RESUMO
Drug resistance and inefficient localization of chemotherapeutic agent limit the current treatment strategy in locally advanced melanoma (MEL), accounting to the 10-year survival rate from 24% to 68%. In this study we constructed anti-PD-L1 conjugated and doxorubicin loaded hollow gold nanoshell (T-HGNS-DOX) for targeted and localized chemo-photothermal therapy of MEL by the conjugation of LA-PEG-anti-PD-L1 antibody and short PEG chain on the surface of HGNS-DOX. Near infrared (NIR) as well as pH dependent drug release profile was observed. Significant uptake of DOX following NIR due to high PD-L1 receptors resulted in pronounced anticancer effect of T-HGNS-DOX. Following intratumoral administration, maximum nanoparticles retention with the significant reduction in tumor growth was observed as a result of elevated apoptosis marker (cleaved caspase-3, cleaved PARP) as well as downregulation of proliferative (Ki-67) and angiogenesis marker (CD31). Cumulatively, our system avoids the systemic toxicities of the nanosystem thereby providing maximum chemotherapeutic retention in tumor.
Assuntos
Anticorpos Monoclonais Humanizados/química , Doxorrubicina/química , Ouro/química , Melanoma/tratamento farmacológico , Melanoma/radioterapia , Nanocápsulas/química , Nanoconchas/química , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Propriedades de SuperfícieRESUMO
PURPOSE: The goal of this study was to develop chemotherapeutic drug-loaded photoactivable stealth polymer-coated silica based- mesoporous titania nanoplatforms for enhanced antitumor activity. METHODS: Both in vitro and in vivo models of solvothermal treated photoactivable nanoplatforms were evaluated for efficient chemo-photothermal activity. A versatile nanocomposite that combined silica based- mesoporous titania nanocarriers (S-MTN) with the promising photoactivable agent, graphene oxide (G) modified with a stealth polymer (P) was fabricated to deliver chemotherapeutic agent, imatinib (I), (referred as S-MTN@IG-P) for near-infrared (NIR)-triggered drug delivery and enhanced chemo-photothermal therapy. RESULTS: The fabricated S-MTN@IG-P nanoplatform showed higher drug loading (~20%) and increased drug release (~60%) in response to light in acidic condition (pH 5.0). As prepared nanoplatform significantly converted NIR light into thermal energy (43.2°C) to produce reactive oxygen species (ROS). The pronounced cytotoxic effect was seen in both colon cancer cells (HCT-116 and HT-29) that was mediated through the chemotherapeutic effect of imatinib and the photothermal and ROS generation effects of graphene oxide. In vivo study also showed that S-MTN@IG-P could significantly accumulate into the tumor area and suppress the tumor growth under NIR irradiation without any biocompatibility issues. CONCLUSION: Cumulatively, the above results showed promising effects of S-MTN@IG-P for effective chemo-phototherapy of colon cancer.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Nanopartículas/uso terapêutico , Fotoquimioterapia/métodos , Titânio/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células HCT116 , Células HT29 , Humanos , Mesilato de Imatinib/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Espécies Reativas de Oxigênio , Dióxido de SilícioRESUMO
Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the heterogeneity of cancer. In this study, we constructed a dual function nanosystem, copper sulfide nanoplatform loaded with the chemotherapeutic drug docetaxel wrapped by a conjugated polymer-peptide for targeted chemo-phototherapy. The nanoconstruct has been successfully designed with a size of 186.1⯱â¯5.2â¯nm, a polydispersity index of 0.18⯱â¯0.01, and zeta potential of -16.4⯱â¯0.1â¯mV. The enhanced uptake and near-infrared-responsive behavior of the nanosystem resulted in efficient drug release, photothermal ablation, effective cytotoxic activity, and potentiated reactive oxygen species generation. The induction of apoptotic markers, enhanced accumulation in the tumor site, and maximum tumor growth inhibition were seen during in vivo studies compared to non-targeted nanoformulations and free drug. Cumulatively, our results indicate that, with low systemic toxicity and better biocompatibility, this nanoconstruct could provide a promising strategy for treating prostate cancer.
