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Objectives: Lipid-based drug delivery systems (DDS) can improve the pharmacokinetic (PK) parameters of some drugs. Especially those with a high volume of distribution (Vd) leading to off-target accumulation and toxicity. Amiodarone as an anti-arrhythmic agent induces hypothyroidism and liver disorders limiting its clinical indication. Materials and Methods: In the present study, amiodarone PK parameters and biodistribution after IV administration of four nano-formulations to rats were compared. The formulations were liposomes, solid lipid nanoparticles (SLN), PEGylated SLN (PEG-SLN), and nanoemulsions (NE). All formulations were optimized. Results: The nanoparticles were spherical with a diameter of 100-200 nm and sustained in vitro drug release in buffer pH 7.4. The best-fitted model for the plasma concentration-time profile was two-compartmental. In vivo studies indicated the most changes in PKs induced after liposome, SLN, and NE administration, respectively. The area under the curve (AUC) and maximum plasma concentration (Cmax) of liposomes, SLN, and NE were 22.5, 2.6, 2.46 times, and 916, 58, and 26 times higher than that of amiodarone solution, respectively (P-value<0.05). The heart-to-liver ratio of amiodarone was higher for nano-formulations compared to drug solution except for liposomes. Conclusion: Lipid-based particles can improve the PK parameters of amiodarone and its distribution in different tissues.
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The development of ionizable lipid (IL) was necessary to enable the effective formulation of small interfering RNA (siRNA) to inhibit P2X7 receptors (P2X7R), a key player in tumor proliferation, apoptosis, and metastasis. In this way, the synthesis and utility of IL for enhancing cellular uptake of lipid nanoparticles (LNP) improve the proper delivery of siRNA-LNPs for knockdown overexpression of P2X7R. Therefore, to evaluate the impact of P2X7 knockdown on breast cancer (BC) migration and apoptosis, a branched and synthesized ionizable lipid (SIL) was performed for efficient transfection of LNP with siRNA for targeting P2X7 receptors (siP2X7) in mouse 4T-1 cells. Following synthesis and structural analysis of SIL, excellent characterization of the LNP was achieved (Z-average 126.8 nm, zeta-potential - 12.33, PDI 0.16, and encapsulation efficiency 85.35%). Afterward, the stability of the LNP was evaluated through an analysis of the leftover composition, and toxic concentration values for SIL and siP2X7 were determined. Furthermore, siP2X7-LNP cellular uptake in the formulation was assessed via confocal microscopy. Following determining the optimal dose (45 pmol), wound healing analysis was assessed using scratch assay microscopy, and apoptosis was evaluated using flow cytometry. The use of the innovative branched SIL in the formulation of siP2X7-LNP resulted in significant inhibition of migration and induction of apoptosis in 4T-1 cells due to improved cellular uptake. Subsequently, the innovative SIL represents a critical role in efficiently delivering siRNA against murine triple-negative breast cancer cells (TNBC) using LNP formulation, resulting in significant efficacy.
