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This study introduces an innovative brain-targeted drug delivery system, RVG-Exo/CBD, utilizing rabies virus glycoprotein (RVG)-engineered exosomes for encapsulating cannabidiol (CBD). The novel delivery system was meticulously characterized, confirming the maintenance of exosomal integrity, size, and successful drug encapsulation with a high drug loading rate of 83.0 %. Evaluation of the RVG-Exo/CBD's brain-targeting capability demonstrated superior distribution and retention in brain tissue compared to unmodified exosomes, primarily validated through in vivo fluorescence imaging. The efficacy of this delivery system was assessed using a behavioral sensitization model in mice, where RVG-Exo/CBD notably suppressed methamphetamine-induced hyperactivity more effectively than CBD alone, indicating a reduction in effective dose and enhanced bioavailability. Overall, the RVG-Exo/CBD system emerges as a promising strategy for enhancing the therapeutic efficacy and safety of CBD, particularly for neurological applications, highlighting its potential for addressing the limitations associated with traditional CBD administration in clinical settings.
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Encéfalo , Cannabidiol , Cannabidiol/administración & dosificación , Cannabidiol/química , Cannabidiol/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Ratones , Masculino , Glicoproteínas/química , Glicoproteínas/metabolismo , Glicoproteínas/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Fragmentos de Péptidos , Proteínas ViralesRESUMEN
Ferroptosis has emerged as a promising therapeutic approach for glioma. However, its efficacy is often compromised by the activated GPX4-reduced glutathione (GSH) system and the poor brain delivery efficiency of ferroptosis inducers. Therefore, suppression of the GPX4-GSH axis to induce the accumulation of lipid peroxides becomes an essential strategy to augment ferroptosis. In this study, we present a metalloimmunological strategy to target the GPX4-GSH axis by inhibiting the cystine/glutamate antiporter system (system Xc-) and glutathione synthesis. To achieve this, we developed a complex of diethyldithiocarbamate (DDC) chelated with copper and ferrous ions (DDC/Cu-Fe) to trigger T-cell immune responses in the tumor microenvironment, as well as to inhibit tumor-associated macrophages, thereby alleviating immunosuppression. To enhance brain delivery, the DDC/Cu-Fe complex was encapsulated into a hybrid albumin and lactoferrin nanoparticle (Alb/LF NP), targeting the nutrient transporters (e.g., LRP-1 and SPARC) overexpressed in the blood-brain barrier (BBB) and glioma cells. The Alb/LF NP effectively promoted the brain accumulation of DDC/Cu-Fe, synergistically induced ferroptosis in glioma cells and activated anticancer immunity, thereby prolonging the survival of glioma-bearing mice. The nanoformulation of DDC/Cu-Fe provides a promising strategy that combines ferroptosis and metalloimmunology for glioma treatment.
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Ferroptosis , Glioma , Animales , Ratones , Biomimética , Cobre , Albúminas , Ditiocarba , Glioma/tratamiento farmacológico , Línea Celular Tumoral , Microambiente TumoralRESUMEN
The protective blood-brain barrier (BBB) prevents most therapeutic agents from entering the brain. Currently, focused ultrasound (FUS) is mostly employed to create microbubbles that induce a cavitation effect to open the BBB. However, microbubbles pass quickly through brain microvessels, substantially limiting the cavitation effect. Here, we constructed a novel perfluoropropane-loaded microbubble, termed ApoER-Pep-MB, which possessed a siloxane bonds-crosslinked surface to increase the microbubble stability against turbulence in blood circulation and was decorated with binding peptide for apolipoprotein E receptor (ApoER-Pep). The microbubble with tailor-made micron size (2 µm) and negative surface charge (-30 mV) performed ApoER-mediated binding rather than internalization into brain capillary endothelial cells. Consequently, the microbubble accumulated on the brain microvessels, based on which even a low-energy ultrasound with less safety risk than FUS, herein diagnostic ultrasound (DUS), could create a strong cavitation effect to open the BBB. Evans Blue and immunofluorescence staining studies demonstrated that the DUS-triggered cavitation effect not only temporarily opened the BBB for 2 h but also caused negligible damage to the brain tissue. Therefore, various agents, ranging from small molecules to nanoscale objects, can be efficiently delivered to target regions of the brain, offering tremendous opportunities for the treatment of brain diseases.