Assuntos
Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Polímeros/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Cobre/química , Doxorrubicina/química , Liberação Controlada de Fármacos/efeitos da radiação , Humanos , Hipertermia Induzida , Masculino , Nanopartículas/química , Peptídeos/química , Peptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Fototerapia , Polímeros/química , Polímeros/efeitos da radiação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Espécies Reativas de Oxigênio/química , Receptores de Somatostatina/genética , Somatostatina/análogos & derivados , Somatostatina/química , Somatostatina/farmacologia , Sulfetos/químicaRESUMO
The interest in removing contagious viruses from indoor air using ventilation and filtration systems is increasing rapidly because people spend most of the day indoors. The development of an effective platform to regenerate the antiviral function of air filters during use and safe abrogation of used filters containing infectious viruses is a challenging task, because an on-demand safe-by-design manufacture system is essential for in-place antiviral coatings, but it has been rarely investigated. With these considerations, an electrically operable dispenser was prepared for decorating continuous ultrafine Fe-Zn, Fe-Ag, or Fe-Cu particles (<5 nm) onto SiO2 nanobeads (ca. 130 nm) to form nanobulges (i.e., nanoroughness for engaging coronavirus spikes) in the aerosol state for 3 min direct deposition on the air filter surfaces. The resulting nanobulges were exposed to human coronaviruses (HCoV; surrogates of SARS-CoV-2) to assess antiviral function. The results were compared with similar-sized individual Zn, Ag, and Cu particles. The nanobulges exhibited comparable antiviral activity to Zn, Ag, and Cu particles while retaining biosafety in both in vitro and in vivo models because of the significantly smaller metallic fractions. This suggests that the bimetallic bulge structures generate reactive oxygen species and Fenton-mediated hydroxyl radicals for inactivating HCoV.
Assuntos
Filtros de Ar , Poluição do Ar em Ambientes Fechados , COVID-19 , Humanos , Dióxido de Silício , SARS-CoV-2 , COVID-19/prevenção & controle , Aerossóis e Gotículas Respiratórios , Antivirais , Poluição do Ar em Ambientes Fechados/análiseRESUMO
The assemblies of anisotropic nanomaterials have attracted considerable interest in advanced tumor therapeutics because of the extended surfaces for loading of active molecules and the extraordinary responses to external stimuli for combinatorial therapies. These nanomaterials were usually constructed through templated or seed-mediated hydrothermal reactions, but the lack of uniformity in size and morphology, as well as the process complexities from multiple separation and purification steps, impede their practical use in cancer nanotherapy. Gas-phase epitaxy, also called aerotaxy (AT), has been introduced as an innovative method for the continuous assembly of anisotropic nanomaterials with a uniform distribution. This process does not require expensive crystal substrates and high vacuum conditions. Nevertheless, AT has been used limitedly to build high-aspect-ratio semiconductor nanomaterials. With these considerations, a modified AT was designed for the continuous in-flight assembly of the cell-penetrating Fenton nanoagents (Mn-Fe CaCO3 (AT) and Mn-Fe SiO2 (AT)) in a single-pass gas flow because cellular internalization activity is essential for cancer nanotherapeutics. The modified AT of Mn-Fe CaCO3 and Mn-Fe SiO2 to generate surface nanoroughness significantly enhanced the cellular internalization capability because of the preferential contact mode with the cancer cell membrane for Fenton reaction-induced apoptosis. In addition, it was even workable for doxorubicin (DOX)-resistant cancer cells after DOX loading on the nanoagents. After combining with immune-checkpoint blockers (antiprogrammed death-ligand 1 antibodies), the antitumor effect was improved further with no systemic toxicity as chemo-immuno-chemodynamic combination therapeutics despite the absence of targeting ligands and external stimuli.