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Asialoglycoprotein receptors (ASGPRs) are highly expressed on hepatocytes and have been used for liver-targeted delivery and hepatocellular carcinoma (HCC) therapy. However, targeted delivery of bortezomib (BTZ) to HCC has not been reported. In this study, N-stearyl lactobionamide (N-SALB) with galactose (Gal) moiety was synthesized as a targeting agent and its structure was confirmed by FT-IR and NMR analyses. N-SALB surface-modified solid lipid nanoparticles (SLNs) loaded with BTZ (Gal-SLNs/BTZ) were developed to target BTZ delivery into HCC cancer cells. The Gal-SLNs/BTZ had an average particle size of 116.3 nm, polydispersity index (PDI) of 0.210, and zeta potential of -13.8 mV. TEM analysis showed their nanometer-sized spherical morphology. The encapsulation efficiency (EE) and drug loading (DL) capacity were 84.5 % and 1.16 %, respectively. Release studies showed that BTZ loaded inside the SLNs was slowly released over a period of 72 h at pH 7.4. Flow cytometry analysis showed significantly higher intracellular uptake of N-SALB-targeted nanoparticles than non-targeted nanoparticles in HepG2 cells. All lipid formulations showed good biocompatibility in the cytotoxicity study using MTT assay. Concentration-dependent cytotoxicity was observed for all formulations, with N-SALB-targeted nanoparticles demonstrating more cytotoxicity against HepG2 cells. The highest percentage of apoptosis was obtained for N-SALB-targeted nanoparticles compared to non-targeted nanoparticles (42.2 % and 8.70 %, respectively). Finally, biodistribution studies in HepG2 bearing nude mice showed that the accumulation of targeted nanoparticles in the tumor was significantly higher than non-targeted nanoparticles.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Ratones , Animales , Bortezomib , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Ratones Desnudos , Distribución Tisular , Espectroscopía Infrarroja por Transformada de Fourier , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas/química , Tamaño de la Partícula , Portadores de Fármacos/uso terapéuticoRESUMEN
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, typically diagnosed in advanced stages. Chemotherapy is necessary for treating advanced liver cancer; however, several challenges affect its effectiveness. These challenges include low specificity, high dosage requirements, high systemic toxicity and severe side effects, which significantly limit the efficacy of chemotherapy. These limitations can hinder the treatment of HCC. This review focuses on the prevalence of HCC, different types of liver cancer and the staging of the disease, along with available treatment methods. Additionally, explores recent and relevant studies on smart drug- and gene-delivery systems specifically designed for HCC. These systems include targeted endogenous and exogenous stimuli-responsive platforms.
Liver cancer is the third leading cause of cancer deaths in the world that is usually diagnosed in the last stages. Chemotherapy is commonly used to treat advanced liver cancer, but it faces several challenges that reduce its effectiveness. These challenges include low specificity (not targeting cancer cells specifically), high dosage requirements and side effects that can affect anywhere in the body. As a result, the efficacy of chemotherapy is significantly limited, making it difficult to treat liver cancer. This review discusses the prevalence of liver cancer, different types of liver cancer and how the disease is staged. It also explores various treatment methods available for liver cancer. Furthermore, the article explores recent and relevant studies on smart drug- and gene-delivery systems that are specifically designed to target liver cancer. These systems include platforms that respond to targeted and internal or external stimuli. They aim to improve the effectiveness of treatment for liver cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Terapia Molecular Dirigida , Técnicas de Transferencia de GenRESUMEN
Nucleosides and purine nucleotides serve as transmitter and modulator agents that extend their functions beyond the cell. In this context, purinergic signaling plays a crucial role in regulating energy homeostasis and modulating metabolic alterations in tumor cells. Therefore, it is essential to consider the pharmacological targeting of purinergic receptors (PUR), which encompass the expression and inhibition of P1 receptors (metabotropic adenosine receptors) as well as P2 receptors (extracellular ATP/ADP) comprising P2X and P2Y receptors. Thus, the pharmacological interaction between inhibitors (such as RNA, monoclonal antibodies, and small molecules) and PUR represents a key aspect in facilitating the development of therapeutic interventions. Moreover, this review explores recent advancements in pharmacological inhibitors and the regulation of innate and adaptive immunity of PUR, specifically in relation to immunological and inflammatory responses. These responses encompass the release of pro-inflammatory cytokines (PIC), the production of reactive oxygen and nitrogen species (ROS and RNS), the regulation of T cells, and the activation of inflammasomes in all human leukocytes.
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Purpose: Poor aqueous solubility hampers the development of several compounds as pharmacological agents. Hence, preparing novel formulations with augmented absorption is a challenge in pharmaceutical industries. In this paper, we have examined the effect of basic amino acids including arginine (ARG), lysine (LYS), and glucosamine (GlucN) on the solubility of ibuprofen (IBU) and piroxicam (PXM) as drugs with limited solubility. We have also studied the effect of the dissolution media with the pH values 1.2 to 7.4. Methods: The saturation shake-flask method was used for solubility studies in the presence of amino acids. Briefly, buffer solutions containing different concentrations of amino acids were prepared. Then, an excess amount of each drug with these buffers was shaken to reach equilibrium. After 48 hours, the upper phase was separated, and solubility was calculated by reading their UV-Vis absorbance. Results: The results illustrated that amino acids increased solubility of both drugs with different ratios, which were pH and concentration-dependent. Solubility improved as the amount of amino acids went up, and this upward pattern was more robust with ARG than LYS. The presence of GlucN in citrate buffer significantly enhanced IBU solubility. The solubility of PXM in accompany of GlucN in water did not change significantly while in citrate buffer solubility enhanced specially at pH 6. Conclusion: Overall, GlucN in citrate buffer and ARG in phosphate buffer could be introduced as the most suitable media for IBU and PXM solubility improvement, respectively.
