Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51.322
Filtrar
1.
Int J Nanomedicine ; 19: 5973-5993, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38895149

RESUMO

Purpose: Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach. Methods: We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT. Results: Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice. Conclusion: Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.


Assuntos
Terapia Genética , Nanomedicina , Nanopartículas , Tumor Rabdoide , Proteína SMARCB1 , Animais , Proteína SMARCB1/genética , Tumor Rabdoide/genética , Tumor Rabdoide/terapia , Tumor Rabdoide/tratamento farmacológico , Terapia Genética/métodos , Camundongos , Linhagem Celular Tumoral , Nanopartículas/química , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/genética , Modelos Animais de Doenças , Teratoma/terapia , Teratoma/genética , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Lipossomos
2.
AAPS PharmSciTech ; 25(6): 140, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890191

RESUMO

Nanotechnology has significantly transformed cancer treatment by introducing innovative methods for delivering drugs effectively. This literature review provided an in-depth analysis of the role of nanocarriers in cancer therapy, with a particular focus on the critical concept of the 'stealth effect.' The stealth effect refers to the ability of nanocarriers to evade the immune system and overcome physiological barriers. The review investigated the design and composition of various nanocarriers, such as liposomes, micelles, and inorganic nanoparticles, highlighting the importance of surface modifications and functionalization. The complex interaction between the immune system, opsonization, phagocytosis, and the protein corona was examined to understand the stealth effect. The review carefully evaluated strategies to enhance the stealth effect, including surface coating with polymers, biomimetic camouflage, and targeting ligands. The in vivo behavior of stealth nanocarriers and their impact on pharmacokinetics, biodistribution, and toxicity were also systematically examined. Additionally, the review presented clinical applications, case studies of approved nanocarrier-based cancer therapies, and emerging formulations in clinical trials. Future directions and obstacles in the field, such as advancements in nanocarrier engineering, personalized nanomedicine, regulatory considerations, and ethical implications, were discussed in detail. The review concluded by summarizing key findings and emphasizing the transformative potential of stealth nanocarriers in revolutionizing cancer therapy. This review enhanced the comprehension of nanocarrier-based cancer therapies and their potential impact by providing insights into advanced studies, clinical applications, and regulatory considerations.


Assuntos
Antineoplásicos , Portadores de Fármacos , Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Animais , Sistemas de Liberação de Medicamentos/métodos , Nanomedicina/métodos , Lipossomos , Micelas , Distribuição Tecidual
3.
Cell Commun Signal ; 22(1): 334, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890646

RESUMO

INTRODUCTION: Balloon flower root-derived exosome-like nanoparticles (BDEs) have recently been proposed as physiologically active molecules with no cytotoxicity. However, the therapeutic effects of drug-induced hepatotoxicity of BDEs have not been elucidated. BDEs contain a large amount of platycodin D, which is widely known to be effective in regulating inflammation and ameliorating systemic toxicity. Thus, the main therapeutic activity of BDEs is attributed to inhibiting the inflammatory response and alleviating toxicity. In this study, we fabricated the hybrid BDEs fused with liposomes containing silymarin (SM) to enhance the synergistic effect on inhibition of acetaminophen-induced hepatotoxicity (APAP). OBJECTIVE: Considering the potential therapeutic effects of BDEs, and the potential to achieve synergistic effects to improve therapeutic outcomes, we constructed hybrid BDEs with a soy lecithin-based liposome loaded with SM. Since liposomes can provide higher thermal stability and have greater structural integrity, these might be more resistant to clearance and enzymatic degradation of drug molecules. METHODS: Hybrid BDEs with liposome-loaded SM (BDEs@lipo-SM) were fabricated by thin-film hydration and extrusion. BDEs@lipo-SM were characterized using dynamic light scattering and high-performance liquid chromatography. After confirmation of the physical properties of BDEs@lipo-SM, various therapeutic properties were evaluated. RESULTS: BDEs@lipo-SM were internalized by hepatocytes and immune cells and significantly decreased mRNA expression of apoptosis and inflammation-relevant cytokines by inhibiting the hepatocyte MAPK pathway. BDEs@lipo-SM significantly induced an increase in glutathione levels and inhibited APAP-induced hepatotoxicity. CONCLUSION: From this study, we know that BDEs are reliable and safe nanovesicles containing natural metabolites derived from balloon flower, and they can facilitate intercellular communication. BDEs are also easily modified to enhance drug loading capacity, targeting effects, and long-term accumulation in vivo. BDEs@lipo-SM have therapeutic benefits for acute liver injury and can alleviate cell death and toxicity. They can be efficiently delivered to the liver and effectively inhibit APAP-induced hepatotoxicity by inhibiting the MAPK signaling pathway and apoptosis, which accelerates liver recovery in the APAP-induced acute liver injury model. These findings highlight that BDEs represent an attractive delivery vehicle for drug delivery.


