RESUMO
Owing to their good stability and high photothermal conversion efficiency, the development of carbon-based nanoparticles has been intensively investigated, while the limitation of unsatisfactory cellular internalization impedes their further clinical application. Herein, we report a novel strategy for fabrication of Fe3O4 yolk-shell mesoporous carbon nanocarriers (Fe3O4@hmC) with monodispersity and uniform size, which presented significantly higher cell membrane adsorption and cellular uptake properties in comparison with common solid silica-supported mesoporous carbon nanoparticles with core-shell structure. Moreover, the MRI performance of this novel Fe-based nanoparticle could facilitate precise tumor diagnosis. More importantly, after DOX loading (Fe3O4@hmC-DOX), owing to synergistic effect of chemo-phototherapy, this therapeutic agent exhibited predominant tumor cell ablation capability under 808 nm NIR laser irradiation, both in vitro and in vivo. Our work has laid a solid foundation for therapeutics with hollowed carbon shell for solid tumor diagnosis and therapy in clinical trials.
Assuntos
Neoplasias da Mama/terapia , Carbono/química , Doxorrubicina/administração & dosagem , Nanopartículas Magnéticas de Óxido de Ferro/química , Animais , Neoplasias da Mama/diagnóstico por imagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Doxorrubicina/química , Feminino , Camundongos , Nanoestruturas , Tamanho da Partícula , Terapia Fototérmica , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
On-demand drug release nanoplatforms are promising alternative strategies for enhancing the therapeutic effect of cancer chemotherapy. However, these nanoplatforms still have many drawbacks including rapid blood clearance, nontargeted specificity, and a lack of immune escape function. Even worse, they are also hindered via the dosage-limiting toxicity of traditional chemotherapeutic drugs. Herein, both dual-functional mannose (enhances the antitumor activity of chemotherapeutic drugs and exhibits an innate affinity against the lectin receptor) and amphiphilic d-α-tocopheryl polyethylene glycol 1000 succinate were selected to be covalently linked via a redox-responsive monothioether linkage. The synthesized self-distinguished polymer (TSM), as a structural motif, can be self-assembled into nanoparticles (TSM NPs) in an aqueous solution, in which doxorubicin (DOX) is loaded by weak interactions (TSM-DOX NPs). These TSM-DOX NPs can provide targeted, on-demand drug release under dual stimuli from lysosomal acidity and glutathione (GSH). In addition, TSM-DOX NPs can be self-distinguished via tumor cells in vitro and specifically self-distinguished from the tumor site in vivo. Further in vitro and in vivo research consistently demonstrated that TSM-DOX NPs display highly synergistic chemotherapeutic effects. Taken together, the data show that the self-distinguished GSH-responsive polymer TSM has the potential to load various therapeutic agents.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polímeros/química , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Ratos , Ratos Sprague-Dawley , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This study was aimed to investigate the effect of green tea extract (GTE) combined with brisk walking on lipid profiles and the liver function in overweight and obese men. Twenty-four participants were randomized to either the GTE group or the placebo group for 12 weeks with a 4-week follow-up. The walking program consisted of four 60-min-sessions/week and all participants were asked to consume two GTE (150mg) or placebo tablets daily. After 12-week intervention, GTE group resulted in a significant difference in the low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels when compared to placebo group (P < 0.01). There was also a significant reduction in the aspartate aminotransferase levels (P < 0.01) in the GTE group, but no change in the placebo group (P >0.05). There was no change in the triglyceride or high-density lipoprotein cholesterol (HDL-C) levels in the placebo group, but a significant reduction was noted in the HDL-C levels in the GTE group (P < 0.05). GTE combined with brisk walking resulted in a significant change in the LDL-C and TC levels, however, a significant reduce in HDL-C in the GTE group. The study has a more positive effect on the liver function than brisk walking alone.
