalized superparamagnetic nanoparticles in comparison to conventional workflows for deep proteomics interrogation. Our automated workflow leverages competitive nanoparticle-protein binding equilibria that quantitatively compress the large dynamic range of proteomes to an accessible scale. Using machine learning, we dissect the contribution of individual physicochemical properties of nanoparticles to the composition of protein coronas. Our results suggest that nanoparticle functionalization can be tailored to protein sets. This work demonstrates the feasibility of deep, precise, unbiased plasma proteomics at a scale compatible with large-scale genomics enabling multiomic studies.
Assuntos
Proteínas Sanguíneas , Aprendizado Profundo , Nanopartículas , Proteômica , Proteínas Sanguíneas/química , Nanopartículas/química , Coroa de Proteína/química , Proteoma , Proteômica/métodosRESUMO
Understanding the interactions between nanomaterials and biological systems plays a pivotal role in enhancing the efficacy of nanomedicine and advancing the disease diagnosis. The nanoparticle-protein corona, an active biomolecular layer, is formed around nanoparticles (NPs) upon mixing with biological fluid. The surface layer which consists of rapidly exchanged biomolecules is called the "soft" corona. The inner layer which is more stable and tightly packed is called the "hard" corona. It has been suggested that the NP-protein corona has a decisive effect on the in vivo fate of nanomedicine upon intravenously administration into the mouse. Furthermore, the features of the NP-protein corona make it a powerful platform to enrich low-abundance proteins from serum/plasma for downstream mass-spectrometry (MS)-based proteomics for biomarker discovery and disease diagnosis.Herein, we summarize our recent work on the development of nanomedicine and disease detection from the level of nano-bio interactions between nanoparticles and biological systems. Nanomedicine has made substantial progress over the past two decades. However, the significant enhancement of overall patient survival by nanomedicine remains a challenge due to the lack of a deep understanding of nano-bio interactions in the clinical setting. The pharmacokinetic effect of the protein corona on PEGylated NPs during blood circulation indicated that the adsorbed apolipoproteins could prolong the circulation time of NPs. This mechanistic understanding of the protein corona (active biomolecule) formed around polymeric NPs offered insights into enhancing the efficacy of nanomedicine from the biological interactions point of view. Moreover, we discuss the basic rationale for developing bioresponsive cancer nanomedicine by exploiting the pathophysiological environment around the tumor, typically the pH, reactive oxygen species (ROS), and redox-responsive supramolecular motifs based on synthetic amphiphilic polymers. The protein corona in vivo determines the biological fate of NPs, whereas it opens a new avenue to enrich low abundant proteins in a biospecimen ex vivo to render them "visible" for downstream analytical workflows, such as MS-based proteomics. Blood serum/plasma, due to easy accessibility and great potential to uncover and monitor physiological and pathological changes in health and disease, has remained a major source of detecting protein biomarker candidates. Inspired by the features of the NP-protein corona, a Proteograph platform, which integrates multi-NP-protein coronas with MS for large-scale efficient and deep proteome profiling has been developed. Finally, we conclude this Account with a better understanding of nano-bio interactions to accelerate the nanomedicine translation and how MS-based proteomics can boost our understanding of the corona composition and facilitate the identification of disease biomarkers.
Assuntos
Nanopartículas/química , Coroa de Proteína/química , Animais , Portadores de Fármacos/química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Imageamento por Ressonância Magnética , Camundongos , Microscopia Confocal , Nanomedicina , Nanopartículas/metabolismo , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oxirredução , Polietilenoglicóis/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Innate immune cells recognize and respond to pathogen-associated molecular patterns. In particular, polysaccharides found in the microbial cell wall are potent activators of dendritic cells (DCs). Here, we report a new class of nanocapsules, termed sugar-capsules, entirely composed of polysaccharides derived from the microbial cell wall. We show that sugar-capsules with a flexible polysaccharide shell and a hollow core efficiently drain to lymph nodes and activate DCs. In particular, sugar-capsules composed of mannan (Mann-capsule) carrying mRNA (mRNA) promote strong DC activation, mRNA translation, and antigen presentation on DCs. Mann-capsules elicit robust antigen-specific CD4+ and CD8α+ T-cell responses with antitumor efficacy in vivo. The strategy presented in this study is generally applicable for utilizing pathogen-derived molecular patterns for vaccines and immunotherapies.