Assuntos
Acetaminofen , Apoptose , Exossomos , Hepatócitos , Sistema de Sinalização das MAP Quinases , Nanopartículas , Silimarina , Apoptose/efeitos dos fármacos , Animais , Nanopartículas/química , Exossomos/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Silimarina/farmacologia , Silimarina/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Humanos , Lipossomos/química , Masculino , Raízes de Plantas , Camundongos Endogâmicos C57BL
4.
Breast Cancer Res ; 26(1): 99, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867302

RESUMO

In this study, we prepared a bionic nanosystem of trastuzumab-functionalized SK-BR-3 cell membrane hybrid liposome-coated pyrotinib (Ptb-M-Lip-Her) for the treatment of HER2-positive breast cancer. Transmission electron microscopy, dynamic light scattering, polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting were used to verify the successful preparation of Ptb-M-Lip-Her. In vitro drug release experiments proved that Ptb-M-Lip-Her had a sustained release effect. Cell uptake experiments and in vivo imaging experiments proved that Ptb-M-Lip-Her had good targeting ability to homologous tumor cells (SK-BR-3). The results of cell experiments such as MTT, flow cytometry, immunofluorescence staining and in vivo antitumor experiments showed that Ptb-M-Lip-Her could significantly promote apoptosis and inhibit the proliferation of SK-BR-3 cells. These results clearly indicated that Ptb-M-Lip-Her may be a promising biomimetic nanosystem for targeted therapy of HER2-positive breast cancer.


Assuntos
Apoptose , Neoplasias da Mama , Lipossomos , Receptor ErbB-2 , Trastuzumab , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Feminino , Lipossomos/química , Trastuzumab/administração & dosagem , Trastuzumab/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Animais , Linhagem Celular Tumoral , Camundongos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos , Terapia de Alvo Molecular , Acrilamidas , Aminoquinolinas
5.
Int J Nanomedicine ; 19: 5273-5295, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38859952

RESUMO

Purpose: Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability. Methods: The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments. Results: DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively. Conclusion: SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.


Assuntos
Artemisininas , Disponibilidade Biológica , Lipossomos , Animais , Lipossomos/química , Lipossomos/farmacocinética , Células CACO-2 , Humanos , Administração Oral , Artemisininas/farmacocinética , Artemisininas/química , Artemisininas/administração & dosagem , Absorção Intestinal/efeitos dos fármacos , Masculino , Distribuição Tecidual , Tamanho da Partícula , Camundongos , Sistema Linfático/metabolismo , Sistema Linfático/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos , Materiais Biomiméticos/farmacocinética , Materiais Biomiméticos/química , Mucosa Intestinal/metabolismo
6.
Int J Nanomedicine ; 19: 5381-5395, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38859950