Assuntos
Catequina , Caminhada , Humanos , Lipídeos , Fígado , Masculino , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Extratos Vegetais/farmacologia , CháRESUMO
The clinical translation of methotrexate (MTX) is limited because of low aqueous solubility, poor bioavailability, low uptake efficiency, and toxicity concerns. Herein, dual-acting MTX (not only targeting folate receptors but also killing cells via inhibition of intracellular folate metabolism) and hyaluronic acid (HA, targeting CD44 receptors) were selected to be covalently linked by the redox-responsive disulfide bond. The synthesized prodrug (HA-SS-MTX) as a molecular structural motif could self-assemble into simple yet multifunctional nanoparticles (HA-SS-MTX NPs) in aqueous solution. The HA-SS-MTX NPs displayed an average diameter of â¼110 nm with a uniformly spherical shape and maintained stability in different physiological media. Moreover, the HA-SS-MTX NPs could exhibit a sharp redox-dependent response for rapid structure disassembly and sequential MTX release compared to the redox-irresponsive group (HA-ADH-MTX NPs). Furthermore, the results of confocal microscopy and flow cytometry verified that the nanosystems were selectively uptaken by cancer cells via folate and CD44 receptor-mediated internalization through the dual-active targeting mechanism. In addition, HA-SS-MTX NPs could accumulate within tumor sites for a longer period. Notably, in vitro and in vivo antitumor results demonstrated that HA-SS-MTX NPs significantly promoted the death of cancer cells and enhanced the inhibition of tumor growth while reducing the toxicity as compared to MTX and HA-ADH-MTX NPs. Therefore, the smart HA-SS-MTX NPs as the simple and efficient platform have great potential in tumor-targeting drug delivery and therapy.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Antagonistas do Ácido Fólico/metabolismo , Ácido Hialurônico/metabolismo , Metotrexato/metabolismo , Nanopartículas/química , Pró-Fármacos/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Liberação Controlada de Fármacos , Feminino , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Células HeLa , Humanos , Receptores de Hialuronatos/antagonistas & inibidores , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Metotrexato/química , Metotrexato/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oxirredução , Distribuição Tecidual , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Locating nanomedicines at the active sites plays a pivotal role in the nanoparticle-based cancer therapy field. Herein, a multifunctional nanotherapeutic is designed by using graphene oxide (GO) nanosheets with rich carboxyl groups as the supporter for hyaluronic acid (HA)-methotrexate (MTX) prodrug modification via an adipicdihydrazide cross-linker, achieving synergistic multistage tumor-targeting and combined chemo-photothermal therapy. As a tumor-targeting biomaterial, HA can increase affinity of the nanocarrier toward CD44 receptor for enhanced cellular uptake. MTX, a chemotherapeutic agent, can also serve as a tumor-targeting enhancer toward folate receptor based on its similar structure with folic acid. The prepared nanosystems possess a sheet shape with a dynamic size of approximately 200 nm and pH-responsive drug release. Unexpectedly, the physiological stability of HA-MTX prodrug-decorated GO nanosystems in PBS, serum, and even plasma is more excellent than that of HA-decorated GO nanosystems, while both of them exhibit an enhanced photothermal effect than GO nanosheets. More importantly, because of good blood compatibility as well as reduced undesired interactions with blood components, HA-MTX prodrug-decorated GO nanosystems exhibited remarkably superior accumulation at the tumor sites by passive and active targeting mechanisms, achieving highly effective synergistic chemo-photothermal therapeutic effect upon near-infrared laser irradiation, efficient ablation of tumors, and negligible systemic toxicity. Hence, the HA-MTX prodrug-decorated hybrid nanosystems have a promising potential for synergistic multistage tumor-targeting therapy.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Grafite/química , Nanoconjugados/química , Fotoquimioterapia/métodos , Neoplasias do Colo do Útero/terapia , Adipatos/química , Adipatos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Feminino , Grafite/metabolismo , Células HeLa , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/metabolismo , Células MCF-7 , Metotrexato/química , Metotrexato/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: This work was intended to develop novel doxorubicin (DOX)/zinc (II) phthalocyanine (ZnPc) co-loaded mesoporous silica (MSNs)@ calcium phosphate (CaP)@PEGylated liposome nanoparticles (NPs) that could efficiently achieve collaborative anticancer therapy by the combination of photodynamic therapy (PDT) and chemotherapy. The interlayer of CaP could be utilized to achieve pH-triggered controllable drug release, promote the cellular uptake, and induce cell apoptosis to further enhance the anticancer