Assuntos
Vacinas Anticâncer , Células Dendríticas/imunologia , Nanocápsulas , Neoplasias Experimentais , Polissacarídeos Bacterianos , RNA Mensageiro , Vacinação , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/química , Vacinas Anticâncer/farmacologia , Células Dendríticas/patologia , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/farmacologia , RNA Mensageiro/química , RNA Mensageiro/farmacologiaRESUMO
Black phosphorus (BP)-based nanomaterials have distinguished advantages and potential applications in various biomedical fields. However, their biological effects in physiological systems remain largely unexplored. Here, we systematically revealed a reactive oxygen species (ROS)-mediated mechanism for the selective killing of cancer cells by BP-based nanosheets. The treatment with BP-based materials can induce higher levels of ROS in cancer cells than in normal cells, leading to significant changes in the cytoskeleton, cell cycle arrest, DNA damage, and apoptosis in tumor cell lines. We revealed that the decreased superoxide dismutase activity by lipid peroxides could be an essential mechanism of the selectively higher ROS generation induced by BP-based nanosheets in cancer cells. In addition, the selective killing effect only occurred within a certain dosage range (named "SK range" in this study). Once exceeding the SK range, BP-based materials could also induce a high ROS production in normal tissues, leading to detectable DNA damage and pathological characteristics in normal organs and raising safety concerns. These findings not only shed light on a new mechanism for the selective killing of cancer cells by BP-based materials but also provide deep insights into the safe use of BP-based therapies.
Assuntos
Dano ao DNA , Fósforo/farmacologia , Espécies Reativas de Oxigênio/química , Linhagem Celular Tumoral , HumanosRESUMO
As a hallmark of solid tumors, hypoxia promotes tumor growth, metastasis, and therapeutic resistance by regulating the expression of hypoxia-related genes. Hypoxia also represents a tumor-specific stimulus that has been exploited for the development of bioreductive prodrugs and advanced drug delivery systems. Cell division cycle 20 (CDC20) functions as an oncogene in tumorigenesis, and we demonstrated the significant upregulation of CDC20 mRNA in the tumor vs paratumor tissues of breast cancer patients and its positive correlation with tumor hypoxia. Herein, a hypoxia-responsive nanoparticle (HRNP) was developed by self-assembly of the 2-nitroimidazole-modified polypeptide and cationic lipid-like compound for delivery of siRNA to specifically target CDC20, a hypoxia-related protumorigenic gene, in breast cancer therapy. The delivery of siCDC20 by HRNPs sufficiently silenced the expression of CDC20 and exhibited potent antitumor efficacy. We expect that this strategy of targeting hypoxia-correlated protumorigenic genes by hypoxia-responsive RNAi nanoparticles may provide a promising approach in cancer therapy.
Assuntos
Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Hipóxia , Nanomedicina , Neoplasias/tratamento farmacológico , Neoplasias/genética , Interferência de RNA , RNA Interferente Pequeno/genéticaRESUMO
Nanotechnology-based RNA interference (RNAi) has shown great promise in overcoming the limitations of traditional clinical treatments for glioblastoma (GBM). However, because of the complexity of brain physiology, simple blood-brain barrier (BBB) penetration or tumor-targeting strategies cannot entirely meet the demanding requirements of different therapeutic delivery stages. Herein, we developed a charge conversional biomimetic nanoplatform with a three-layer core-shell structure to programmatically overcome persistent obstacles in siRNA delivery to GBM. The resulting nanocomplex presents good biocompatibility, prolonged blood circulation, high BBB transcytosis, effective tumor accumulation, and specific uptake by tumor cells in the brain. Moreover, red blood cell membrane (RBCm) disruption and effective siRNA release can be further triggered elegantly by charge conversion from negative to positive in the endo/lysosome (pH 5.0-6.5) of tumor cells, leading to highly potent target-gene silencing with a strong anti-GBM effect. Our study provides an intelligent biomimetic nanoplatform tailored for systemically siRNA delivery to GBM, leveraging Angiopep-2 peptide-modified, immune-free RBCm and charge conversional components. Improved therapeutic efficacy, higher survival rates, and minimized systemic side effects were achieved in orthotopic U87MG-luc human glioblastoma tumor-bearing nude mice.