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Barrera Hematoencefálica , Microburbujas , Barrera Hematoencefálica/metabolismo , Células Endoteliales , Ultrasonografía , EndotelioRESUMEN
Depression is a chronic mental disorder which threatens human health and lives. However, the treatment of depression remains challenging largely due to blood brain barrier (BBB), which restricts drugs from entering the brain, resulting in a poor distribution of antidepressants in the brain. In this work, a novel brain-targeted drug delivery system was developed based on borneol-modified PEGylated graphene oxide (GO-PEG-BO). GO-PEG-BO was characterized and proved to possess excellent biocompatibility. By incorporating borneol, GO-PEG-BO could penetrate BBB efficiently by opening tight junctions and inhibiting the efflux system of BBB. The targeted distribution of GO-PEG-BO in the brain was observed by an in vivo biodistribution study. Moreover, GO-PEG-BO exhibited a neuroprotective effect, which is beneficial to the treatment of depression. Ginsenoside Rg1 (GRg1), which can relieve depressive symptoms but difficult to cross BBB, was loaded to GO-PEG-BO for the therapy of depression. In depressive rats, GRg1/GO-PEG-BO improved stress-induced anhedonia, despair and anxiety, and comprehensively relieved the depressive symptoms. In conclusion, GO-PEG-BO could serve as a promising nanocarrier for brain-targeted drug delivery, and provide a new strategy for the therapy of depression.
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Encéfalo , Depresión , Ratas , Humanos , Animales , Depresión/tratamiento farmacológico , Distribución Tisular , PolietilenglicolesRESUMEN
The brain-targeted delivery of therapeutic oligonucleotides has been investigated as a new treatment modality for various brain diseases, such as brain tumors. However, delivery efficiency into the brain has been limited due to the blood-brain barrier. In this research, brain-targeted exosome-mimetic cell membrane nanovesicles (CMNVs) were designed to enhance the delivery of therapeutic oligonucleotides into the brain. First, CMNVs were produced by extrusion with isolated C6 cell membrane fragments. Then, CMNVs were decorated with cholesterol-linked T7 peptides as a targeting ligand by hydrophobic interaction, producing T7-CMNV. T7-CMNV was in aqueous solution maintained its nanoparticle size for over 21 days. The targeting and delivery effects of T7-CMNVs were evaluated in an orthotopic glioblastoma animal model. 2'-O-metyl and cholesterol-TEG modified anti-microRNA-21 oligonucleotides (AMO21c) were loaded into T7-CMNVs, and biodistribution experiments indicated that T7-CMNVs delivered AMO21c more efficiently into the brain than CMNVs, scrambled T7-CMNVs, lipofectamine, and naked AMO21c after systemic administration. In addition, AMO21c down-regulated miRNA-21 (miR-21) levels in glioblastoma tissue most efficiently in the T7-CMNVs group. This enhanced suppression of miR-21 resulted in the up-regulation of PDCD4 and PTEN. Eventually, brain tumor size was reduced in the T7-CMNVs group more efficiently than in the other control groups. With stability, low toxicity, and targeting efficiency, T7-CMNVs may be useful to the development of oligonucleotide therapy for brain tumors.