effects. METHODS: MSNs were first synthesized as core particles in which the pores were diffusion-filled with DOX, then the cores were coated by CaP followed by the liposome encapsulation with ZnPc to form the final DOX/ZnPc co-loaded MSNs@CaP@PEGylated liposome. RESULTS: A core-interlayer-shell MSNs@CaP@PEGylated liposomes was developed as a multifunctional theranostic nanoplatform. In vitro experiment indicated that CaP could not only achieve pH-triggered controllable drug release, promote the cellular uptake of the NPs, but also generate high osmotic pressure in the endo/lysosomes to induce cell apoptosis. Besides, the chemotherapy using DOX and PDT effect was achieved by the photosensitizer ZnPc. Furthermore, the MSNs@CaP@PEGylated liposomes showed outstanding tumor-targeting ability by enhanced permeability and retention (EPR) effect. CONCLUSIONS: The novel prepared MSNs@CaP@PEGylated liposomes could serve as a promising multifunctional theranostic nanoplatform in anticancer treatment by synergic chemo-PDT and superior tumor-targeting ability.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Nanopartículas/química , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/administração & dosagem , Nanomedicina Teranóstica/métodos , Antibióticos Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Fosfatos de Cálcio/química , Terapia Combinada/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Indóis/administração & dosagem , Indóis/farmacocinética , Isoindóis , Lipossomos , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Polietilenoglicóis/química , Silicatos/química , Compostos de ZincoRESUMO
BACKGROUND: Since the anticancer drugs have diverse inhibited mechanisms to the cancer cells, the use of two or more kinds of anticancer agents may achieve excellent therapeutic effects, especially to the drug-resistant tumors. RESULTS: In this study, we developed a kind of dual drug [methotrexate (MTX) and 10-hydroxycamptothecine (HCPT)] loaded nanoneedles (DDNDs) with pronounced targeting property, high drug loading and prolonged drug release. The anti-solvent precipitation of the HCPT and MTX modified PEG-b-PLGA (PEG-b-PLGA-MTX, PPMTX) leads to nucleation of nanoneedles with nanocrystalline HCPT as the core wrapped with PPMTX as steric stabilizers. In vitro cell uptake studies showed that the DDNDs revealed an obviously targeting property and entered the HeLa cells easier than the nanoneedles without MTX modification. The cytotoxicity tests illustrated that the DDNDs possessed better killing ability to HeLa cells than the individual drugs or their mixture in the same dose, indicating its good synergistic effect and targeting property. The in vivo studies further confirmed these conclusions. CONCLUSIONS: This approach led to a promising sustained drug delivery system for cancer diagnosis and treatment.
Assuntos
Antineoplásicos/química , Camptotecina/análogos & derivados , Portadores de Fármacos/química , Metotrexato/química , Nanopartículas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Células HeLa , Humanos , Metotrexato/administração & dosagem , Metotrexato/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Confocal , Microscopia Eletrônica de Varredura , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Polietilenoglicóis/química , Poliglactina 910/química , Distribuição Tecidual , Transplante HeterólogoRESUMO
In this study, we used Shirasu porous glass membrane(SPG) as a template and hydroxy camptothecin (HCPT) as a model drug to prepare the comet-shaped Me PEG [methoxyl poly(ethylene glycol)]- PLGA [poly(lactic-co-glycolic acid)-HCPT amphiphilic block copolymer. Our method was optimized by the orthogonal design method. The partical size, zeta potential, drug-loaded content, yield, shape and status of the obtained comet-shaped Me PEG-PLGA-HCPT particles were further characterized by dynamic light scattering(DLS), scanning electron microscopy(SEM)/transmission electron microscopy (TEM), X-ray diffraction(XRD) and differential scanning calorimetry (DSC) et al, respectively. In vitro release was preliminary evaluated. MTT assay to preliminary evaluate the cytotoxicity of particles against human liver BEL-7402 cells. Based on these experimental results, the optimal preparation conditions contain: weight ratio of HCPT to Me PEG-PLGA was 1:1, nitrogen pressure was 100 k Pa and SPG membrane pore size was 1.1 µm. The particles exhibited a comet-shaped shape, fairly uniform size and were well dispersed. The drug-loading content was 46.2%, with yield of 96.4%, and zeta-31.4 m V. The distribution of HCPT in particles was very uniform, and HCPT showed a amorphous state existed in particles. The release behavior in vitro showed sustained releasing, and with the drug loading content in proportion to the release of the drug. MTT test indicated that the HCPT-loaded comet-shaped particles had enhanced the cytotoxicity against human liver BEL-7402 cells relatively to the HCPT-loaded spherical particles in vitro. The results showed a promising potential application of the preparation in clinical treatment of tumor.