Assuntos
Materiais Biomiméticos , Neoplasias Encefálicas , Glioblastoma , Interferência de RNA , RNA Interferente Pequeno , Animais , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Materiais Biomiméticos/farmacologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Camundongos , Camundongos Nus , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ultrasound (US)-mediated sonodynamic therapy (SDT) has emerged as a superior modality for cancer treatment owing to the non-invasiveness and high tissue-penetrating depth. However, developing biocompatible nanomaterial-based sonosensitizers with efficient SDT capability remains challenging. Here, we employed a liquid-phase exfoliation strategy to obtain a new type of two-dimensional (2D) stanene-based nanosheets (SnNSs) with a band gap of 2.3â eV, which is narrower than those of the most extensively studied nano-sonosensitizers, allowing a more efficient US-triggered separation of electron (e- )-hole (h+ ) pairs for reactive oxygen species (ROS) generation. In addition, we discovered that such SnNSs could also serve as robust near-infrared (NIR)-mediated photothermal therapy (PTT) agents owing to their efficient photothermal conversion, and serve as nanocarriers for anticancer drug delivery owing to the inherent 2D layered structure. This study not only presents general nanoplatforms for SDT-enhanced combination cancer therapy, but also highlights the utility of 2D SnNSs to the field of nanomedicine.
Assuntos
Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/terapia , Terapia Fototérmica , Sesquiterpenos/química , Terapia por Ultrassom , Terapia Combinada , Portadores de Fármacos/química , Humanos , Estrutura Molecular , Nanomedicina , Neoplasias/metabolismo , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Ondas UltrassônicasRESUMO
The emergence of novel two-dimensional (2D) monoelemental materials (Xenes) has shown remarkable potential for their applications in different fields of technology, as well as addressing new discoveries in fundamental science. Xenes (e.g., borophene, silicene, germanene, stanene, phosphorene, arsenene, antimonene, bismuthene, and tellurene) are of particular interest because they are the most chemically tractable materials for synthetic exploration. Owing to their excellent physical, chemical, electronic and optical properties, Xenes have been regarded as promising agents for biosensors, bioimaging, therapeutic delivery, and theranostics, as well as in several other new bio-applications. In this tutorial review, we summarize their general properties including the classification of Xenes according to their bulk properties. The synthetic and modification methods of Xenes are also presented. Furthermore, the representative Xene nanoplatforms for various biomedical applications are highlighted. Finally, research progress, challenges, and perspectives for the future development of Xenes in biomedicines are discussed.
Assuntos
Materiais Biocompatíveis/química , Nanoestruturas/química , Animais , Materiais Biocompatíveis/uso terapêutico , Técnicas Biossensoriais/métodos , Humanos , Modelos Moleculares , Nanoestruturas/uso terapêutico , Nanoestruturas/ultraestrutura , Nanotecnologia/métodos , Imagem Óptica/métodos , Nanomedicina Teranóstica/métodosRESUMO
Nanoparticles (NPs) formulated with cationic lipids and/or polymers have shown substantial potential for systemic delivery of RNA therapeutics such as small interfering RNA (siRNA) for the treatment of cancer and other diseases. While both cationic lipids and polymers have demonstrated the promise to facilitate siRNA encapsulation and endosomal escape, they could also hamper cytosolic siRNA release due to charge interaction and induce potential toxicities. Herein, a unique polymer-prodrug hybrid NP platform was developed for multistage siRNA delivery and combination cancer therapy. This NP system is composed of (i) a hydrophilic polyethylene glycol (PEG) shell, (ii) a hydrophobic NP core made with a tumor microenvironment (TME) pH-responsive polymer, and (iii) charge-mediated complexes of siRNA and amphiphilic cationic mitoxantrone (MTO)-based prodrug that are encapsulated in the NP core. After intravenous administration, the long-circulating NPs accumulate in tumor tissues and then rapidly release the siRNA-prodrug complexes via TME pH-mediated NP disassociation for subsequent tissue penetration and cytosolic transport. With the overexpressed esterase in tumor cells to hydrolyze the amphiphilic structure of the prodrug and thereby induce destabilization of the siRNA-prodrug complexes, the therapeutic siRNA and anticancer drug MTO can be efficiently released in the cytoplasm, ultimately leading to the combinational inhibition of tumor growth via concurrent RNAi-mediated gene silencing and MTO-mediated chemotherapy.