Assuntos
Nanoestruturas , Neoplasias , Humanos , Dióxido de Silício/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Doxorrubicina/química , Nanoestruturas/química , Apoptose , Linhagem Celular TumoralRESUMO
The significant advances in nano-drug delivery systems (NDDS) for anticancer agents have led to the development of computational techniques, such as machine learning and neural networks to identify the optimal architectural and compositional design in a wide variety of therapeutic nanoformulations. On the other hand, few studies have examined downsized plug-in reaction-ware embodied in an autonomous platform for the instant reconfigurable production of engineered nanomaterials to guide optimal NDDS designs and delivery strategies. This paper describes an on-demand system for an electrically operable, continuously processible material produced by sequential spray pyrolysis and vibrating spray for single-pass NDDS assembly. In particular, a mild chemotherapeutic NDDS consisting of amorphous boron nitride (a-BN; a stable base material for loading), doxorubicin (DOX; an anticancer drug), and folic acid-chitosan conjugate (FACHI; a targeting and antiopsonic agent), called a-BN-DOX@FACHI, was fabricated using the developed system. a-BN-DOX@FACHI was assessed for the pH-responsive release of DOX, targeting of the folate receptor, and its resistance to opsonization and macrophage phagocytosis. a-BN-DOX@FACHI was found to be a mild cancer chemotherapeutic with reasonable biosafety. Integrating a metal ablation device with the developed on-demand system enabled the reconfiguration of NDDS from a-BN-DOX@FACHI to a-BN-Au-DOX@FACHI or a-BN-Pt-cisplatin@bovine serum albumin to add a photothermal effect with a range of architectures and compositions.
Assuntos
Antineoplásicos , Sistemas de Liberação de Medicamentos , Aerossóis , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Fármacos por NanopartículasRESUMO
Low immunogenicity and immunosuppressive tumor microenvironments are major hurdles in the application of cancer immunotherapy. To date, several immunogenic cell death (ICD) inducers have been reported to boost cancer immunotherapy by triggering ICD. ICD is characterized by the release of proinflammatory cytokines, danger-associated molecular patterns (DAMPs) and tumor associated antigens which will generate anticancer immunity by triggering adaptive immune cells. However, application of ICD inducers is limited due to severe toxicity issues and inefficient localization in the tumor microenvironment. To circumvent these challenges, stimuli-responsive nanoparticles have been exploited for improving cancer immunotherapy by limiting its toxicity. The combination of stimuli-responsive nanoparticles with an ICD inducer serves as a promising strategy for increasing the clinical applications of ICD induction in cancer immunotherapy. Here, we outline recent advances in ICD mediated by stimuli-responsive nanoparticles that may be near-infrared (NIR)-responsive, pH-responsive, redox responsive, pH and enzyme responsive, or pH and redox responsive, and evaluate their significant potential for successful clinical translation in cancer immunotherapy.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Humanos , Morte Celular Imunogênica , Imunoterapia , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
Amalgamation of the reactive oxygen species (ROS)-responsive stimulus with nanoparticles has gained considerable interest owing to their high tumor specificity. Hypoxia plays a pivotal role in the acceleration of intracellular ROS production. Herein, we report the construction of a cancer cell (PD-L1)- and ROS-responsive, dual-targeted, temozolomide (TMZ)-laden nanosystem which offers a better anticancer effect in a hypoxic tumor microenvironment. A dual-targeted system boosted permeation in the cancer cells. Hypoxic conditions elevating the high ROS level accelerated the in situ release of TMZ from anti-PD-L1-TKNPs. Hyperaccumulated ROS engendered from TMZ caused oxidative damage leading to mitochondria-mediated apoptosis. TMZ fabricated in the multifunctional nanosystem (anti-PD-L1-TMZ-TKNPs) provided excellent tumor accumulation and retarded tumor growth under in vivo conditions. The elevated apoptosis effect with the activation of an apoptotic marker, DNA double-strand breakage marker, and downregulation of the angiogenesis marker in the tumor tissue following treatment with anti-PD-L1-TMZ-TKNPs exerts robust anticancer effect. Collectively, the nanoconstruct offers deep tumor permeation and high drug release and broadens the application of the ROS-responsive nanosystem for a successful anticancer effect.