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There is mounting experimental evidence that blocking angiotensin receptor type 1 activity can prevent the occurrence of hypertension in spontaneously hypertensive rats. Studies have proved this strategy via evasive means, such as intracerebrovascular injections, making clinical translation difficult. This study aimed to develop penetratin and transferrin functionalized liposomes as a delivery tool to safely deliver losartan potassium (an angiotensin receptor blocker) to the brain. Penetratin and transferrin functionalized losartan-loaded liposomes were prepared via the post-insertion technique. Losartan-loaded liposomes were cationic, approximately 150 nm in size, entrapping 66.8 ± 1.5% of losartan. All formulations were well tolerated and internalized by primary and cultured cells in 4 h. Further, the ability to deliver losartan potassium across the blood-brain barrier was evaluated in vivo in Wistar Kyoto rats either in solution or when encapsulated within liposomal nanoparticles. Upon intravenous administration, we did not find a detectable amount of losartan in the brain tissue of rats that received free losartan solution. Contrarily, liposome formulations could deliver losartan to the brain, with a brain AUC and mean resident time of 163.304 ± 13.09 and 8.623 h ± 0.66, respectively. In addition, no toxicity was observed in the animals that received the losartan-loaded liposomes.
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Hipertensión , Nanopartículas , Ratas , Animales , Losartán , Liposomas , Encéfalo/metabolismo , Hipertensión/tratamiento farmacológico , Ratas Endogámicas SHR , Ratas Endogámicas WKY , TransferrinaRESUMEN
Post-traumatic stress disorder (PTSD), which normally follows psychological trauma, has been increasingly studied as a brain disease. However, the blood-brain barrier (BBB) prevents conventional drugs for PTSD from entering the brain. Our previous studies proved the effectiveness of cannabidiol (CBD) against PTSD, but low water solubility, low brain targeting efficiency and poor bioavailability restricted its applications. Here, a bionic delivery system, camouflage CBD-loaded macrophage-membrane nanovesicles (CMNVs), was constructed via co-extrusion of CBD with macrophage membranes, which had inflammatory and immune escape properties. In vitro anti-inflammatory, cellular uptake and pharmacokinetic experiments respectively verified the anti-inflammatory, inflammatory targeting and immune escape properties of CMNVs. Brain targeting and excellent anti-PTSD effects of CMNVs had been validated in vivo by imaging and pharmacodynamics studies. In our study, the potential of ultrasound to open BBBs and improve the brain-targeted delivery of CBD was evaluated. In conclusion, this cell membrane bionic delivery system assisted with ultrasound had good therapeutic effect against PTSD mice, which is expected to help convey CBD to inflammatory areas within the brain and alleviate the symptoms of PTSD.
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Cannabidiol , Trastornos por Estrés Postraumático , Ratones , Animales , Cannabidiol/farmacología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/diagnóstico , Biomimética , Macrófagos , Antiinflamatorios/uso terapéuticoRESUMEN
Head-mounted medical devices (HMDs) are disruptive inventions representing laboratories and clinical institutions worldwide are climbing the apexes of brain science. These complex devices are inextricably linked with a wide range knowledge containing the Physics, Imaging, Biomedical engineering, Biology and Pharmacology, particularly could be specifically designed for individuals, and finally exerting integrated bio-effect. The salient characteristics of them are non-invasive intervening in human brain's physiological structures, and alterating the biological process, such as thermal ablating the tumor, opening the BBB to deliver drugs and neuromodulating to enhance cognitive performance or manipulate prosthetic. The increasing demand and universally accepted of them have set off a dramatic upsurge in HMDs' studies, seminal applications of them span from clinical use to psychiatric disorders and neurological modulation. With subsequent pre-clinical studies and human trials emerging, the mechanisms of transcranial stimulation methods of them were widely studied, and could be basically came down to three notable approach: magnetic, electrical and ultrasonic stimulation. This review provides a comprehensive overviews of their stimulating mechanisms, and recent advances in clinic and military. We described the potential impact of HMDs on brain science, and current challenges to extensively adopt them as promising alternative treating tools.