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OBJECTIVE: This study was intended to explore and evaluate the appropriate methods for preparation of Amphotericin B (AmB) liposomes with acceptable characteristics. SIGNIFICANCE: This project provides pre-formulations for industrial manufacturing of liposomal AmB which confers improved properties, besides reduced toxicity compared with the plain drug. METHODS: At first, Solubility screening tests were performed, and in the following, three liposome preparation methods including ethanol injection, solvent evaporation, and solvent-free method were examined. In the following, the physicochemical characteristics of the prepared liposomes as well as size, size distribution, zeta potential (ZP), morphology, drug loading, loading capacity, physicochemical stability, and drug-lipid interaction studies were investigated. HPLC was applied for analyzing AmB. RESULTS: In all three methods, liposomes with acceptable characteristics were obtained. The size range of liposomes was 150.3 to 263.9 nm and polydispersity index ≤0.32. In morphologic evaluations, the liposomes have appeared as spherical and separate vesicles. A physical loading of AmB without specific interaction between components was achieved. The lyophilized powder in the solvent-free method was physicochemically stable for 6 months without changes in appearance; the remaining drug after 6-month storage at 25 °C and 60% RH, accounts for 91.5 ± 0.5% compared with the initial drug loaded in liposomes, and degradation pattern follows a linear order. CONCLUSION: As a result, AmB-loaded liposomes were prepared in three applicable methods. The solvent-free method can be considered the most economical and environmental-friendly.
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Anfotericina B , Liposomas , Anfotericina B/química , Liposomas/química , Antifúngicos/química , SolubilidadRESUMEN
Many nutraceuticals present problems due to their poor water solubility or stability, which prevents the final bioactivity achievement. For that reason, the oral administration of KYNA complexed with HPß-CD and ßNS-CDI nanosponges was evaluated in mice. The solvent-free technology was used to prepare the complexes in a complete comparison between kneading in ball milling and classical inclusion complex preparation. The solvent-free ones showed higher strength and efficiency with ball milling, considerably reducing time. A 50 mg KYNA/kg/day dosage was orally administered in formulations showing a higher bioavailability when the nutraceutical was complexed with ßNS-CDI compared to HPß-CD and free KYNA, respectively. Several antioxidant statuses demonstrated a higher global antioxidant level perfectly related to bioavailability. Finally, the formulation of KYNA reduced the temporal oxidative stress damage in the kidney and liver, making ßNS-CDI the best formulation. These results suggest an important future application of cyclodextrin-based nanosponges for the oral delivery of nutraceuticals and their stabilization.
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Ciclodextrinas , Ratones , Animales , Ácido Quinurénico , Solventes , Disponibilidad Biológica , Antioxidantes/farmacología , SolubilidadRESUMEN
BACKGROUND: Fish is a great nutritious food and provides quality protein and a variety of vitamins and minerals. This contributes significantly to the economy and food security in Iran. However, there are safety concerns related to the presence of zoonotic parasites. OBJECTIVES: The objective of this study is, therefore, to review fish-borne zoonotic parasites in Iran. METHODS: Keywords such as fish-borne, parasites, zoonotic, Iran, and some names of fish-borne zoonotic parasites were searched in databases including PubMed, Science Direct, Elsevier, SID, Magiran, Irandoc, Google Scholar and the World Health Organization. RESULTS: The most common fish-borne parasites with zoonotic potential identified in reports in the literature were the protozoa Balantidium spp., Myxobolus spp. and Sarcosystis sp.; the trematodes Heterophyes heterophyes and Clinostomum complanatum; the cestodes Ligula intestinalis and Diphyllobothrium latum; the nematodes Pseudoterranova sp., Anisakis spp., Contracaecum spp., Raphidascaris spp., Eustrongylides spp. and Capillaria sp.; and the acanthocephal Corynosoma spp. CONCLUSIONS: The potential risk factors for the transmission of fish-borne zoonotic parasites to humans are consumption of raw or undercooked infected fish, contact with contaminated water and contact with infected fish. There is a need for epidemiological surveillance of fish for parasites with zoonotic potential and of occurrence of infections in humans to better understand the public health significance and design prevention programs.