Assuntos
Camptotecina/administração & dosagem , Portadores de Fármacos/química , Ácido Láctico/química , Ácido Poliglicólico/química , Varredura Diferencial de Calorimetria , Linhagem Celular , Humanos , Nanopartículas , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Difração de Raios XRESUMO
The design of nanoscale drug delivery systems for the targeted codelivery of multiple therapeutic drugs still remains a formidable challenge (ACS Nano, 2013, 7, 9558-9570; ACS Nano, 2013, 7, 9518-9525). In this article, both mitomycin C (MMC) and methotrexate (MTX) loaded DSPE-PEG micelles (MTX-M-MMC) were prepared by self-assembly using the dialysis technique, in which MMC-soybean phosphatidylcholine complex (drug-phospholipid complex) was encapsulated within MTX-functionalized DSPE-PEG micelles. MTX-M-MMC could coordinate an early phase active targeting effect with a late-phase synergistic anticancer effect and enable a multiple-responsive controlled release of both drugs (MMC was released in a pH-dependent pattern, while MTX was released in a protease-dependent pattern). Furthermore, MTX-M-MMC could codeliver both drugs to significantly enhance the cellular uptake, intracellular delivery, cytotoxicity, and apoptosis in vitro and improve the tumor accumulation and penetration and anticancer effect in vivo compared with either both free drugs treatment or individual free drug treatment. To our knowledge, this work provided the first example of the systemically administrated, orthogonally functionalized, and self-assisted nanoscale micelles for targeted combination cancer chemotherapy. The highly convergent therapeutic strategy opened the door to more simplified, efficient, and flexible nanoscale drug delivery systems.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Metotrexato/administração & dosagem , Mitomicina/administração & dosagem , Animais , Biofarmácia , Portadores de Fármacos/química , Sinergismo Farmacológico , Feminino , Células HeLa , Humanos , Metotrexato/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Mitomicina/farmacocinética , Nanocápsulas/química , Nanotecnologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The particle shape of the drug delivery systems had a strong impact on their in vitro and in vivo performance, but there was limited availability of techniques to produce the specific shaped drug carriers. In this article, the novel methotrexate (MTX) decorated MPEG-PLA nanobacillus (MPEG-PLA-MTX NB) was prepared by the self-assembly technique followed by the extrusion through SPG membrane with high N2 pressure for targeted drug delivery, in which Janus-like MTX was not only used as a specific anticancer drug but could also be served as a tumor-targeting ligand. The MPEG-PLA-MTX NBs demonstrated much higher in vitro and in vivo targeting efficiency compared to the MPEG-PLA-MTX nanospheres (MPEG-PLA-MTX NSs) and MPEG-PLA nanospheres (MPEG-PLA NSs). In addition, the MPEG-PLA-MTX NBs also displayed much more excellent in vitro and in vivo antitumor activity than the MPEG-PLA-MTX NSs and free MTX injection. To our knowledge, this work provided the first example of the integration of the shape design (which mediated an early phase tumor accumulation and a late-phase cell internalization) and Janus-faced function (which mediated an early phase active targeting effect and a late-phase anticancer effect) on the basis of nanoscaled drug delivery systems. The highly convergent and cooperative drug delivery strategy opens the door to more drug delivery systems with new shapes and functions for cancer therapy.