RESUMO

Background: Current immunotherapies with unexpected severe side effects and treatment resistance have not resulted in the desired outcomes for patients with melanoma, and there is a need to discover more effective medications. Cytotoxin (CTX) from Cobra Venom has been established to have favorable cytolytic activity and antitumor efficacy and is regarded as a promising novel anticancer agent. However, amphiphilic CTX with excellent anionic phosphatidylserine lipid-binding ability may also damage normal cells. Methods: We developed pH-responsive liposomes with a high CTX load (CTX@PSL) for targeted acidic-stimuli release of drugs in the tumor microenvironment. The morphology, size, zeta potential, drug-release kinetics, and preservation stability were characterized. Cell uptake, apoptosis-promoting effects, and cytotoxicity were assessed using MTT assay and flow cytometry. Finally, the tissue distribution and antitumor effects of CTX@PSL were systematically assessed using an in vivo imaging system. Results: CTX@PSL exhibited high drug entrapment efficiency, drug loading, stability, and a rapid release profile under acidic conditions. These nanoparticles, irregularly spherical in shape and small in size, can effectively accumulate at tumor sites (six times higher than free CTX) and are rapidly internalized into cancer cells (2.5-fold higher cell uptake efficiency). CTX@PSL displayed significantly stronger cytotoxicity (IC50 0.25 µg/mL) and increased apoptosis in than the other formulations (apoptosis rate 71.78±1.70%). CTX@PSL showed considerably better tumor inhibition efficacy than free CTX or conventional liposomes (tumor inhibition rate 79.78±5.93%). Conclusion: Our results suggest that CTX@PSL improves tumor-site accumulation and intracellular uptake for sustained and targeted CTX release. By combining the advantages of CTX and stimuli-responsive nanotechnology, the novel CTX@PSL nanoformulation is a promising therapeutic candidate for cancer treatment.


Assuntos
Antineoplásicos , Venenos Elapídicos , Lipossomos , Lipossomos/química , Concentração de Íons de Hidrogênio , Animais , Venenos Elapídicos/química , Venenos Elapídicos/farmacologia , Humanos , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Camundongos , Apoptose/efeitos dos fármacos , Liberação Controlada de Fármacos , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos , Nanopartículas/química
7.
Int J Nanomedicine ; 19: 5193-5211, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38859958

RESUMO

Purpose: Ovarian cancer is a fatal gynecologic malignancy with a high rate of abdominal metastasis. Chemotherapy still has a poor clinical prognosis for ovarian cancer patients, with cell proliferation and angiogenesis leading to invasion, migration, and recurrence. To overcome these obstacles, we constructed a novel HA-modified paclitaxel and diosgenin liposome (PEG-TK-HA-PDLPs) using two novel functional materials, DSPE-PEG2000-HA and DSPE-PEG2000-TK-PEG5000, to specifically deliver the drugs to the tumor site in order to reduce OC cell proliferation and anti-angiogenic generation, thereby inhibiting invasion and migration. Methods and Results: PEG-TK-HA-PDLPs were prepared by film dispersion, with ideal physicochemical properties and exhibits active targeting for enhanced cellular uptake. The ZIP synergy score for PTX and Dios was calculated using the online SynergyFinder software to be 3.15, indicating synergy. In vitro results showed that PEG-TK-HA-PDLPs were highly cytotoxic to ID8 cells, induced ID8 cell apoptosis, and inhibited ID8 cell migration and invasion. In vivo studies showed that PEG-TK-HA-PDLPs could prolong the circulation time in the blood, accumulate significantly in the tumor site, and effectively fight against angiogenesis with significant anti-tumor effects. Conclusion: The production of PEG-TK-HA-PDLPs is an effective strategy for the treatment of OC.


Assuntos
Apoptose , Diosgenina , Ácido Hialurônico , Lipossomos , Neoplasias Ovarianas , Paclitaxel , Polietilenoglicóis , Espécies Reativas de Oxigênio , Feminino , Lipossomos/química , Lipossomos/farmacocinética , Paclitaxel/farmacologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Diosgenina/farmacologia , Diosgenina/química , Diosgenina/farmacocinética , Diosgenina/administração & dosagem , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Linhagem Celular Tumoral , Polietilenoglicóis/química , Animais , Espécies Reativas de Oxigênio/metabolismo , Humanos , Apoptose/efeitos dos fármacos , Sinergismo Farmacológico , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidiletanolaminas
8.
Sci Rep ; 14(1): 13362, 2024 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862754