Assuntos
Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Neoplasias/genética , RNA Interferente Pequeno/farmacologia , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/química , Mitoxantrona/química , Mitoxantrona/farmacologia , Nanopartículas/química , Nanoestruturas/química , Neoplasias/terapia , Polietilenoglicóis/química , Polímeros/química , Polímeros/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , RNA Interferente Pequeno/genética , Microambiente Tumoral/efeitos dos fármacosRESUMO
Diabetes mellitus is a lifelong metabolic disease that requires frequent subcutaneous injections of insulin. However, this method of administration can be associated with patient discomfort and local tissue infection. Oral delivery of insulin has been pursued as a more convenient method for diabetes treatment, given its likely superior patient compliance and convenience as well as cost-effectiveness. However, various biological barriers hinder the clinical translation of oral insulin. The rapid development of nanotechnology over the last decade offers great promise in improving the bioavailability of oral insulin. This Minireview provides an overview of biological barriers to oral insulin delivery, summarizes significant technological advances, and outlines future perspectives in oral insulin formulations as well as their hypoglycaemic effects.
Assuntos
Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Administração Oral , Sistemas de Liberação de Medicamentos/métodos , HumanosRESUMO
Structural morphology is the key parameter for efficacy of nanomedicine. To date, lipid-based nanomaterial has been the most widely used material in nanomedicine and many other biomedical applications. However, to the best of our knowledge, there has not been an in-depth or systematic investigation of the structure-function relationship of lipid-based nanostructures. In this report, we investigated the formulation of novel lipid-based nanostructures via simple tuning of lipid combinations. To prove this concept, we used a combination of various ratios of simple and common phospholipids with different chain lengths (14-carbon chain DMPC: 6-carbon chain DHPC) to find out whether a myriad of novel lipid nanostructures could be obtained. Interestingly, many combinations resulted in distinct lipid nanostructures. Drug encapsulation tests confirmed that they are able to load large amounts of drugs for biological application. In vivo anti-tumor efficacy revealed that certain lipid nanostructures possessed superior tumor retardation effects.
Assuntos
Portadores de Fármacos/química , Engenharia , Nanoestruturas/química , Fosfolipídeos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , CamundongosRESUMO
The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adipose tissue and angiogenesis, which facilitates the homing of targeted NPs to adipose angiogenic vessels, thereby amplifying their delivery. We show that i.v. administration of these NPs can target WAT vasculature, stimulate the angiogenesis that is required for the transformation of adipose tissue, and transform WAT into brown-like adipose tissue, by the up-regulation of angiogenesis and brown adipose tissue markers. In a diet-induced obese mouse model, these angiogenesis-targeted NPs have inhibited body weight gain and modulated several serological markers including cholesterol, triglyceride, and insulin, compared with the control group. These findings suggest that angiogenesis-targeting moieties with angiogenic stimulator-loaded NPs could be incorporated into effective therapeutic regimens for clinical treatment of obesity and other metabolic diseases.
Assuntos
16,16-Dimetilprostaglandina E2/administração & dosagem , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/irrigação sanguínea , Nanopartículas/administração & dosagem , Neovascularização Fisiológica , Obesidade/prevenção & controle , Tiazolidinedionas/administração & dosagem , Animais , Metabolismo dos Carboidratos , Dieta , Sistemas de Liberação de Medicamentos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanomedicina , RosiglitazonaRESUMO
Anaplastic thyroid cancer (ATC), one of the most aggressive solid tumors, is characterized by rapid tumor growth and severe metastasis to other organs. Owing to the lack of effective treatment options, ATC has a mortality rate of â¼100% and median survival of less than 5 months. RNAi nanotechnology represents a promising strategy for cancer therapy through nanoparticle (NP) -mediated delivery of RNAi agents (e.g., siRNA) to solid tumors for specific silencing of target genes driving growth and/or metastasis. Nevertheless, the clinical success of RNAi cancer nanotherapies remains elusive in large part because of the suboptimal systemic siRNA NP delivery to tumors and the fact that tumor heterogeneity produces variable NP accumulation and thus, therapeutic response. To address these challenges, we here present an innovative theranostic NP platform composed of a near-infrared (NIR) fluorescent polymer for effective in vivo siRNA delivery to ATC tumors and simultaneous tracking of the tumor accumulation by noninvasive NIR imaging. The NIR polymeric NPs are small (â¼50 nm), show long blood circulation and high tumor accumulation, and facilitate tumor imaging. Systemic siRNA delivery using these NPs efficiently silences the expression of V-Raf murine sarcoma viral oncogene homolog B (BRAF) in tumor tissues and significantly suppresses tumor growth and metastasis in an orthotopic mouse model of ATC. These results suggest that this theranostic NP system could become an effective tool for NIR imaging-guided siRNA delivery for personalized treatment of advanced malignancies.
