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1.
Phytomedicine ; 80: 153356, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33039729

RESUMO

BACKGROUND: Using natural polysaccharides from Traditional Chinese Medicine as nanodrug delivery systems have considerable potential for tumor diagnostics and therapeutics. PURPOSE: On the basis of targeted therapy and combining the advantages of natural polysaccharides (angelica polysaccharide, APS) and natural Chinese medicine (curcumin, Cur) to design functionalized nanoparticles to improve the therapeutic through cell membrane encapsulation and immunotherapy. STUDY DESIGN AND METHODS: Cur-loaded, glycyrrhetic acid (GA)-APS-disulfide bond (DTA)-Cur nanomicelle (GACS-Cur), which were prepared by the dialysis method. GACS-Cur was encapsulated with the membranes from red blood cells (RBCm) termed GACS-Cur@RBCm, which were prepared by the principle of extrusion using a miniature extruder. The developed formulations were subjected to various in vitro and in vivo evaluation tests. RESULTS: The resulting APS nanocarriers supported a favorable drug-loading capacity, biocompatibility, and enhanced synergistic anti-hepatoma effects both in vitro and in vivo. After administration in mice, in vivo imaging results showed that the GACS-Cur and RBCm-coated groups had an obvious stronger tumor tissue targeting ability than the control treatment groups. Additionally, the immunomodulatory effect increased IL-12, TNF-α and IFN-γ expression and CD8+ T cell infiltration (1.9-fold) than that of the saline group. Notably, in comparison with hyaluronic acid (HA) nanocarriers, APS nanocarriers possess higher anti-hepatoma efficiency and targeting capabilities and, thus, should be further studied for a wide range of anti-cancer applications. CONCLUSION: Our data demonstrated that APS nanocarriers encapsulated with erythrocyte membrane mighty be a promising clinical method in the development of efficacy, safety and targeting of liver cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Curcumina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Polissacarídeos/química , Angelica/química , Animais , Antineoplásicos Fitogênicos/imunologia , Antineoplásicos Fitogênicos/farmacologia , Biomimética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Curcumina/farmacologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células Hep G2 , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos Nus , Micelas , Nanopartículas/administração & dosagem , Nanopartículas/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Biomaterials ; 267: 120389, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33130319

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses.


Assuntos
/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , DNA/sangue , Desoxirribonuclease I/uso terapêutico , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Neutrófilos/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , /imunologia , Síndrome da Liberação de Citocina/etiologia , Desoxirribonuclease I/administração & dosagem , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Indóis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , NF-kappa B/sangue , Neutrófilos/enzimologia , Peroxidase/sangue , Polietilenoglicóis , Poliglactina 910 , Polímeros , Sepse/etiologia , Sepse/imunologia
3.
Food Chem ; 340: 127894, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32906059

RESUMO

A novel delivery system using micron-scale grape skin powder (GSP) was developed that enhanced loading, stability and bioaccessibility of trans-resveratrol (trans-Res). Vacuum assisted infusion of GSP results in a high yield (~1 mg/g) of trans-Res and improved photostability of infused trans-Res in GSP exposed to UV-A light. The release of trans-Res from GSP was ~ 45% during gastric digestion and the total release in the intestinal phase during sequential digestion processes using low and high bile salts was ~ 70% and ~ 90%, respectively. Moreover, the release of endogenous polyphenols in GSP during simulated gastrointestinal digestion was similar to the release profile of infused resveratrol, suggesting strong interactions of infused resveratrol with the GSP matrix. In summary, this research illustrates a novel approach to utilize food by-products to enhance stability and bioaccessibility of bioactive compounds.


Assuntos
Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Resveratrol/química , Resveratrol/farmacocinética , Vitis/química , Digestão , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Frutas/química , Fenóis/análise , Fotólise , Pós/química , Resveratrol/administração & dosagem , Raios Ultravioleta , Vácuo
4.
Int J Nanomedicine ; 15: 9587-9610, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33293809

RESUMO

Bacterial infections are the main infectious diseases and cause of death worldwide. Antibiotics are used to treat various infections ranging from minor to life-threatening ones. The dominant route to administer antibiotics is through oral delivery and subsequent gastrointestinal tract (GIT) absorption. However, the delivery efficiency is limited by many factors such as low drug solubility and/or permeability, gastrointestinal instability, and low antibacterial activity. Nanotechnology has emerged as a novel and efficient tool for targeting drug delivery, and a number of promising nanotherapeutic strategies have been widely explored to overcome these obstacles. In this review, we explore published studies to provide a comprehensive understanding of the recent progress in the area of orally deliverable nano-antibiotic formulations. The first part of this article discusses the functions and underlying mechanisms by which nanomedicines increase the oral absorption of antibiotics. The second part focuses on the classification of oral nano-antibiotics and summarizes the advantages, disadvantages and applications of nanoformulations including lipid, polymer, nanosuspension, carbon nanotubes and mesoporous silica nanoparticles in oral delivery of antibiotics. Lastly, the challenges and future perspective of oral nano-antibiotics for infection disease therapy are discussed. Overall, nanomedicines designed for oral drug delivery system have demonstrated the potential for the improvement and optimization of currently available antibiotic therapies.