Assuntos
Bacillus , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Polímeros/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Portadores de Fármacos/química , Citometria de Fluxo , Células HeLa , Humanos , Ácido Láctico/química , Metotrexato/administração & dosagem , Camundongos , Nanopartículas/química , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/químicaRESUMO
A mitomycin C (MMC)-soybean phosphatidyhlcholine complex loaded in phytosomes was previously reported for the purpose of developing a MMC drug delivery system (Mol. Pharmaceutics 2013, 10, 90-101), but this approach was limited by rapid elimination from the body and lack of target specificity. In this article, to overcome these limitations, MMC-soybean phosphatidyhlcholine complex-loaded phytosomes (MMC-loaded phytosomes) as drug carriers were surface-functionalized with folate-PEG (FA-PEG) to achieve reduced toxicity and a superior MMC-mediated therapeutic effect. For this purpose, FA was conjugated to DSPE-PEG-NH2, and the resultant DSPE-PEG-FA was introduced into the lipid moiety of the phytosomes via a postinsertion technique. The prepared FA-PEG-functionalized MMC-loaded phytosomes (FA-PEG-MMC-loaded phytosomes) have a particle size of 201.9 ± 2.4 nm, a PDI of 0.143 ± 0.010, a zeta potential of -27.50 ± 1.67 mV, a spherical shape, and sustained drug release. The remarkable features of FA-PEG-MMC-loaded phytosomes included increased cellular uptake in HeLa cells and higher accumulation in H22 tumor-bearing mice over that of the PEG-MMC-loaded phytosomes. Furthermore, FA-PEG-MMC-loaded phytosomes were associated with enhanced cytotoxic activity in vitro and an improved antitumor effect in vivo compared to that resulting from free MMC injection. These results suggest that FA-PEG-MMC-loaded phytosomes may be useful drug delivery systems for widening the therapeutic window of MMC in clinical trials.
Assuntos
Ácido Fólico/análogos & derivados , Ácido Fólico/química , Glycine max/química , Lipossomos/química , Mitomicina/química , Polietilenoglicóis/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/administração & dosagem , Células HeLa , Humanos , Lipossomos/administração & dosagem , Masculino , Camundongos , Camundongos Nus , Mitomicina/administração & dosagem , Tamanho da Partícula , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Polietilenoglicóis/administração & dosagem , Polímeros/administração & dosagem , Polímeros/química , Ratos , Ratos Sprague-DawleyRESUMO
Most present drug-phospholipid delivery systems were based on a water-insoluble drug-phospholipid complex but rarely water-soluble drug-phospholipid complex. Mitomycin C (MMC) is a water-soluble anticancer drug extensively used in first-line chemotherapy but is limited by its poor aqueous stability in vitro, rapid elimination from the body, and lack of target specificity. In this article, we report the MMC-soybean phosphatidylcholine complex-loaded PEG-lipid-PLA hybrid nanoparticles (NPs) with Folate (FA) functionalization (FA-PEG-PE-PLA NPs@MMC-SPC) for targeted drug delivery and dual-controlled drug release. FA-PEG-PE-PLA NPs@MMC-SPC comprise a hydrophobic core (PLA) loaded with MMC-SPC, an amphiphilic lipid interface layer (PE), a hydrophilic shell (PEG), and a targeting ligand (FA) on the surface, with a spherical shape, a nanoscaled particle size, and high drug encapsulation efficiency of almost 95%. The advantage of the new drug delivery systems is the early phase controlled drug release by the drug-phospholipid complex and the late-phase controlled drug release by the pH-sensitive polymer-lipid hybrid NPs. In vitro cytotoxicity and hemolysis assays demonstrated that the drug carriers were cytocompatible and hemocompatible. The pharmacokinetics study in rats showed that FA-PEG-PE-PLA NPs@MMC-SPC significantly prolonged the blood circulation time compared to that of the free MMC. More importantly, FA-PEG-PE-PLA NPs@MMC-SPC presented the enhanced cell uptake/cytotoxicity in vitro and superior tumor accumulation/therapeutic efficacy in vivo while reducing the systemic toxicity. A significant accumulation of MMC in the nuclei as the site of MMC action achieved in FA-PEG-PE-PLA NPs@MMC-SPC made them ideal for MMC drug delivery. This study may provide an effective strategy for the design and development of the water-soluble drug-phospholipid complex-based targeted drug delivery and sustained/controlled drug release.