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Encéfalo , Ultrasonido , HumanosRESUMEN
The treatment of glioblastoma remains a huge challenge due to the lack of an efficient way to deliver drugs across the blood-brain barrier (BBB), and the pharmacotherapy options are very limited. In this work, a biomimetic BBB-penetrating albumin nanosystem modified by a brain-targeting peptide was designed for co-delivering a TGF-ß receptor I (TGFßRI) inhibitor (LY2157299) and an mTOR inhibitor (celastrol). The albumin nanosystem can target nAChRs overexpressed both on the BBB and glioma cells, thereby promoting drug delivery into the glioma. The biomimetic nanoparticles could repolarize tumor-associated macrophages (TAMs) from M2 to M1 phenotype by suppressing the STAT6 pathway, thereby reducing TGF-ß1 secretion and inducing cell apoptosis. In addition, the treatment also blocked TGF-ß/SMAD2 signaling pathway. The glioma-targeting ability and therapeutic efficacy were confirmed in an orthotopic glioma mouse model. The biomimetic nanoparticles significantly prolonged the survival rate, showing a decrease in the proportion of M2-like TAMs and the levels of TGF-ß1 and lactic acid in the glioma tissues. This delivery and treatment strategy provides a new approach for the treatment of gliomas.
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Neoplasias Encefálicas , Glioma , Nanopartículas , Albúminas/metabolismo , Animales , Biomimética , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Glioma/tratamiento farmacológico , Glioma/metabolismo , Terapia de Inmunosupresión , Ratones , Triterpenos Pentacíclicos , Pirazoles , Quinolinas , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Glioblastoma (GBM) is a central nervous system tumor with poor prognosis due to the rapid development of resistance to mono chemotherapy and poor brain targeted delivery. Chemoimmunotherapy (CIT) combines chemotherapy drugs with activators of innate immunity that hold great promise for GBM synergistic therapy. Herein, we chose temozolomide, TMZ, and the epigenetic bromodomain inhibitor, OTX015, and further co-encapsulated them within our well-established erythrocyte membrane camouflaged nanoparticle to yield ApoE peptide decorated biomimetic nanomedicine (ABNM@TMZ/OTX). Our nanoplatform successfully addressed the limitations in brain-targeted drug co-delivery, and simultaneously achieved multidimensional enhanced GBM synergistic CIT. In mice bearing orthotopic GL261 GBM, treatment with ABNM@TMZ/OTX resulted in marked tumor inhibition and greatly extended survival time with little side effects. The pronounced GBM treatment efficacy can be ascribed to three key factors: (i) improved nanoparticle-mediated GBM targeting delivery of therapeutic agents by greatly enhanced blood circulation time and blood-brain barrier penetration; (ii) inhibited cellular DNA repair and enhanced TMZ sensitivity to tumor cells; (iii) enhanced anti-tumor immune responses by inducing immunogenic cell death and inhibiting PD-1/PD-L1 conjugation leading to enhanced expression of CD4+ and CD8+ T cells. The study validated a biomimetic nanomedicine to yield a potential new treatment for GBM.
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Drug delivery to the brain has been a significant challenge in treating neurodegenerative disorders such as Alzheimer's disease due to the presence of the blood-brain barrier, which primarily obstructs the access of drugs and biomolecules into the brain. Several methods to overcome the blood-brain barrier have been employed, such as chemical disruption, surgical intervention, focused ultrasound, intranasal delivery, and the use of nanocarriers. Nanocarrier systems remain the method of choice and have shown promising results over the past decade to achieve better drug targeting. Polymeric nanocarriers and lipidic nanoparticles act as a carrier system providing better encapsulation of drugs, site-specific delivery, increased bioavailability, and sustained release of drugs. The surface modifications and functionalization of these nanocarrier systems have greatly facilitated targeted drug delivery. The safety and efficacy of these nanocarrier systems have been ascertained by several in vitro and in vivo models. In the present review, we have elaborated on recent developments of nanoparticles as a drug delivery system for Alzheimer's disease, explicitly focusing on polymeric and lipidic nanoparticles.