RESUMO

The Increase in infections caused by resistant strains of Pseudomonas aeruginosa poses a formidable challenge to global healthcare systems. P. aeruginosa is capable of causing severe human infections across diverse anatomical sites, presenting considerable therapeutic obstacles due to its heightened drug resistance. Niosomal drug delivery systems offer enhanced pharmaceutical potential for loaded contents due to their desirable properties, mainly providing a controlled-release profile. This study aimed to formulate an optimized niosomal drug delivery system incorporating stearylamine (SA) to augment the anti-bacterial and anti-biofilm activities of quercetin (QCT) against both standard and clinical strains of P. aeruginosa. QCT-loaded niosome (QCT-niosome) and QCT-loaded SA- niosome (QCT-SA- niosome) were synthesized by the thin-film hydration technique, and their physicochemical characteristics were evaluated by field emission scanning electron microscopy (FE-SEM), zeta potential measurement, entrapment efficacy (EE%), and in vitro release profile. The anti-P. aeruginosa activity of synthesized niosomes was assessed using minimum inhibitory and bactericidal concentrations (MICs/MBCs) and compared with free QCT. Additionally, the minimum biofilm inhibitory and eradication concentrations (MBICs/MBECs) were carried out to analyze the ability of QCT-niosome and QCT-SA-niosome against P. aeruginosa biofilms. Furthermore, the cytotoxicity assay was conducted on the L929 mouse fibroblasts cell line to evaluate the biocompatibility of the formulated niosomes. FE-SEM analysis revealed that both synthesized niosomal formulations exhibited spherical morphology with different sizes (57.4 nm for QCT-niosome and 178.9 nm for QCT-SA-niosome). The EE% for cationic and standard niosomal formulations was reported at 75.9% and 59.6%, respectively. Both formulations showed an in vitro sustained-release profile, and QCT-SA-niosome exhibited greater stability during a 4-month storage time compared to QCT-niosome. Microbial experiments indicated that both prepared formulations had higher anti-bacterial and anti-biofilm activities than free QCT. Also, the QCT-SA-niosome exhibited greater reductions in MIC, MBC, MBIC, and MBEC values compared to the QCT-niosome at equivalent concentrations. This study supports the potential of QCT-niosome and QCT-SA-niosome as effective agents against P. aeruginosa infections, manifesting significant anti-bacterial and anti-biofilm efficacy alongside biocompatibility with L929 cell lines. Furthermore, our results suggest that optimized QCT-niosome with cationic lipids could efficiently target P. aeruginosa cells with negligible cytotoxic effect.


Assuntos
Antibacterianos , Biofilmes , Sistemas de Liberação de Medicamentos , Lipossomos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas , Pseudomonas aeruginosa , Quercetina , Pseudomonas aeruginosa/efeitos dos fármacos , Lipossomos/química , Quercetina/farmacologia , Quercetina/química , Quercetina/administração & dosagem , Animais , Biofilmes/efeitos dos fármacos , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/administração & dosagem , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Cátions/química , Humanos , Lipídeos/química , Linhagem Celular , Aminas
9.
Sci Adv ; 10(24): eado4791, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38865465

RESUMO

The stemness loss-associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, LNPs reverses the mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits the accelerated senescence of AT2 cells. Concurrently, pathological epithelial remodeling and fibroblast activation induced by impaired AT2 cells are terminated, ultimately prompting alveolar regeneration. Our data demonstrated that the mRNA-LNP system exhibited high protein expression in lung epithelial cells, which markedly extricated the alveolar collapse and prolonged the survival of fibrosis mice, providing a clinically viable strategy against IPF.