Assuntos
Sistemas de Liberação de Medicamentos , Glycine max/química , Mitomicina/química , Nanopartículas/química , Fosfatidilcolinas/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/química , Ligantes , Masculino , Camundongos , Transplante de Neoplasias , Tamanho da Partícula , Poliésteres , Polietilenoglicóis/química , Polímeros/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Água/químicaRESUMO
BACKGROUND: Artesunate (ASA) acts as an â¢O2- source through the breakdown of endoperoxide bridges catalyzed by Fe2+, yet its efficacy in ASA-based nanodrugs is limited by poor intracellular delivery. METHODS: ASA-hyaluronic acid (HA) conjugates were formed from hydrophobic ASA and hydrophilic HA by an esterification reaction first, and then self-targeting nanomicelles (NM) were developed using the fact that the amphiphilic conjugates of ASA and HA are capable of self-assembling in aqueous environments. RESULTS: These ASA-HA NMs utilize CD44 receptor-mediated transcytosis to greatly enhance uptake by breast cancer cells. Subsequently, endogenous Fe2+ from the tumor catalyzes the released ASA to produce highly toxic â¢O2- radicals to kill tumor cells, although sustained tumor growth inhibition can be achieved via in vivo experiments. CONCLUSIONS: Self-targeting NMs represent a promising strategy for enhancing ASA-based treatments, leveraging clinically approved drugs to expedite drug development and clinical research in oncology.
RESUMO
Nanozymes, as nanomaterials with natural enzyme activities, have been widely applied to deliver various therapeutic agents to synergistically combat the progression of malignant tumors. However, currently common inorganic nanozyme-based drug delivery systems still face challenges such as suboptimal biosafety, inadequate stability, and inferior tumor selectivity. Herein, a super-stable amino acid-based metallo-supramolecular nanoassembly (FPIC NPs) with peroxidase (POD)- and glutathione oxidase (GSHOx)-like activities was fabricated via Pt4+-driven coordination co-assembly of l-cysteine derivatives, the chemotherapeutic drug curcumin (Cur), and the photosensitizer indocyanine green (ICG). The superior POD- and GSHOx-like activities could not only catalyze the decomposition of endogenous hydrogen peroxide into massive hydroxyl radicals, but also deplete the overproduced glutathione (GSH) in cancer cells to weaken intracellular antioxidant defenses. Meanwhile, FPIC NPs would undergo degradation in response to GSH to specifically release Cur, causing efficient mitochondrial damage. In addition, FPIC NPs intrinsically enable fluorescence/photoacoustic imaging to visualize tumor accumulation of encapsulated ICG in real time, thereby determining an appropriate treatment time point for tumoricidal photothermal (PTT)/photodynamic therapy (PDT). In vitro and in vivo findings demonstrated the quadruple orchestration of catalytic therapy, chemotherapeutics, PTT, and PDT offers conspicuous antineoplastic effects with minimal side reactions. This work may provide novel ideas for designing supramolecular nanoassemblies with multiple enzymatic activities and therapeutic functions, allowing for wider applications of nanozymes and nanoassemblies in biomedicine.
Assuntos
Curcumina , Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Aminoácidos , Terapia Combinada , Verde de Indocianina/farmacologia , Neoplasias/tratamento farmacológico , Corantes , Oxirredução , Linhagem Celular TumoralRESUMO
Currently, the copolymer of dopamine (DA) and pyrrole (PY) via chemical and electrochemical oxidation usually requires additional oxidants, and lacks flexibility in regulating the size and morphology, thereby limiting the broad applications of DA-PY copolymer in biomedicine. Herein, the semiquinone radicals produced by the self-oxidation of DA is ingeniously utilized as the oxidant to initiate the following copolymerization with PY, and a series of quinone-rich polydopamine-pyrrole copolymers (PDAm-nPY) with significantly enhanced absorption in near-infrared (NIR) region without any additional oxidant assistance is obtained. Moreover, the morphology and size of PDAm-nPY can be regulated by changing the concentration of DA and PY, thereby optimizing nanoscale PDA0.05-0.15PY particles (≈ 150 nm) with excellent NIR absorption and surface modification activity are successfully synthesized. Such PDA0.05-0.15PY particles show effective photoacoustic (PA) imaging and photothermal therapy (PTT) against 4T1 tumors in vivo. Furthermore, other catechol derivatives can also copolymerize with PY under the same conditions. This work by fully utilizing the semiquinone radical active intermediates produced through the self-oxidation of DA reduces the dependence on external oxidants in the synthesis of composite materials and predigests the preparation procedure, which provides a novel, simple, and green strategy for the synthesis of other newly catechol-based functional copolymers.