Assuntos
Apoptose , Antígeno B7-H1/metabolismo , Mitocôndrias/metabolismo , Nanopartículas , Espécies Reativas de Oxigênio/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Compostos de Sulfidrila/metabolismoRESUMO
Targeted and stimuli-sensitive nanobombs for the release of therapeutic agents after laser irradiation of the tumor site are gaining widespread attention as personalized anticancer regimens. In this study, redox and photo dual-responsive, folate receptor-targeted nanourchin carriers for chemo-, photodynamic, and photothermal therapy were constructed by the amalgamation of an outer layer of polyethylene glycol (PEG)-S-S-methotrexate (MTX) and an inner core of indocyanine green (ICG)-loaded bismuth sulfide (Bi2S3) nanoparticles for cancer treatment. MTX introduces the carrier to folate receptors resulting in the internalization of nanoparticles into cancer cells, specifically and increasingly. In the reducing environment inside cancer cells, MTX was cleaved, resulting in a burst release that effectively inhibited tumor growth. Simultaneously, the fusion of Bi2S3 and ICG in the inner core absorbed energy from a near-infrared radiation (NIR) laser to generate heat and reactive oxygen species, which further ablated the tumors and synergistically enhanced the anticancer activity of MTX. These results indicate the successful preparation of combined nanourchins (NUs) showing GSH-induced and laser-responsive release of MTX and ICG, accompanied by hyperthermia via Bi2S3 and ICG. Effective in vitro cellular internalization, cellular cytotoxicity, and pro-apoptotic behavior of the nanosystem were achieved through a targeting, redox, and NIR-responsive combination strategy. In vivo biodistribution and photothermal imaging also revealed tumor-selective and -retentive, as well as thermally responsive attributes. Ultimately, this in vivo antitumor study shows an effective tumor ablation by these nanourchins without affecting the vital organs. Our findings indicate that using these targeted redox- and laser-responsive combination therapeutic carriers can be a promising strategy in folate receptor-expressing tumors.
Assuntos
Hipertermia Induzida , Nanopartículas , Neoplasias , Bismuto , Linhagem Celular Tumoral , Humanos , Verde de Indocianina , Neoplasias/tratamento farmacológico , Oxirredução , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Sulfetos , Distribuição TecidualRESUMO
Anticancer regimens have been substantially enriched through monoclonal antibodies targeting immune checkpoints, programmed cell death-1/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4. Inconsistent clinical efficacy after solo immunotherapy may be compensated by nanotechnology-driven combination therapy. We loaded human serum albumin (HSA) nanoparticles with paclitaxel (PTX) via nanoparticle albumin-bound technology and pooled them with anti-PD-L1 monoclonal antibody through a pH-sensitive linker for targeting and immune response activation. Our tests demonstrated satisfactory preparation of paclitaxel-loaded, PD-L1-targeted albumin nanoparticles (PD-L1/PTX@HSA). They had small particle size (~200 nm) and polydispersity index (~0.12) and successfully incorporated each constituent. Relative to normal physiological pH, the formulation exhibited higher drug-release profiles favoring cancer cell-targeted release at low pH. Modifying nanoparticles with programmed cell death-ligand 1 increased cancer cell internalization in vitro and tumor accumulation in vivo in comparison with non-PD-L1-modified nanoparticles. PD-L1/PTX@HSA constructed by nanoparticle albumin-bound technology displayed successful tumor inhibition efficacy both in vitro and in vivo. There was successful effector T-cell infiltration, immunosuppressive programmed cell death-ligand 1, and regulatory T-cell suppression because of cytotoxic T-lymphocyte antigen-4 synergy. Moreover, PD-L1/PTX@HSA had low organ toxicity. Hence, the anti-tumor immune responses of PD-L1/PTX@HSA combined with chemotherapy and cytotoxic T-lymphocyte antigen-4 is a potential anti-tumor strategy for improving quantitative and qualitative clinical efficacy.