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Parásitos , Trematodos , Animales , Humanos , Irán/epidemiología , Peces/parasitología , Salud PúblicaRESUMEN
Aptamers are synthetic single-stranded oligonucleotides (such as RNA and DNA) evolved in vitro using Systematic Evolution of Ligands through Exponential enrichment (SELEX) techniques. Aptamers are evolved to have high affinity and specificity to targets; hence, they have a great potential for use in therapeutics as delivery agents and/or in treatment strategies. Aptamers can be chemically synthesized and modified in a cost-effective manner and are easy to hybridize to a variety of nano-particles and other agents which has paved a way for targeted therapy and diagnostics applications such as in breast tumors. In this review, we systematically explain different aptamer adoption approaches to therapeutic or diagnostic uses when addressing breast tumors. We summarize the current therapeutic techniques to address breast tumors including aptamer-base approaches. We discuss the next aptamer-based therapeutic and diagnostic approaches targeting breast tumors. Finally, we provide a perspective on the future of aptamer-based sensors for breast therapeutics and diagnostics. In this section, the therapeutic applications of aptamers will be discussed for the targeting therapy of breast cancer.
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Aptámeros de Nucleótidos , Neoplasias de la Mama , Humanos , Femenino , Técnica SELEX de Producción de Aptámeros , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Aptámeros de Nucleótidos/uso terapéutico , Sistemas de Liberación de Medicamentos , LigandosRESUMEN
INTRODUCTION: The argument around cancer therapy is an old one. Using chemotherapeutic drugs, as one of the most effective strategies in treatment of malignancies, is restricted by various issues that progress during therapy and avoid achieving clinical endpoints. Multidrug resistance (MDR), frequently mediated by ATP-binding cassette (ABC) transporters, is one of the most recognized obstacles in the success of pharmacological anticancer approaches. These transporters efflux diverse drugs to extracellular environment, causing MDR and responsiveness of tumor cells to chemotherapy diminishes. AREAS COVERED: Several strategies have been used to overcome MDR phenomenon. Succession in this field requires complete knowledge about features and mechanism of ABC transporters. In this review, conventional synthetic and natural inhibitors are discussed first and then novel approaches including RNA, monoclonal antibodies, nanobiotechnology, and structural modification techniques are represented. EXPERT OPINION: With increasing frequency of MDR in cancer cells, it is essential to develop new drugs to inhibit MDR. Using knowledge acquired about ABC transporter's structure, rational design of inhibitors is possible. Also, some herbal products have shown to be potential lead compounds in drug discovery for reversal of MDR.