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Enfermedad de Alzheimer , Nanopartículas , Enfermedad de Alzheimer/tratamiento farmacológico , Barrera Hematoencefálica , Encéfalo , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Humanos , Lípidos/químicaRESUMEN
Parkinson's disease (PD) is characterized by the progressive deterioration of dopamine (DA) neurons, and therapeutic endeavors are aimed at preventing DA loss. However, lack of effective brain delivery approaches limits this strategy. In this study, a "Trojan horse" system is used for substantia nigra-targeted delivery of a blood brain barrier-penetrating peptide (RVG29) conjugated to the surface of nanoparticles loaded with the natural autophagy inducer 4,4'-dimethoxychalcone (DMC) (designated as RVG-nDMC). Here, the neuroprotective effects of DMC are demonstrated in PD. Specifically, RVG-nDMC penetrates the blood brain barrier with enhanced brain-targeted delivery efficiency and is internalized by DA neurons and microglia. In vivo studies demonstrate that RVG-nDMC ameliorates motor deficits and nigral DA neuron death in PD mice without causing overt adverse effects in the brain or other major organs. Moreover, RVG-nDMC reverses tyrosine hydroxylase ubiquitination and degradation, alleviates oxidative stress in DA neurons, and exerts antiinflammatory effects in microglia. The "Trojan horse" strategy for targeted delivery of DMC thus provides a potentially powerful and clinically feasible approach for PD intervention.
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Chalcona/análogos & derivados , Chalcona/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Fármacos Neuroprotectores/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Barrera Hematoencefálica/metabolismo , Chalcona/uso terapéutico , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/uso terapéutico , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
Effective intracerebral delivery acetylcholinesterase (AChE) reactivator is key for the acute organophosphorus (OPs) poison treatment. However, the blood-brain barrier (BBB) restricts the transport of these drugs from blood into the brain. Herein, we developed transferrin receptor (TfR) aptamer-functionalized liposomes (Apt-LP) that could deliver AChE reactivator (obidoxime) across the BBB to act against paraoxon (POX) poisoning. The aptamer had strong affinity for TfR and was modified with 3'-inverted deoxythymidine (dT) to improve serum stability. The uptake of Apt-LP by bEnd.3 cells was significantly higher than that of non-targeting liposomes. The ability of Apt-LP to penetrate intact BBB was confirmed in in vitro BBB mice model and in vivo biodistribution studies. Treatment of POX-poisoned mice with Apt-LP-LuH-6 reactivated 18% of the brain AChE activity and prevented brain damage to some extent. Taken together, these results showed that Apt-LP may be used as a promising brain-targeted drug delivery system against OPs toxicity.
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Reactivadores de la Colinesterasa , Cloruro de Obidoxima , Animales , Encéfalo , Liposomas , Ratones , Compuestos Organofosforados , Distribución TisularRESUMEN
Glioblastoma multiforme (GBM), a common type of brain cancer, has a very poor prognosis. In general, viable GBM cells exhibit elevated phosphatidylserine (PS) on their membrane surface compared to healthy cells. We have developed a drug, saposin C-dioleoylphosphatidylserine (SapC-DOPS), that selectively targets cancer cells by honing in on this surface PS. To examine whether SapC-DOPS, a stable, blood-brain barrier-penetrable nanovesicle, could be an effective delivery system for precise targeted therapy of radiation, we iodinated several carbocyanine-based fluorescent reporters with either stable iodine (127I) or radioactive isotopes (125I and 131I). While all of the compounds, when incorporated into the SapC-DOPS delivery system, were taken up by human GBM cell lines, we chose the two that best accumulated in the cells (DiI (22,3) and DiD (16,16)). Pharmacokinetics were conducted with 125I-labeled compounds and indicated that DiI (22,3)-SapC-DOPS had a time to peak in the blood of 0.66 h and an elimination half-life of 8.4 h. These values were 4 h and 11.5 h, respectively, for DiD (16,16)-SapC-DOPS. Adult nude mice with GBM cells implanted in their brains were treated with 131I-DID (16,16)-SapC-DOPS. Mice receiving the radionuclide survived nearly 50% longer than the control groups. These data suggest a potential novel, personalized treatment for a devastating brain disease.