Assuntos
Indóis , Oxirredução , Polímeros , Pirróis , Indóis/química , Polímeros/química , Pirróis/química , Animais , Camundongos , Polimerização , Técnicas Fotoacústicas , Linhagem Celular Tumoral , Terapia Fototérmica , Nanopartículas/química , Feminino , Camundongos Endogâmicos BALB CRESUMO
A novel formulation system of phytosomes loaded with mitomycin C-soybean phosphatidylcholine (MMC-SPC) complex (MMC-loaded phytosomes) was prepared by a solvent evaporation method combined with a nanoprecipitation technique for the purpose of development of an MMC drug delivery system. The MMC-loaded phytosomes were evaluated by average particle size, zeta-potential, and residual drug-loading content as well as an in vitro drug release profile. Furthermore, in vitro stability tests and in vitro/vivo biological evaluations of the MMC-loaded phytosomes were performed. DSC, FTIR, and XRD demonstrated that MMC interacted physically with SPC within the phytosomes. DLS and ELS described a dispersion with an average particle size of 210.87 nm, a narrow size distribution (PDI 0.251), and a zeta-potential of -33.38 mV. SEM, TEM, and AFM images showed that the MMC-loaded phytosomes were spherical and intact vesicles. In vitro stability tests demonstrated that the average particle size and residual drug-loading content of the MMC-loaded phytosomes had no evident change at different storage conditions. In vitro drug release profiles indicated biphasic behavior with an initial burst release, followed by a subsequent prolonged sustained release. In vitro cytotoxicity assays with H(22) cells showed that the MMC-loaded phytosomes had remarkable cytotoxicity. In vivo antitumor effect of the MMC-loaded phytosomes also revealed a dose-dependent and superior curative inhibitory effect on tumor growth without loss of body weight compared to free MMC. Histopathological analysis of specimens taken from tumor tissues indicated that MMC-loaded phytosomes had lethal effect to hepatoma cell. These findings suggested that the MMC-loaded phytosomes can serve as a promising and effective formulation for drug delivery and cancer therapy.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Glycine max/química , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Mitomicina/administração & dosagem , Fosfatidilcolinas/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Estabilidade de Medicamentos , Masculino , Camundongos , Mitomicina/química , Nanotecnologia/métodos , Tamanho da Partícula , Fosfatidilcolinas/administração & dosagem , Solubilidade , Solventes/químicaRESUMO
Targeted drug delivery is a precise and effective strategy in oncotherapy that can accurately deliver drugs to tumor cells or tissues to enhance their therapeutic effect and, meanwhile, weaken their undesirable side effects on normal cells or tissues. In this research field, a large number of researchers have achieved significant breakthroughs and advances in oncotherapy. Typically, nanocarriers as a promising drug delivery strategy can effectively deliver drugs to the tumor site through enhanced permeability and retention (EPR) effect-mediated passive targeting and various types of receptor-mediated active targeting, respectively. Herein, we review recent targeted drug delivery strategies and technologies for enhancing oncotherapy. In addition, we also review two mainstream drug delivery strategies, passive and active targeting, based on various nanocarriers for enhancing tumor therapy. Meanwhile, a comparison and combination of passive and active targeting are also carried out. Furthermore, we discuss the associated challenges of passive and active targeted drug delivery strategies and the prospects for further study.