Assuntos
Imagem Óptica/métodos , RNA Interferente Pequeno/administração & dosagem , Nanomedicina Teranóstica/métodos , Carcinoma Anaplásico da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Animais , Feminino , Inativação Gênica , Células HeLa , Humanos , Camundongos Nus , Camundongos SCID , Nanopartículas/efeitos adversos , Nanopartículas/química , Proteínas Proto-Oncogênicas B-raf/genética , Carcinoma Anaplásico da Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite the broad antitumor spectrum of cisplatin, its therapeutic efficacy in cancer treatment is compromised by the development of drug resistance in tumor cells and systemic side effects. A close correlation has been drawn between cisplatin resistance in tumor cells and increased levels of intracellular thiol-containing species, especially glutathione (GSH). The construction of a unique nanoparticle (NP) platform composed of poly(disulfide amide) polymers with a high disulfide density for the effective delivery of Pt(IV) prodrugs capable of reversing cisplatin resistance through the disulfide-group-based GSH-scavenging process, as described herein, is a promising route by which to overcome limitations associated with tumor resistance. Following systematic screening, the optimized NPs (referred to as CP5 NPs) showed a small particle size (76.2 nm), high loading of Pt(IV) prodrugs (15.50% Pt), a sharp response to GSH, the rapid release of platinum (Pt) ions, and notable apoptosis of cisplatin-resistant A2780cis cells. CP5 NPs also exhibited long blood circulation and high tumor accumulation after intravenous injection. Moreover, in vivo efficacy and safety results showed that CP5 NPs effectively inhibited the growth of cisplatin-resistant xenograft tumors with an inhibition rate of 83.32% while alleviating serious side effects associated with cisplatin. The GSH-scavenging nanoplatform is therefore a promising route by which to enhance the therapeutic index of Pt drugs used currently in cancer treatment.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Amidas/química , Animais , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Dissulfetos/química , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/química , Glutationa/administração & dosagem , Glutationa/química , Humanos , Camundongos , Nanopartículas/química , Neoplasias/patologia , Polímeros/química , Pró-Fármacos/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
As a new family member of the emerging two-dimensional (2D) monoelemental materials (Xenes), germanene has shown promising advantages over the prototypical 2D Xenes, such as black phosphorus (BP) and graphene. However, efficient manufacture of novel germanene nanostructures is still a challenge. Herein, a simple top-down approach for the liquid-exfoliation of ultra-small germanene quantum dots (GeQDs) is presented. The prepared GeQDs possess an average lateral size of about 4.5â nm and thickness of about 2.2â nm. The functionalized GeQDs were demonstrated to be robust photothermal agents (PTAs) with outstanding photothermal conversion efficacy (higher than those of graphene and BPQDs), superior stability, and excellent biocompatibility. As a proof-of-principle, 2D GeQDs-based PTAs were used in fluorescence/photoacoustic/photothermal-imaging-guided hyperpyrexia ablation of tumors. This work could expand the application of 2D germanene to the field of photonic cancer nanomedicine.