Assuntos
Nanopartículas , Albuminas , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , ImunoterapiaRESUMO
The transmembrane proteins, CD47 and signal-regulatory protein α are overexpressed in cancer cells and macrophages, respectively, and facilitate the escape of cancer cells from macrophage-mediated phagocytosis. The immunomodulatory and targeting properties of CD47, the chemotherapeutic effects of dabrafenib (D), and the anti-programmed death-1 antibodies (PD-1) pave the way for effective chemoimmunomodulation-mediated anticancer combination therapy. In this study, CD47-conjugated, D-loaded human serum albumin (HSA) nanosystems were fabricated by modified nanoparticle albumin-bound technology. Cis-aconityl-PEG-maleimide (CA), an acid-labile linker, was used to conjugate D@HSA and CD47; the resultant CD47-CA@D@HSA exhibited tumor-specificity through receptor targeting, as well as preferential cleavage and drug release in the acidic tumor microenvironment (pH 5) compared to normal physiological pH conditions (pH 6.5, 7.4). The successful preparation of nanosized (â¼220 nm), narrowly dispersed (â¼0.13) CD47-CA@D@HSA was proven by physicochemical characterization. In vitro and in vivo internalization, accumulation, cytotoxicity, and apoptosis were observed to be higher with CD47-conjugated nanoconstructs, than with free D or non-targeted nanoconstructs. CD47-CA@D@HSA was found to promote the infiltration of cytotoxic T cells and tumor-associated macrophages into tumors and improve in vivo tumor inhibition. Administration in combination with PD-1 further improved antitumor efficacy by promoting immune responses that blocked the immune checkpoint. No signs of toxicity were seen in mice treated with the nanoconstructs; the formulation was, therefore, thought to be biocompatible and as having potential for clinical use. The targeted chemoimmunomodulation achieved by this combination therapy was found to combat major immunosuppressive facets, making it a viable candidate for use in the treatment of cancer.
Assuntos
Antígeno CD47 , Albumina Sérica Humana , Animais , Imidazóis/farmacologia , Camundongos , Oximas , FagocitoseRESUMO
Senescent cells drive atherosclerosis at all stages and contribute to cardiovascular disease. However, the markers in these senescent aortic plaques have not been well studied, creating a huge obstacle in the exploration of a precise and efficient system for atherosclerosis treatment. Recently, CD9 has been found to induce cellular senescence and aggravated atherosclerotic plaque formation in apolipoprotein E knockout (ApoE-/-) mice. In the present study, this result has been leveraged to develop CD9 antibody-modified, hyaluronic acid-coated mesoporous silica nanoparticles with a hyaluronidase-responsive drug release profile. In invitro models of senescent foamy macrophages and senescent endothelial cells stimulated with oxidized high-density-lipoprotein, the CD9 antibody-modified mesoporous silica nanoparticles exhibit high cellular uptake; reduce the reactive oxygen species level, high-density lipoprotein oxidation, and production of TNF-α and IL-6; and attenuate the senescence process, contributing to improved cell viability. In vivo experiment demonstrated that these nanoparticles can successfully target the senescent lesion areas, deliver the anti-senescence drug rosuvastatin to the senescent atherosclerotic plaques (mainly endothelial cells and macrophages), and alleviate the progression of atherosclerosis in ApoE-/- mice. By providing deep insight regarding the markers in senescent atherosclerotic plaque and developing a nano-system targeting this lesion area, the study proposes a novel and an accurate therapeutic approach for mitigating atherosclerosis through senescent cell clearance.