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Antineoplásicos , Neoplasias , Transportadoras de Casetes de Unión a ATP , Adenosina Trifosfato/farmacología , Adenosina Trifosfato/uso terapéutico , Anticuerpos Monoclonales/farmacología , Descubrimiento de Drogas , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , ARN/farmacología , ARN/uso terapéuticoRESUMEN
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by progressive cognitive impairment and memory loss. The mammalian target of rapamycin (mTOR) signaling pathway could regulate learning and memory. The effect of rapamycin (Rapa) on mTOR activity could slow or prevent the progression of AD by affecting various essential cellular processes. Previously, we prepared transferrin (Tf) decorated-nanostructured lipid carriers (NLCs) for rapamycin (150 ± 9 nm) to protect the drug from chemical and enzymatic degradation and for brain targeted delivery of rapamycin. Herein, the effect of Tf-NLCs compared to untargeted anionic-NLCs and free rapamycin, were studied in amyloid beta (Aß) induced rat model of AD. Behavioral test revealed that the Rapa Tf-NLCs were able to significantly improve the impaired spatial memory induced by Aß. Histopathological studies of hippocampus also showed neural survival in Rapa Tf-NLCs treated group. The immunosuppressive, and delayed wound healing adverse effects in the rapamycin solution treated group were abolished by incorporating the drug into NLCs. The Aß induced oxidative stress was also reduced by Rapa Tf-NLCs. Molecular studies on the level of Aß, autophagy (LC3) and apoptotic (caspase-3) markers, and mTOR activity revealed that the Rapa Tf-NLCs decreased the Aß level and suppressed the toxic effects of Aß plaques by modulating the mTOR activity and autophagy, and decreasing the apoptosis level. As a conclusion, the designed Tf-NLCs could be an appropriate and a safe brain delivery system for rapamycin and make this drug more efficient in AD for improving memory and neuroprotection.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Lípidos/química , Mamíferos/metabolismo , Trastornos de la Memoria , Ratas , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Transferrina/químicaRESUMEN
The development of a therapeutic system for hepatic fibrosis has become a research hotspot to date. Butein, a simple chalcone derivative, displays anti-fibrotic effects through different pathways. However, impurities, low solubility, and low concentration in the target tissue hinder therapy with herbal ingredients. Hepatic stellate cells (HSCs), the vitamin A (VA) storage cells, as the main contributors to liver fibrogenesis, are not readily accessible to drugs owing to their anatomical location. Targeted delivery of therapeutics to the activated HSCs is therefore critical for successful treatment. For these reasons, the current study aimed at increasing butein delivery to the liver. Hence, high purity butein was synthesized in three steps. A novel VA-Myrj52 ester conjugate was also synthesized using all-trans retinoic acid and a hydrophilic emulsifier (Myrj52) as a targeting agent. Next, butein was encapsulated inside the novel VA-modified solid lipid nanoparticles (VA-SLNs) and studied in vitro and in vivo. According to our evaluations, negatively charged SLNs with a mean diameter of 150 nm and entrapment efficacy of 75 % were successful in liver fibrosis amelioration. Intraperitoneal (i.p.) injection of VA-SLNs in fibrotic rats, for four weeks long, reduced serum AST and ALT by 58% (P, 0.001) and 72% (P, 0.05), respectively, concerning the CCl4 group. Additionally, histologic damage score decline and normalization of tissue oxidative stress markers collectively confirmed the efficacy of formulations in hepatic fibrosis and kidney damage amelioration.
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Chalconas , Animales , Células Estrelladas Hepáticas/metabolismo , Liposomas , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Nanopartículas , Ratas , Vitamina A/metabolismoRESUMEN
BACKGROUND: Mesenchymal-based therapy has been utilized as a practical approach in the treatment of renal ischemia/reperfusion (I/R) injury. However, low cell retention and survival in the ischemic site have remained challenging issues. To bridge this gap, the integrin receptor-binding RGD peptide-functionalized, s-nitroso-n-acetyl penicillamine (SNAP)-loaded hydrogel was used to transplant Wharton's jelly-mesenchymal stem cells (WJ-MSCs). METHODS: Apart from physicochemical and rheological characterizations that confirmed entangled interlocking ß-sheets with nanofibrous morphology, real-time RT-PCR, ROS production, serum biomarker concentrations, and histopathological alterations were explored in a mouse model to assess the therapeutic efficacy of formulations in the treatment of renal I/R injury. RESULTS: The RGD-functionalized Fmoc-diphenylalanine (Fmoc-FF + Fmoc-RGD) hydrogel supported the spread and proliferation of WJ-MSCs in vivo. Notably, intralesional injection of nitric oxide donor combined with the embedded WJ-MSCs caused superior recovery of renal I/R injury compared to free WJ-MSCs alone in terms of histopathological scores and renal function indices. Compared to the I/R control group, oxidative stress and inducible nitric oxide synthase (iNOS) expression biomarkers showed a significant decline, whereas endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) expression exhibited a significant increment, indicating regeneration of the injured endothelial tissue. CONCLUSION: The findings confirmed that the hydrogels containing WJ-MSCs and nitric oxide donors can promote the regeneration of renal I/R injuries by increasing angiogenic factors and cell engraftment.