Assuntos
Bleomicina , Muco , Nanopartículas , Animais , Nanopartículas/química , Camundongos , Muco/metabolismo , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Modelos Animais de Doenças , Administração por Inalação , Lipídeos/química , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Humanos , Lipossomos
10.
Science ; 384(6701): 1196-1202, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38870301

RESUMO

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Edição de Genes , Pulmão , Nanopartículas , Células-Tronco , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Camundongos , Fibrose Cística/terapia , Fibrose Cística/genética , Pulmão/metabolismo , Células-Tronco/metabolismo , Humanos , Lipídeos , Organoides , Células Epiteliais/metabolismo , Sistemas CRISPR-Cas , Terapia Genética/métodos , Lipossomos
11.
Pharmazie ; 79(3): 49-56, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38872271

RESUMO

Multidrug resistance, severe side effects, and high cancer treatment costs are still well-known issues and remain an open challenge. These factors reduce the therapy's efficiency and safety, seriously affecting human health. Developing therapeutic approaches based on plant extracts, especially based on essential oils with cytotoxic and antioxidant properties, could be of efficacious strategies. This work incorporated Thymus capitatus essential oil (TEO) in liposomes. Thymus capitatus is a plant native to the northern region of Albania and found specifically in the Mediterranean region. TEO has several biological activities and cytotoxic properties. Due to its volatility, poor solubility, and chemical instability, however, its applicability is restricted. Incorporation into liposomes enables its effective use because the exposure time to the active compounds can be extended, increasing its efficacy against colorectal cancer cell lines, as highlighted in in vitro studies. TEO demonstrated detectable cytotoxic action against HT-29 colorectal cancer cells, and this action could be enhanced by applying various formulations of TEO-loaded liposomes to this cell line. Among the tested nanosystems, TEO-Phospholipon 90H liposomes showed more significant cytotoxic effects than TEO-Lipoid S100 liposomes and TEO-Phospholipon 85G liposomes. TEO-Phospholipon 90 H liposomes also maintained its physicochemical stability for six months at 25 °C. This research suggests that TEO, particularly when encapsulated in TEO-Phospholipon 90 H liposomes, may offer a promising therapeutic approach. However, these findings are based on in vitro studies and further in vivo research is needed to validate the efficacy and safety of this approach in clinical settings.


Assuntos
Sobrevivência Celular , Lipossomos , Óleos Voláteis , Thymus (Planta) , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Humanos , Células HT29 , Thymus (Planta)/química , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem
13.
Chem Pharm Bull (Tokyo) ; 72(6): 529-539, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38839372

RESUMO

Lipid nanoparticles (LNPs), used for mRNA vaccines against severe acute respiratory syndrome coronavirus 2, protect mRNA and deliver it into cells, making them an essential delivery technology for RNA medicine. The LNPs manufacturing process consists of two steps, the upstream process of preparing LNPs and the downstream process of removing ethyl alcohol (EtOH) and exchanging buffers. Generally, a microfluidic device is used in the upstream process, and a dialysis membrane is used in the downstream process. However, there are many parameters in the upstream and downstream processes, and it is difficult to determine the effects of variations in the manufacturing parameters on the quality of the LNPs and establish a manufacturing process to obtain high-quality LNPs. This study focused on manufacturing mRNA-LNPs using a microfluidic device. Extreme gradient boosting (XGBoost), which is a machine learning technique, identified EtOH concentration (flow rate ratio), buffer pH, and total flow rate as the process parameters that significantly affected the particle size and encapsulation efficiency. Based on these results, we derived the manufacturing conditions for different particle sizes (approximately 80 and 200 nm) of LNPs using Bayesian optimization. In addition, the particle size of the LNPs significantly affected the protein expression level of mRNA in cells. The findings of this study are expected to provide useful information that will enable the rapid and efficient development of mRNA-LNPs manufacturing processes using microfluidic devices.