Assuntos
Aterosclerose , Células Endoteliais , Macrófagos , Nanopartículas , Placa Aterosclerótica , Animais , Aorta , Aterosclerose/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Camundongos Knockout para ApoE , Placa Aterosclerótica/tratamento farmacológico , Dióxido de SilícioRESUMO
The hindrances in achieving clinically translatable anticancer platforms are being tackled through nanotechnology-based formulations. In this study, stimuli-responsive, phytoactive constituent-loaded nanophytoliposomes were fabricated for designing a specific antitumor platform. Ursolic acid (UA)-loaded nanophytoliposomes (UA-PLL-HA.P) enwrapped in a poly-L-lysine (PLL) coat and hyaluronic acid (HA) were nanosized; these nanophytoliposomes had spherical morphology, slightly negative charge, and an in-range polydispersity index (~0.25). Successful fabrication of the nanosystem was proven through several characterization methods and the pH- and enzyme-responsiveness of the nanosystem was assessed through a release study. The cellular internalization in CD44 receptor-expressing cell lines was amplified by enhanced permeation and retention as well as by active targeting. In vitro antitumor behavior was confirmed through in vitro cytotoxic and apoptotic activity of the nanosystem. Similarly, in vivo imaging showed exceptional biodistribution in the tumor in agreement with the in vitro findings. Moreover, the tumor inhibitory rate of UA-PLL-HA.P was significantly higher, and was ascribed to the targeting potential and stimuli-responsiveness. In summary, UA-PLL-HA.P exhibited pronounced anticancer effect and could open a number of possibilities for discovering novel phytoconstituent-incorporated nanoformulations.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ácido Hialurônico/química , Nanopartículas , Neoplasias/tratamento farmacológico , Polilisina/química , Polímeros Responsivos a Estímulos/química , Triterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Lipossomos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Distribuição Tecidual , Triterpenos/química , Triterpenos/metabolismo , Ácido UrsólicoRESUMO
As well as the exploration of translatable delivery nanosystems for cancer therapeutic agents, the development of automatable continuous-flow manufacturing technology comprising digitally controlled reactions for the on-demand production of pharmaceuticals is an important challenge in anticancer nanomedicine. Most attempts to resolve these issues have involved the development of alternative reactions, formulations, or constructs containing stimulus components aimed at producing multiple approaches for highly efficacious combination cancer therapies. However, there has been no report of a platform based on plug-in execution that enables continuous-flow manufacture in a compact, reconfigurable manner, although an optimal platform technology may be a prerequisite for the timely translation of recently developed nanomedicines. To this end, we describe the development of a platform toward digitizable, continuous manufacture by a serial combination of plug-in reactionwares (heating plates, a spraying cup, and a photochamber) for single-pass flow fabrication. Specifically, we fabricated three different composite nanoblocks consisting of Au1Ag9 (<8 nm; stimulus component), docetaxel (an anticancer drug), and bovine serum albumin (a protective and targeting agent) using our system, with the result of producing nanoblocks with photothermally modulatable and structurally disintegratable properties. These were examined for effectiveness in near-infrared-induced chemothermal cancer therapy and renal excretion of Au1Ag9 particles and exhibited high anticancer efficacy and warrantable biosafety.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Humanos , Nanomedicina , Neoplasias/tratamento farmacológico , Fototerapia , Prata/uso terapêuticoRESUMO
The consolidation of nanovectors with biological membranes has recently been a subject of interest owing to the prolonged systemic circulation time and delayed clearance by the reticuloendothelial system of such systems. Among the different biomembranes, the macrophage membrane has a similar systemic circulation time, with an additional chemotactic aptitude, targeting integrin proteins. In this study, we aimed to establish a laser-activated, disintegrable, and deeply tumor-penetrative nanoplatform. We used a highly tumor-ablative and laser-responsive disintegrable copper sulfide nanoparticle, loaded it with paclitaxel, and camouflaged it with the macrophage membrane for the fabrication of PTX@CuS@MMNPs. The in vitro paclitaxel release profile was favorable for release in the tumor microenvironment, and the release was accelerated after laser exposure. Cellular internalization was improved by membrane encapsulation. Cellular uptake, cytotoxicity, reactive oxygen species generation, and apoptosis induction of PTX@CuS@MMNPs were further improved upon laser exposure, and boosted permeation was achieved by co-administration of the tumor-penetrating peptide iRGD. In vivo tumor accumulation, tumor inhibition rate, and apoptotic marker expression induced by PTX@CuS@MMNPs were significantly improved by laser irradiation and iRGD co-administration. PTX@CuS@MMNPs induced downregulation of cellular proliferation and angiogenic markers but no significant changes in body weight, survival, or significant toxicities in vital organs after laser exposure, suggesting their biocompatibility. The disintegrability of the nanosystem, accredited to biodegradability, favored efficient elimination from the body. In conclusion, PTX@CuS@MMNPs showed promising traits in combination therapies for excellent tumor eradication.