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Terapia Biológica/métodos , Glioblastoma/radioterapia , Glioblastoma/terapia , Nanotecnología/métodos , Fosfatidilserinas/metabolismo , Animales , Humanos , Ratones , Ratones DesnudosRESUMEN
PURPOSE: Currently, the treatment of brain metastases from non-small cell lung cancer (NSCLC) is rather difficult in the clinic. A combination of small molecule-targeted drug and chemo-drug is a promising therapeutic strategy for the treatment of NSCLC brain metastases. But the efficacy of this combination therapy is not satisfactory due to the blood-brain barrier (BBB). Therefore, it is urgent to develop a drug delivery system to enhance the synergistic therapeutic effects of small molecule-targeted drug and chemo-drug for the treatment of NSCLC brain metastases. METHODS: T7 peptide installed and osimertinib (AZD9291) loaded intracellular glutathione (GSH) responsive doxorubicin prodrug self-assembly nanocarriers (T7-DSNPs/9291) have been developed as a targeted co-delivery system to enhance the combined therapeutic effect on brain metastases from NSCLC. In vitro cell experiments, including intracellular uptake assay, in vitro BBB transportation, and MTT assay were used to demonstrate the efficacy of T7-DSNPs/9291 in NSCLC brain metastasis in vitro. Real-time fluorescence imaging analysis, magnetic resonance imaging analysis, and Kaplan-Meier survival curves were used to study the effect of T7-DSNPs/9291 on an animal model in vivo. RESULTS: T7-DSNPs/9291 could significantly enhance BBB penetration of AZD9291 and doxorubicin via transferrin receptor-mediated transcytosis. Moreover, T7-DSNPs/9291 showed significant anti-NSCLC brain metastasis effect and prolonged median survival of an intracranial NSCLC brain metastasis animal model. CONCLUSION: T7-DSNPs/9291 is a potential drug delivery system for the combined therapy of brain metastasis from NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Portadores de Fármacos/administración & dosificación , Neoplasias Pulmonares/patología , Acrilamidas/administración & dosificación , Compuestos de Anilina/administración & dosificación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Colágeno Tipo IV/química , Doxorrubicina/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones Endogámicos BALB C , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Fragmentos de Péptidos/química , Profármacos/administración & dosificación , Profármacos/química , Receptores de Transferrina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Our previous work indicates the lymphatic network and perivascular spaces or tissues might be involved in the facial intradermal brain-targeted delivery of Evans blue (EB). In this article, we presented the detailed involvement of both, and the linkage between lymphatic network and perivascular spaces or tissues. The in-vivo imaging, the trigeminal transection and immunohistochemistry were used. In-vivo imaging indicated intradermal injection in the mystacial pad (i.d.) delivered EB into the brain at 2-, 6- and 24 h, while intranasal injection (i.n.) delivered EB into the rostral head and intravenous injection (i.v.) diffused EB weakly into the brain. Trigeminal perineurial and epineurial EB occurred along the perivascular spaces or tissues and along brain vessels. EB diffused into the lymphatic vessels and submandibular lymph nodes. Moreover, perineurial and epineurial EB co-located or overlaid with Lyve1 immuno-reactivity and VEGF antibody, and lymphatic network connected with perivascular spaces or tissues, suggesting lymphatic system-perivascular spaces might involve in the EB delivery with i.d. The trigeminal transection reduced the trigeminal epineurial and perineurial EB and brain EB along vessels. EB diffused in the fasciculus and the perineurium, blood and lymphatic vessels in the mystacial pad, mystacial EB overlaid VEGF or Lyve1 antibody. In summary, the dermal-trigeminal-brain perivascular spaces or tissues and the linkage to the lymphatic network mediated the intradermal brain-targeted delivery.