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Nanofibras , Daño por Reperfusión , Gelatina de Wharton , Animales , Hidrogeles , Integrinas/metabolismo , Isquemia/terapia , Riñón/patología , Células Madre Mesenquimatosas/metabolismo , Ratones , Óxido Nítrico/metabolismo , Péptidos/metabolismo , Fenilalanina , Daño por Reperfusión/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Objectives: The current study's objectives were to obtain different extracts and essential oils of Symphytum kurdicum and Symphytum asperrimum and to determine the chemical composition, as well as to evaluate free radical scavenging activity (IC50) and minimum bactericidal concentration (MBC), and the effect of liposomal formulation on antimicrobial properties. Materials and Methods: Air-dried powdered aerial parts of S. kurdicum and S. asperrimum were used. The antioxidant and antibacterial properties, essential oil compositions, total phenol, and flavonoid contents of different fractions were determined by DPPH test, disk diffusion assay, gas chromatography-mass spectrometry, Folin-ciocalteu reagent, and colorimetric assay method, respectively. The film hydration method was used to fabricate nanoparticles. Results: GC-MS analysis indicated that hexafarnesyl acetone was a major essential oil component. n-butanol and ethyl acetate extracts of S. kurdicum had the highest anti-oxidant activity. Extracts of both plants showed antimicrobial activity. The extracts' maximum inhibition zones against Staphylococcus epidermidis were established. A particle size analyzer detected the formulation size of 140 nm. The optimum formulation of liposomes contains the ratio of 75 mg lecithin, 25 mg cholesterol, and 50 mg herbal extract. Despite the nanoparticles' appropriate particle size, the liposomal extract's antimicrobial effect was lower than that of the free form. Conclusion: Our findings demonstrated that extracts have significant antibacterial and anti-oxidant activities, attributed to their bioactive constituents.
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INTRODUCTION: Compared to normal cells, malignant cancer cells require more iron for their growth and rapid proliferation, which can be supplied by a high expression level of transferrin receptor (TfR). It is well known that the expression of TfR on the tumor cells is considerably higher than that of normal cells, which makes TfR an attractive target in cancer therapy. AREAS COVERED: In this review, the primary focus is on the role of TfR as a valuable tool for cancer-targeted drug delivery, followed by the full coverage of available TfR ligands and their conjugation chemistry to the surface of liposomes. Finally, the most recent studies investigating the potential of TfR-targeted liposomes as promising drug delivery vehicles to different cancer cells are highlighted with emphasis on their improvement possibilities to become a part of future cancer medicines. EXPERT OPINION: Liposomes as a valuable class of nanocarriers have gained much attention toward cancer therapy. From all the studies that have exploited the therapeutic and diagnostic potential of TfR on cancer cells, it can be realized that the systematic assessment of TfR ligands applied for liposomal targeted delivery has yet to be entirely accomplished.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Ligandos , Liposomas/metabolismo , Neoplasias/tratamiento farmacológico , Receptores de Transferrina/metabolismo , Transferrina/metabolismoRESUMEN
In the last decade, the development of messenger RNA (mRNA) therapeutics by lipid nanoparticles (LNP) leads to facilitate clinical trial recruitment, which improves the efficacy of treatment modality to a large extent. Although mRNA-LNP vaccine platforms for the COVID-19 pandemic demonstrated high efficiency, safety and adverse effects challenges due to the uncontrolled immune responses and inappropriate pharmacological interventions could limit this tremendous efficacy. The current study reveals the interplay of immune responses with LNP compositions and characterization and clarifies the interaction of mRNA-LNP therapeutics with dendritic, macrophages, neutrophile cells, and complement. Then, pharmacological profiles for mRNA-LNP delivery, including pharmacokinetics and cellular trafficking, were discussed in detail in cancer types and infectious diseases. This review study opens a new and vital landscape to improve multidisciplinary therapeutics on mRNA-LNP through modulation of immunopharmacological responses in clinical trials.