Assuntos
Lipídeos , Aprendizado de Máquina , Nanopartículas , Tamanho da Partícula , RNA Mensageiro , Nanopartículas/química , Lipídeos/química , Humanos , SARS-CoV-2/genética , Etanol/química , Teorema de Bayes , Dispositivos Lab-On-A-Chip , Lipossomos
14.
Artif Cells Nanomed Biotechnol ; 52(1): 334-344, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38833335

RESUMO

Drug delivery through Liposomes has shown tremendous potential in terms of the therapeutic application of nanoparticles. There are several drug-loaded liposomal formulations approved for clinical use that help mitigate harmful effects of life-threatening diseases. Developments in the field of liposomal formulations and drug delivery have made it possible for clinicians and researchers to find therapeutic solutions for complicated medical conditions. A key aspect in the development of drug-loaded liposomes is a careful review of optimization techniques to improve the overall formulation stability and efficacy. Optimization studies help in improving/modulating the various properties of drug-loaded liposomes and are vital for the development of this class of delivery systems. A comprehensive overview of the various process variables and factors involved in the optimization of drug-loaded liposomes is presented in this review. The influence of different independent variables on drug release and loading properties with the application of a statistical experimental design is also explained in this article.


Periodically, liposomes have shown tremendous potential as drug carriers as they are multifunctional nanoparticles with a unique ability to deliver drugs and other therapeutic moieties to target sites in the body. The use of statistical experimental designs and optimization models to develop drug-loaded liposomes is considered the most effective step in formulation development. A careful consideration of various factors and variables in optimizing liposome formulations has been specifically described in this review article. Thorough understanding of different factors that affect drug loading and release in liposomes provides deeper insights in achieving a stable, efficacious drug formulation. There are several new aspects and concepts which need to be explored as part of formulation development and optimization of drug-loaded liposomes and this article hopes to shed light on some important aspects in this scientific journey.


Assuntos
Liberação Controlada de Fármacos , Lipossomos , Lipossomos/química , Humanos
15.
AAPS PharmSciTech ; 25(5): 125, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834759

RESUMO

DOX liposomes have better therapeutic effects and lower toxic side effects. The targeting ability of liposomes is one of the key factors affecting the therapeutic effect of DOX liposomes. This study developed two types of targeted liposomes. Sialic acid (SA)-modified liposomes were designed to target the highly expressed Siglec-1 receptor on tumor-associated macrophages surface. Phosphatidylserine (PS)-modified liposomes were designed to promote phagocytosis by monocyte-derived macrophages through PS apoptotic signaling. In order to assess and compare the therapeutic potential of different targeted pathways in the context of anti-tumor treatment, we compared four phosphatidylserine membrane materials (DOPS, DSPS, DPPS and DMPS) and found that liposomes prepared using DOPS as material could significantly improve the uptake ability of RAW264.7 cells for DOX liposomes. On this basis, normal DOX liposomes (CL-DOX) and SA-modified DOX liposomes (SAL-DOX), PS-modified DOX liposomes (PS-CL-DOX), SA and PS co-modified DOX liposomes (PS-SAL-DOX) were prepared. The anti-tumor cells function of each liposome on S180 and RAW264.7 in vitro was investigated, and it was found that SA on the surface of liposomes can increase the inhibitory effect. In vivo efficacy results exhibited that SAL-DOX and PS-CL-DOX were superior to other groups in terms of ability to inhibit tumor growth and tumor inhibition index, among which SAL-DOX had the best anti-tumor effect. Moreover, SAL-DOX group mice had high expression of IFN-γ as well as IL-12 factors, which could significantly inhibit mice tumor growth, improve the immune microenvironment of the tumor site, and have excellent targeted delivery potential.


Assuntos
Doxorrubicina , Lipossomos , Ácido N-Acetilneuramínico , Fosfatidilserinas , Macrófagos Associados a Tumor , Animais , Camundongos , Ácido N-Acetilneuramínico/química , Células RAW 264.7 , Fosfatidilserinas/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Fagocitose/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Apoptose/efeitos dos fármacos
16.
ACS Nano ; 18(24): 15729-15743, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38839059