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Encéfalo/metabolismo , Colorantes/administración & dosificación , Sistemas de Liberación de Medicamentos , Azul de Evans/administración & dosificación , Administración Intranasal , Animales , Colorantes/farmacocinética , Azul de Evans/farmacocinética , Inmunohistoquímica , Inyecciones Intradérmicas , Inyecciones Intravenosas , Ganglios Linfáticos/metabolismo , Vasos Linfáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Ratas Sprague-Dawley , Factores de Tiempo , Distribución Tisular , Nervio Trigémino/metabolismoRESUMEN
Effective treatment of malignant glioma still remains a formidable challenge due to lack of the effective BBB-permeable drugs and efficient brain delivery methods, and the pharmacotherapy options are very limited. Therefore, to develop an effective therapeutic strategy is a pressing need. In this work, a noncytotoxic drug combination (i.e., simvastatin and fenretinide) was revealed to be potent for treating glioma, which was co-encapsulated into a TPGS-TAT-embedded lactoferrin nanoparticle system for achieving brain-targeted biomimetic delivery via the LRP-1 receptor. It was shown that the lactoferrin nanoparticle repolarized the tumor-associated macrophages from the M2 phenotype to M1 via regulating the STAT6 pathway, as well as induced the ROS-mediated mitochondrial apoptosis by inhibiting the Ras/Raf/p-Erk pathway in the glioma cells. The antiglioma efficacy was further demonstrated in both the subcutaneous and orthotopic glioma models. The repolarization of tumor-associated macrophages not only prompted the ROS generation but also induced the innate immunity (e.g., antitumor cytokine release). This delivery and therapeutic strategy provides a novel modality for the glioma treatment.
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Neoplasias Encefálicas/tratamiento farmacológico , Portadores de Fármacos/metabolismo , Fenretinida/administración & dosificación , Glioma/tratamiento farmacológico , Lactoferrina/metabolismo , Macrófagos/efectos de los fármacos , Simvastatina/administración & dosificación , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Femenino , Fenretinida/farmacocinética , Fenretinida/farmacología , Fenretinida/uso terapéutico , Glioma/metabolismo , Glioma/patología , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Nanopartículas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Simvastatina/farmacocinética , Simvastatina/farmacología , Simvastatina/uso terapéuticoRESUMEN
Malignant glioma is one of the most untreatable cancers because of the formidable blood-brain barrier (BBB), through which few therapeutics can penetrate and reach the tumors. Biologics have been booming in cancer therapy in the past two decades, but their application in brain tumor has long been ignored due to the impermeable nature of BBB against effective delivery of biologics. Indeed, it is a long unsolved problem for brain delivery of macromolecular drugs, which becomes the Holy Grail in medical and pharmaceutical sciences. Even assisting by targeting ligands, protein brain delivery still remains challenging because of the synthesis difficulties of ligand-modified proteins. Herein, we propose a rocket-like, multistage booster delivery system of a protein toxin, trichosanthin (TCS), for antiglioma treatment. TCS is a ribosome-inactivating protein with the potent activity against various solid tumors but lack of specific action and cell penetration ability. To overcome the challenge of its poor druggability and site-specific modification, intein-mediated ligation was applied, by which a gelatinase-cleavable peptide and cell-penetrating peptide (CPP)-fused recombinant TCS toxin can be site-specifically conjugated to lactoferrin (LF), thus constructing a BBB-penetrating, gelatinase-activatable cell-penetrating nanohybrid TCS toxin. This nanohybrid TCS system is featured by the multistage booster strategy for glioma dual-targeting delivery. First, LF can target to the BBB-overexpressing low-density lipoprotein receptor-related protein-1 (LRP-1), and assist with BBB penetration. Second, once reaching the tumor site, the gelatinase-cleavable peptide acts as a separator responsive to the glioma-associated matrix metalloproteinases (MMPs), thus releasing to the CPP-fused toxin. Third, CPP mediates intratumoral and intracellular penetration of TCS toxin, thereby enhancing its antitumor activity. The BBB penetration and MMP-2-activability of this delivery system were demonstrated. The antiglioma activity was evaluated in the subcutaneous and orthotopic animal models. Our work provides a useful protocol for improving the druggability of such class of protein toxins and promoting their in-vivo application for targeted cancer therapy.