RESUMO
Oxidative stress-based antitumor modalities derived from reactive oxygen species (ROS) storms have attracted increasing attention. Nevertheless, low delivery efficiency, poor selectivity, hypoxia and overexpressed glutathione (GSH) have severely restricted the sustainable generation of the ROS storm in tumor cells. Herein, we design a bioengineered nanogenerator by coordination-driven co-assembly of sonosensitizer indocyanine green (ICG), Fenton-like agent copper ion (Cuâ ¡) and mitochondrial respiratory inhibitor metformin (MET), which is then camouflaged by a cancer cytomembrane to induce a sustainable intracellular ROS storm for on-demand self-reinforcing sono-chemodynamic oncotherapy. Such a nanogenerator with a core-shell structure, suitable diameter and outstanding stability can efficiently accumulate in tumor regions and then internalize into tumor cells through the camouflaging and homologous targeting strategy of the cancer cytomembrane. The nanogenerator shows an exceptional instability under the triple stimulations of acidic lysosomes, overexpressed GSH and ultrasound (US) radiation, thereby resulting in the rapid disassembly and burst drug release. Interestingly, the released MET significantly enhances the sonodynamic therapy (SDT) efficacy of the released ICG by inhibiting mitochondrial respiration and meanwhile the released Cuâ ¡ obviously reduces ROS elimination by downregulating overexpressed GSH for self-amplifying and self-protecting the intracellular ROS storm. Moreover, such a nanogenerator almost completely achieves the tumor ablation in vivo in a single therapy cycle. Taken together, our bioengineered nanogenerator with a sustainable ROS storm can provide a promising strategy for ROS storm-based oncotherapy.
Assuntos
Metformina , Neoplasias , Humanos , Espécies Reativas de Oxigênio , Estresse Oxidativo , Engenharia Biomédica , Cobre/farmacologia , Liberação Controlada de Fármacos , Glutationa , Verde de Indocianina , Metformina/farmacologia , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Peróxido de HidrogênioRESUMO
Although oxidative stress-based antitumor modality derived from reactive oxygen species (ROS) storm has attracted considerable attention in copper-based nanomaterials, its efficiency is still weakened by the insufficient hydrogen peroxide (H2O2) and overexpressed glutathione (GSH) in a tumor microenvironment (TME). In view of this, we designed an engineered programmable spike-like nanogenerator via the coordination-driven co-assembly of Evans Blue (EB), copper ions (CuII), and 5-hydroxy-p-naphthoquinone (HND). For programmable nanogenerators, the introduction of EB as a stabilizer-like component can not only adjust its morphology but also achieve its visual tracking. Interestingly, such programmable nanogenerators can be efficiently enriched in tumor regions and then internalized into tumor cells due to ECH with spike-like morphology. Notably, once the nanogenerator is disintegrated and burst to release the drug upon acidic lysosome and endogenous GSH triggering, the released HND can not only efficiently amplify endogenous H2O2 by intracellular oxidoreductases but also down-regulate the peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin 1) activity. In addition, the released CuII ions can efficiently catalyze the degradation of the endogenous H2O2 to amplify hydroxyl radicals (ËOH) and down-regulate the overexpressed GSH to reduce ËOH elimination for on-demand cascade-amplifying oxidative stress. Importantly, such programmable nanogenerators show an excellent antitumor effect via down-regulating the Pin 1 activity and cascade-amplifying oxidative stress. In this study, we propose a spatiotemporally programmable cascade nanogenerator for oxidative stress-based antitumor therapy.
Assuntos
Cobre , Peróxido de Hidrogênio , Cobre/farmacologia , Peróxido de Hidrogênio/metabolismo , Microambiente Tumoral , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Glutationa/metabolismoRESUMO
How to efficiently synthesize toxic chemo-drugs in the hypoxia tumor microenvironment still faces a huge challenge. Herein, we have tailored engineered vehicle-free nanoreactors by coordination-driven co-assembly of photosensitizer indocyanine green (ICG), transition metal platinum (Pt), and nontoxic 1,5-dihydroxynaphthalene (DHN) to self-amplify O2 and cascade chemo-drug synthesis in tumor cells for self-reinforcing hypoxic oncotherapy. Once vehicle-free nanoreactors are internalized into tumor cells, they show a serious instability that results in rapid disassembly and on-demand drug release under the stimuli of acidic lysosome and laser radiation. Notably, the released Pt can efficiently decompose the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia, which is conducive to enhancing the photodynamic therapy (PDT) efficiency of the released ICG. Complementarily, a large amount of the 1O2 generated by PDT can efficiently oxidize the released nontoxic DHN into the highly toxic chemo-drug juglone. Therefore, such vehicle-free nanoreactors can achieve intracellular on-demand cascade chemo-drug synthesis and self-reinforce photo-chemotherapeutic efficacy on the hypoxic tumor. On the whole, such a simple, flexible, efficient, and nontoxic therapeutic strategy will broaden the study of on-demand chemo-drug synthesis and hypoxic oncotherapy.