RESUMO

Lipid nanoparticles (LNP) have emerged as pivotal delivery vehicles for RNA therapeutics. Previous research and development usually assumed that LNPs are homogeneous in population, loading density, and composition. Such perspectives are difficult to examine due to the lack of suitable tools to characterize these physicochemical properties at the single-nanoparticle level. Here, we report an integrated spectroscopy-chromatography approach as a generalizable strategy to dissect the complexities of multicomponent LNP assembly. Our platform couples cylindrical illumination confocal spectroscopy (CICS) with single-nanoparticle free solution hydrodynamic separation (SN-FSHS) to simultaneously profile population identity, hydrodynamic size, RNA loading levels, and distributions of helper lipid and PEGylated lipid of LNPs at the single-particle level and in a high-throughput manner. Using a benchmark siRNA LNP formulation, we demonstrate the capability of this platform by distinguishing seven distinct LNP populations, quantitatively characterizing size distribution and RNA loading level in wide ranges, and more importantly, resolving composition-size correlations. This SN-FSHS-CICS analysis provides critical insights into a substantial degree of heterogeneity in the packing density of RNA in LNPs and size-dependent loading-size correlations, explained by kinetics-driven assembly mechanisms of RNA LNPs.


Assuntos
Lipídeos , Nanopartículas , Tamanho da Partícula , Nanopartículas/química , Lipídeos/química , RNA/química , Cromatografia/métodos , RNA Interferente Pequeno/química , Análise Espectral/métodos , Lipossomos
17.
J Cell Mol Med ; 28(11): e18477, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38853458

RESUMO

Given the pathological role of Tau aggregation in Alzheimer's disease (AD), our laboratory previously developed the novel Tau aggregation inhibitor peptide, RI-AG03. As Tau aggregates accumulate intracellularly, it is essential that the peptide can traverse the cell membrane. Here we examine the cellular uptake and intracellular trafficking of RI-AG03, in both a free and liposome-conjugated form. We also characterize the impact of adding the cell-penetrating peptide (CPP) sequences, polyarginine (polyR) or transactivator of transcription (TAT), to RI-AG03. Our data show that liposome conjugation of CPP containing RI-AG03 peptides, with either the polyR or TAT sequence, increased cellular liposome association three-fold. Inhibition of macropinocytosis modestly reduced the uptake of unconjugated and RI-AG03-polyR-linked liposomes, while having no effect on RI-AG03-TAT-conjugated liposome uptake. Further supporting macropinocytosis-mediated internalization, a 'fair' co-localisation of the free and liposome-conjugated RI-AG03-polyR peptide with macropinosomes and lysosomes was observed. Interestingly, we also demonstrate that RI-AG03-polyR detaches from liposomes following cellular uptake, thereby largely evading organellar entrapment. Collectively, our data indicate that direct membrane penetration and macropinocytosis are key routes for the internalization of liposomes conjugated with CPP containing RI-AG03. Our study also demonstrates that peptide-liposomes are suitable nanocarriers for the cellular delivery of RI-AG03, furthering their potential use in targeting Tau pathology in AD.


Assuntos
Peptídeos Penetradores de Células , Lipossomos , Nanopartículas , Pinocitose , Proteínas tau , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Lipossomos/química , Humanos , Proteínas tau/metabolismo , Proteínas tau/química , Nanopartículas/química , Pinocitose/efeitos dos fármacos , Peptídeos/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Lisossomos/metabolismo , Sistemas de Liberação de Medicamentos/métodos
18.
PLoS One ; 19(6): e0297451, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38857220

RESUMO

Traumatic brain injury has faced numerous challenges in drug development, primarily due to the difficulty of effectively delivering drugs to the brain. However, there is a potential solution in targeted drug delivery methods involving antibody-drug conjugates or nanocarriers conjugated with targeting antibodies. Following a TBI, the blood-brain barrier (BBB) becomes permeable, which can last for years and allow the leakage of harmful plasma proteins. Consequently, an appealing approach for TBI treatment involves using drug delivery systems that utilize targeting antibodies and nanocarriers to help restore BBB integrity. In our investigation of this strategy, we examined the efficacy of free antibodies and nanocarriers targeting a specific endothelial surface marker called vascular cell adhesion molecule-1 (VCAM-1), which is known to be upregulated during inflammation. In a mouse model of TBI utilizing central fluid percussion injury, free VCAM-1 antibody did not demonstrate superior targeting when comparing sham vs. TBI brain. However, the administration of VCAM-1-targeted nanocarriers (liposomes) exhibited a 10-fold higher targeting specificity in TBI brain than in sham control. Flow cytometry and confocal microscopy analysis confirmed that VCAM-1 liposomes were primarily taken up by brain endothelial cells post-TBI. Consequently, VCAM-1 liposomes represent a promising platform for the targeted delivery of therapeutics to the brain following traumatic brain injury.