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Antineoplásicos/farmacocinética , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Nanopartículas/química , Tricosantina/farmacocinética , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Péptidos de Penetración Celular/química , Células HeLa , Humanos , Inteínas , Lactoferrina/química , Lactoferrina/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Células MCF-7 , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Unión Proteica , Tricosantina/administración & dosificación , Tricosantina/uso terapéuticoRESUMEN
The development of delivery systems to transport some specific radiotracers across the blood-brain barrier (BBB) needs to be investigated for brain imaging. [18F]FLT (3'-deoxy-3'-18F-fluoro-l-thymidine), an analogue substrate of the nucleoside thymidine, has been developed as a proliferation tracer for oncological PET studies. Unfortunately, low-grade brain tumors are poorly visualized due to the low uptake of [18F]FLT in brain tissue, preventing its use in PET imaging to detect brain tumors at an early stage. Based on our previous work, a redox chemical delivery system (CDS) related to Bodor's strategy was developed to enable the penetration of FLT into the brain. To this end, FLT was covalently linked to a series of lipophilic carriers based on a 1,4-dihydroquinoline structure. To determine the best carrier, various sets of [11C]CDS-FLT were prepared and injected into rats. Pleasingly, in vivo results let us suggest that this CDS is a promising approach to overcome the BBB to target low-grade brain tumors for PET imaging.
Asunto(s)
Didesoxinucleósidos/administración & dosificación , Animales , Barrera Hematoencefálica , Química Encefálica , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Didesoxinucleósidos/análisis , Didesoxinucleósidos/farmacocinética , Difusión , Sistemas de Liberación de Medicamentos , Radioisótopos de Flúor , Interacciones Hidrofóbicas e Hidrofílicas , Marcaje Isotópico , Resonancia Magnética Nuclear Biomolecular , Oxidación-Reducción , Quinolinas , Ratas , Ratas Sprague-DawleyRESUMEN
An ideal brain-targeted nanocarrier must be sufficiently potent to penetrate the blood-brain barrier (BBB) and sufficiently competent to target the cells of interest with adequate optimized physiochemical features and biocompatibility. However, it is an enormous challenge to the researchers to organize the above-mentioned properties into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. Herein, we demonstrate a straightforward strategy for brain targeting by encapsulating doxorubicin (DOX) into a naturally available and unmodified apoferritin nanocage (DOX-loaded APO). APO can specifically bind to cells expressing transferrin receptor 1 (TfR1). Because of the high expression of TfR1 in both brain endothelial and glioma cells, DOX-loaded APO can cross the BBB and deliver drugs to the glioma with TfR1. Subsequent research demonstrated that the DOX-loaded APO had good physicochemical properties (particle size of 12.03 ± 0.42 nm, drug encapsulation efficiency of 81.8 ± 1.1%) and significant penetrating and targeting effects in the coculture model of bEnd.3 and C6 cells in vitro. In vivo imaging revealed that DOX-loaded APO accumulated specifically in brain tumor tissues. Additionally, in vivo tumor therapy experiments (at a dosage of 1 mg/kg DOX) demonstrated that a longer survival period was observed in mice that had been treated with DOX-loaded APO (30 days) compared with mice receiving free DOX solution (19 days).