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Membrana Celular/química , Macrófagos/química , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cobre/química , Cobre/efeitos da radiação , Cobre/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/efeitos da radiação , Portadores de Fármacos/toxicidade , Raios Infravermelhos , Nanopartículas Metálicas/efeitos da radiação , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7RESUMO
Background: Phytosterols significantly reduce the risk of cancer by directly inhibiting tumor growth, inducing apoptosis, and inhibiting tumor metastasis. Stigmasterol (STS), a phytosterol, exhibits anticancer effects against various cancers, including breast cancer. Chemotherapeutics, including doxorubicin (DOX), might act synergistically with phytosterol against the proliferation and metastasis of breast cancer. Although such compounds can show potential anticancer activity, their combined effect with suitable formulation has not investigated yet.Methods: Hyaluronic acid (HA)-modified PEGylated DOX-STS loaded phyto-liposome was fabricated via a thin-film hydration method. The prepared phyto-liposome was optimized with regards to its physicochemical and other properties. Further, in vitro and in vivo study was carried out in breast cancer cells expressing a different level of CD44 receptors.Results: The particle size of prepared HA-DOX-STS-lipo was 173.9 ± 2.4 nm, and showed pH-depended DOX release, favoring the effective tumor targetability. The in vitro anticancer activity of HA-DOX-STS-lipo was significantly enhanced in MDA-MB-231, CD44-overexpressing cells relative to MCF-7 cells demonstrating HA-mediated targeting effect. HA-DOX-STS-lipo accumulated more and increased antitumor efficacy in the MDA-MB-231 xenograft tumor model expressing high levels of CD44, suggesting the potential of carrier system toward CD44-overexpressing tumors.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , Fitosteróis/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Lipossomos , Células MCF-7 , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hyaluronic acid (HA) assisted effective internalization into CD44 receptor-overexpressing cancer cells, which could offer an excellent cytotoxic profile and tumor alterations. In this study, duo-photothermal agents (copper sulfide (CuS) and graphene oxide (GO)), chemotherapeutic drug (doxorubicin (DOX)), and targeting moiety (HA) were incorporated into a complexed nanoconstruct for trio-responsive chemo-phototherapy. The nanosystem (CuS(DOX)-GO-HA) was demonstrating its responsive drug release and escalated photothermal behavior. The hyperthermia and photodynamic effect were observed along with efficient ROS generation in the presence of dual photosensitizers. The in vivo biodistribution and photothermal profile reflected a high accumulation and retention of the nanoconstruct in the tumor. Importantly, nanoconstructs effectively inhibit tumor growth based on tumor volume analysis and the altered expression of apoptosis, cell proliferation, and angiogenesis markers. Collectively, these findings suggest that this nanoconstruct has excellent antitumor effects in CD44 overexpressed cells showing the potential for clinical translation in the future.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/terapia , Carcinoma de Células Escamosas/terapia , Doxorrubicina/farmacologia , Ácido Hialurônico/administração & dosagem , Nanopartículas/administração & dosagem , Fotoquimioterapia , Animais , Antibióticos Antineoplásicos/química , Apoptose , Neoplasias da Mama/patologia , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Terapia Combinada , Cobre/química , Doxorrubicina/química , Feminino , Grafite/química , Humanos , Ácido Hialurônico/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Copper sulfide nanoparticles (CuS NPs), emerging nanoplatforms with dual diagnostic and therapeutic applications, are being actively investigated in this era of "war on cancer" owing to their versatility and adaptability. This article discusses the pros and cons of using CuS NPs in diagnostics, therapeutics, and theranostics. The first section introduces CuS NPs and discusses the features that render them more advantageous than other established nanoplatforms in cancer management. Subsequent sections include specific in vitro and in vivo results of different studies showing the potential of CuS NPs as nanoplatforms. Methods used for visualization (photoacoustic imaging and magnetic resonance imaging) of CuS NPs and treatment (phototherapy and combinatorial therapy) have also been discussed. Furthermore, the challenges and opportunities associated with using CuS NPs have been elucidated. Further investigations on CuS NPs are required to translate it for clinical applications.