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Tratamiento Farmacológico de COVID-19 , Nanopartículas , Humanos , Lípidos , Liposomas , Nanopartículas/uso terapéutico , Pandemias , ARN Mensajero/genéticaRESUMEN
The effective treatment of glioma through conventional chemotherapy is proved to be a great challenge in clinics. The main reason is due to the existence of two physiological and pathological barriers respectively including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) that prevent most of the chemotherapeutics from efficient delivery to the brain tumors. To address this challenge, an ideal drug delivery system would efficiently traverse the BBB and BBTB and deliver the therapeutics into the glioma cells with high selectivity. Herein, a targeted delivery system was developed based on nanostructured lipid carriers (NLCs) modified with two proteolytically stable D-peptides, D8 and RI-VAP (Dual NLCs). D8 possesses high affinity towards nicotine acetylcholine receptors (nAChRs), overexpressed on brain capillary endothelial cells (BCECs), and can penetrate through the BBB with high efficiency. RI-VAP is a specific ligand of cell surface GRP78 (csGRP78), a specific angiogenesis and cancer cell-surface marker, capable of circumventing the BBTB with superior glioma-homing property. Dual NLCs could internalize into BCECs, tumor neovascular endothelial cells, and glioma cells with high specificity and could penetrate through in vitro BBB and BBTB models with excellent efficiency compared to non-targeted or mono-targeted NLCs. In vivo whole-animal imaging and ex vivo imaging further confirmed the superior targeting capability of Dual NLCs towards intracranial glioma. When loaded with Bortezomib (BTZ), Dual NLCs attained the highest therapeutic efficiency by means of superior in vitro cytotoxicity and apoptosis and prolonged survival rate and efficient anti-glioma behavior in intracranial glioma bearing mice. Collectively, the designed targeting platform in this study could overcome multiple barriers and effectively deliver BTZ to glioma cells, which represent its potential for advanced brain cancer treatment with promising therapeutic outcomes.
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Neoplasias Encefálicas , Glioma , Animales , Barrera Hematoencefálica/metabolismo , Bortezomib/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Células Endoteliales/metabolismo , Glioma/tratamiento farmacológico , Lípidos/uso terapéutico , RatonesRESUMEN
For successful translation of targeting nanomedicines from bench to bedside, it is vital to address their most common drawbacks namely rapid clearance and off-target accumulation. These complications evidently originate from a phenomenon called "protein corona (PC) formation" around the surface of targeting nanoparticles (NPs) which happens once they encounter the bloodstream and interact with plasma proteins with high collision frequency. This phenomenon endows the targeting nanomedicines with a different biological behavior followed by an unexpected fate, which is usually very different from what we commonly observe in vitro. In addition to the inherent physiochemical properties of NPs, the targeting ligands could also remarkably dictate the amount and type of adsorbed PC. As very limited studies have focused their attention on this particular factor, the present review is tasked to discuss the best simulated environment and latest characterization techniques applied to PC analysis. The effect of PC on the biological behavior of targeting NPs engineered with different targeting moieties is further discussed. Ultimately, the recent progresses in manipulation of nano-bio interfaces to achieve the most favorite therapeutic outcome are highlighted.
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Nanopartículas , Corona de Proteínas , NanomedicinaRESUMEN
The existence of the blood-brain barrier (BBB) makes the clinical chemotherapy of glioma a formidable challenge, because it hinders the passage of different chemotherapeutics into the brain and reduces the overall therapeutic efficiency. Therefore, it is necessary to design a drug delivery system in way that would favor the transportation of anti-cancer agents across the BBB and increase their selective accumulation within the tumor cells without affecting the normal tissues. Transferrin receptor (TfR) that shows an elevated level of expression on the BBB and glioma cells emerges as a promising tool for brain targeted delivery and glioma therapy. However, only a limited number of studies have comparatively evaluated the functionally of TfR targeting ligands. Herein, a series of liposomal formulations modified with the most well-known TfR targeting peptides including T12 (also known as THR), B6, and T7 was developed and their brain targeting capability and selective glioma accumulation was comparatively evaluated in vitro and in vivo. Among all TfR targeting or non-targeting groups, T7-modified liposomes (T7-LS) showed the highest BBB penetration capacity and brain distribution and displayed an enhanced accumulation in glioma cells. When loaded with vincristine (VCR), as a model chemotherapeutic, T7-LS/VCR could achieve the best anti-glioma outcome by means of targeted cytotoxicity and apoptosis in vitro. The obtained results suggested T7-LS as a potential platform for effective brain targeted delivery and glioma therapy in clinic.