Assuntos
Barreira Hematoencefálica , Lesões Encefálicas Traumáticas , Nanopartículas , Molécula 1 de Adesão de Célula Vascular , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Camundongos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Nanopartículas/química , Lipossomos , Masculino , Sistemas de Liberação de Medicamentos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos
19.
Hum Vaccin Immunother ; 20(1): 2358570, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38853516

RESUMO

Among all natural and synthetic toxins, botulinum neurotoxins (BoNTs), produced by Clostridium botulinum in an anaerobic environment, are the most toxic polymer proteins. Currently, the most effective modalities for botulism prevention and treatment are vaccination and antitoxin use, respectively. However, these modalities are associated with long response time for active immunization, side effects, and donor limitations. As such, the development of more promising botulism prevention and treatment modalities is warranted. Here, we designed an mRNA encoding B9-hFc - a heavy-chain antibody fused to VHH and human Fc that can neutralize BoNT serotype B (BoNT/B) effectively - and assessed its expression in vitro and in vivo. The results confirmed that our mRNA demonstrates good expression in vitro and in vivo. Moreover, a single mRNA lipid nanoparticle injection effectively prevents BoNT/B intoxication in vivo, with effects comparable to those of protein antibodies. In conclusion, we explored and clarified whether mRNA drugs encoding neutralizing antibodies prevent BoNT/B intoxication. Our results provide an efficient strategy for further research on the prevention and treatment of intoxication by botulinum toxin.


Assuntos
Anticorpos Neutralizantes , Toxinas Botulínicas Tipo A , Botulismo , RNA Mensageiro , Anticorpos Neutralizantes/imunologia , Animais , Botulismo/prevenção & controle , Botulismo/imunologia , Toxinas Botulínicas Tipo A/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Camundongos , Humanos , Feminino , Nanopartículas , Camundongos Endogâmicos BALB C , Anticorpos Antibacterianos/imunologia , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/administração & dosagem , Lipossomos
20.
Nat Commun ; 15(1): 5010, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866762

RESUMO

Primary human hepatocyte (PHH) transplantation is a promising alternative to liver transplantation, whereby liver function could be restored by partial repopulation of the diseased organ with healthy cells. However, currently PHH engraftment efficiency is low and benefits are not maintained long-term. Here we refine two male mouse models of human chronic and acute liver diseases to recapitulate compromised hepatocyte proliferation observed in nearly all human liver diseases by overexpression of p21 in hepatocytes. In these clinically relevant contexts, we demonstrate that transient, yet robust expression of human hepatocyte growth factor and epidermal growth factor in the liver via nucleoside-modified mRNA in lipid nanoparticles, whose safety was validated with mRNA-based COVID-19 vaccines, drastically improves PHH engraftment, reduces disease burden, and improves overall liver function. This strategy may overcome the critical barriers to clinical translation of cell therapies with primary or stem cell-derived hepatocytes for the treatment of liver diseases.


Assuntos
Fator de Crescimento de Hepatócito , Hepatócitos , Nanopartículas , RNA Mensageiro , Animais , Hepatócitos/metabolismo , Hepatócitos/transplante , Humanos , Camundongos , Masculino , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Nanopartículas/química , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento de Hepatócito/genética , Modelos Animais de Doenças , Fígado/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , COVID-19/terapia , Hepatopatias/terapia , Hepatopatias/metabolismo , Hepatopatias/genética , Proliferação de Células , SARS-CoV-2/genética , Lipossomos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...