Assuntos
Fototerapia/métodos , Pontos Quânticos/química , Nanomedicina Teranóstica/métodos , HumanosRESUMO
Biodegradable polymeric nanoparticles (NPs) have demonstrated significant potential to improve the systemic delivery of RNA interference (RNAi) therapeutics, such as small interfering RNA (siRNA), for cancer therapy. However, the slow and inefficient siRNA release inside tumor cells generally observed for most biodegradable polymeric NPs may result in compromised gene silencing efficacy. Herein, a biodegradable and redox-responsive NP platform, composed of a solid poly(disulfide amide) (PDSA)/cationic lipid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery to tumor cells, is developed. This newly generated NP platform can efficiently encapsulate siRNA under extracellular environments and can respond to the highly concentrated glutathione (GSH) in the cytoplasm to induce fast intracellular siRNA release. By screening a library of PDSA polymers with different structures and chain lengths, the optimized NP platform shows the unique features of i) long blood circulation, ii) high tumor accumulation, iii) fast GSH-triggered intracellular siRNA release, and iv) exceptionally effective gene silencing. Together with the facile polymer synthesis technique and robust NP formulation enabling scale-up, this new redox-responsive NP platform may become an effective tool for RNAi-based cancer therapy.
Assuntos
Nanopartículas/química , Citoplasma/metabolismo , Glutationa/química , Humanos , Oxirredução , Interferência de RNARESUMO
RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets and for treatment of a myriad of important human diseases including cancer. However, the effective systemic in vivo delivery of small interfering RNA (siRNA) to tumors remains a formidable challenge. Using a robust self-assembly strategy, we develop a unique nanoparticle (NP) platform composed of a solid polymer/cationic lipid hybrid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery. The new generation lipid-polymer hybrid NPs are small and uniform, and can efficiently encapsulate siRNA and control its sustained release. They exhibit long blood circulation (t1/2 â¼ 8 h), high tumor accumulation, effective gene silencing, and negligible in vivo side effects. With this RNAi NP, we delineate and validate the therapeutic role of Prohibitin1 (PHB1), a target protein that has not been systemically evaluated in vivo due to the lack of specific and effective inhibitors, in treating non-small cell lung cancer (NSCLC) as evidenced by the drastic inhibition of tumor growth upon PHB1 silencing. Human tissue microarray analysis also reveals that high PHB1 tumor expression is associated with poorer overall survival in patients with NSCLC, further suggesting PHB1 as a therapeutic target. We expect this long-circulating RNAi NP platform to be of high interest for validating potential cancer targets in vivo and for the development of new cancer therapies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/terapia , Nanopartículas , RNA Interferente Pequeno/sangue , Proteínas Repressoras/genética , Humanos , Proibitinas , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genéticaRESUMO
Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.
Assuntos
Antígenos/administração & dosagem , Antígenos/química , Tolerância Imunológica , Terapia de Imunossupressão/métodos , Nanopartículas/química , Animais , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Encefalomielite Autoimune Experimental/terapia , Fator VIII/imunologia , Feminino , Hemocianinas/administração & dosagem , Hemofilia A/imunologia , Hemofilia A/terapia , Humanos , Hipersensibilidade Tardia/imunologia , Hipersensibilidade Tardia/terapia , Imunidade Humoral , Imunossupressores/administração & dosagem , Ácido Láctico/química , Camundongos , Camundongos Endogâmicos BALB C , Nanocápsulas/administração & dosagem , Nanocápsulas/química , Nanopartículas/administração & dosagem , Oligodesoxirribonucleotídeos/administração & dosagem , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Peptídeos/administração & dosagem , Peptídeos/química , Peptídeos/imunologia , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteínas/administração & dosagem , Proteínas/química , Proteínas/imunologia , Proteínas Recombinantes/imunologia , Sirolimo/administração & dosagemRESUMO
Nanoscale materials are increasingly found in consumer goods, electronics, and pharmaceuticals. While these particles interact with the body in myriad ways, their beneficial and/or deleterious effects ultimately arise from interactions at the cellular and subcellular level. Nanoparticles (NPs) can modulate cell fate, induce or prevent mutations, initiate cell-cell communication, and modulate cell structure in a manner dictated largely by phenomena at the nano-bio interface. Recent advances in chemical synthesis have yielded new nanoscale materials with precisely defined biochemical features, and emerging analytical techniques have shed light on nuanced and context-dependent nano-bio interactions within cells. In this review, we provide an objective and comprehensive account of our current understanding of the cellular uptake of NPs and the underlying parameters controlling the nano-cellular interactions, along with the available analytical techniques to follow and track these processes.