Assuntos
Cobre/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Sulfetos/uso terapêutico , Animais , Humanos , Nanomedicina TeranósticaRESUMO
Metformin (MET) is a common treatment for type II diabetes. Here, we demonstrate the anticancer activity of a polymeric metformin derivative. We successfully synthesized the polypeptide (poly-l-lysine [PLL]) derivative of metformin (LysMET) and demonstrated its capacity as an anticancer therapeutic and gene carrier. miRNA-320a was loaded into the cationic LysMET and enveloped in a lipid bilayer, and a MUC1-specific aptamer was conjugated to the surface (A-Lipo@mLysMET). The LysMET-containing guanidine moiety was more tolerable than the secondary amine-containing PLL. LysMET showed similar efficacy to MET in the induction of HT-29 tumor suppression, indicating the importance of the biguanide moiety. The synergistic effect of miRNA-320a and LysMET treatment significantly decreased cell viability compared with LysMET treatment alone, which was attributed to the role of miRNA in the ß-catenin pathway. A-Lipo@mLysMET showed excellent antitumor efficacy and significantly reduced the tumor burden in all groups. AMPKα phosphorylation was markedly increased by LysMET compared with the control, with significant inhibition of the mTOR pathway. The TUNEL assay showed that apoptosis was the main mechanism responsible for cancer cell death and that A-Lipo@mLysMET resulted in the highest proportion of TUNEL-positive cells (â¼36%). No noticeable organ damage was observed after treatment with either LysMET or A-Lipo@mLysMET, confirming the excellent safety profile of guanide-modified polymers. Overall, we demonstrated the feasibility of LysMET for the effective control of tumor progression as well as its dual role, as both a drug and a gene carrier.
RESUMO
Near-infrared (NIR)-responsive drug delivery systems have enhanced tumor ablative efficiency through permeation and retention effects. Graphene oxide (GO) has shown great potential both in photothermal therapy and in drug delivery. Thus, in this study, we designed an ambient spark-generated GO, wrapped on topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSN-NH2-TPT-CGO), to function as an efficient platform for pH-dependent sustained release of TPT. HMSN-NH2-TPT-CGO also exhibited a combined chemo-photothermal effect within a single carrier system. This developed system was stable with a uniform particle size (â¼190â¯nm) and was demonstrated to possess a sufficient heat-absorbing capacity to induce tumor cell ablation. We performed the ablation of tumor cells both in vitro and in vivo in combination with photothermal therapy and chemotherapy using the spark-generated functional GO and HMSN. The prepared nanocarriers demonstrated high cellular uptake, apoptosis, and G0/G1 cell cycle arrest. In vivo study using the MDA-MB-231 xenograft model revealed the ultraefficient tumor ablative performance of HMSN-NH2-TPT-CGO compared with that of free TPT, with no toxic effect on vital organs. Altogether, the optimized nanocarriers presented a significant potential to act as a vehicle for cancer treatment. STATEMENT OF SIGNIFICANCE: This is the first study that uses spark-generated graphene oxide nanoflakes to cover the topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSNs) to treat breast cancer. Dense silica was used as a hard template to prepare the HMSNs attributing to a high drug payload. The concentration of Na2CO3 was precisely controlled to minimize the silica etching time within 70â¯min. The use of the nanographene flakes served a dual purpose, first, by acting as a capping agent to prevent the premature release of drug and, second, by serving as a nano heater that significantly ablates the tumor cells. The prepared nanocarriers (NCs) exhibited effective and enhanced in vitro and in vivo apoptosis, as well as significant tumor growth inhibition even after 15â¯days of treatment time, with no toxic effect to the vital organs. The NCs enhanced in vitro tumor cell killing effects and served as an effective carrier for in vivo tumor regression, thereby highlighting the enormous potential of this system for breast cancer therapy.