Assuntos
Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Administração Oral , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Humanos , Absorção Intestinal/efeitos dos fármacos , Lipídeos/química , Nanotubos de Carbono/química , Polímeros/química , Dióxido de Silício/química , Solubilidade
5.
Int J Nanomedicine ; 15: 9197-9210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33239876

RESUMO

Acne is a common skin disease that affect over 80% of adolescents. It is characterized by inflammation of the hair bulb and the attached sebaceous gland. To date, many strategies have been used to treat acne as a function of the disease severity. However, common treatments for acne seem to show several side effects, from local irritation to more serious collateral effects. The use of topical vesicular carriers able to deliver active compounds is currently considered as an excellent approach in the treatment of different skin diseases. Many results in the literature have proven that drug delivery systems are useful in overcoming the toxicity induced by common drug therapies, while maintaining their therapeutic efficacy. Starting from these assumptions, the authors reviewed drug delivery systems already realized for the topical treatment of acne, with a focus on their limitations and advantages over conventional treatment strategies. Although their exact mechanism of permeation is not often completely clear, deformable vesicles seem to be the best solution for obtaining a specific delivery of drugs into the deeper skin layers, with consequent increased local action and minimized collateral effects.


Assuntos
Acne Vulgar/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Administração Tópica , Adolescente , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/uso terapêutico , Humanos , Absorção Cutânea/efeitos dos fármacos
6.
Int J Nanomedicine ; 15: 8609-8621, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33177821

RESUMO

Introduction: Nanoparticles (NPs), as drug delivery systems, appear to be a promising tool for prolonged therapeutic strategies as they allow a controlled drug release over time. However, most of the studies found in the literature simply contemplate the use of a single or low number of dosages with low NPs concentrations. In the context of chronic diseases, like Alzheimer's disease, cancer or human immunodeficiency virus (HIV), where the therapeutic scheme is also chronic, studies with numerous repeated dosages are often neglected. Methods: We screened different NPs, polymeric and lipid-based, in a repeated-dose toxicity study, to evaluate the safety and tissue distribution of promising nanocarriers to be used in the treatment of long-lasting diseases. Results: After administrating 24 high concentrated doses of the selected NPs intraperitoneally (i.p.) (3 times a week for 2 months), animals have presented NPs accumulation in different tissues. However, neither toxicity, bodyweight changes nor clinical signs of disease were observed. Discussion: This work demonstrates no general adverse effects upon the studied NPs repeated-dose exposure, indicating the most promising NPs to be used in the different therapeutic circumstances, which may be useful in chronic diseases treatment.


Assuntos
Portadores de Fármacos/farmacocinética , Nanopartículas/química , Nanopartículas/toxicidade , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/toxicidade , Sistemas de Liberação de Medicamentos/métodos , Feminino , Lipídeos/química , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/farmacocinética , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Distribuição Tecidual , Testes de Toxicidade
7.
Int J Nanomedicine ; 15: 8659-8672, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33177824

RESUMO

Background: Leishmaniasis is a neglected disease, and the current therapeutic arsenal for its treatment is seriously limited by high cost and toxicity. Nanostructured lipid carriers (NLCs) represent a promising approach due to high drug loading capacity, controlled drug release profiles and superior stability. Here, we explore the efficacy of a unique pH-sensitive amphotericin B-loaded NLC (AmB-NLC) in Leishmania braziliensis infection in vitro and in vivo. Methods and Results: AmB-NLC was assessed by dynamic light scattering and atomic force microscopy assays. The carrier showed a spherical shape with a nanometric size of 242.0 ± 18.3 nm. Zeta potential was suggestive of high carrier stability (-42.5 ± 1.5 mV), and the NLC showed ~99% drug encapsulation efficiency (EE%). In biological assays, AmB-NLC presented a similar IC50 as free AmB and conventional AmB deoxycholate (AmB-D) (11.7 ± 1.73; 5.3 ± 0.55 and 13 ± 0.57 ng/mL, respectively), while also presenting higher selectivity index and lower toxicity to host cells, with no observed production of nitric oxide or TNF-α by in vitro assay. Confocal microscopy revealed the rapid uptake of AmB-NLC by infected macrophages after 1h, which, in association with more rapid disruption of AmB-NLC at acidic pH levels, may directly affect intracellular parasites. Leishmanicidal effects were evaluated in vivo in BALB/c mice infected in the ear dermis with L. braziliensis and treated with a pentavalent antimonial (Sb5+), liposomal AmB (AmB-L) or AmB-NLC. After 6 weeks of infection, AmB-NLC treatment resulted in smaller ear lesion size in all treated mice, indicating the efficacy of the novel formulation. Conclusion: Here, we preliminarily demonstrate the effectiveness of an innovative and cost-effective AmB-NLC formulation in promoting the killing of intracellular L. braziliensis. This novel carrier system could be a promising alternative for the future treatment of cutaneous leishmaniasis.


Assuntos
Anfotericina B/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Nanoestruturas/administração & dosagem , Anfotericina B/farmacocinética , Anfotericina B/farmacologia , Animais , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Feminino , Concentração de Íons de Hidrogênio , Leishmania braziliensis/efeitos dos fármacos , Leishmania braziliensis/patogenicidade , Lipídeos/química , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/química
8.
Nat Commun ; 11(1): 5618, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154372

RESUMO

Systemic chemotherapy remains the backbone of many cancer treatments. Due to its untargeted nature and the severe side effects it can cause, numerous nanomedicine approaches have been developed to overcome these issues. However, targeted delivery of therapeutics remains challenging. Engineering microrobots is increasingly receiving attention in this regard. Their functionalities, particularly their motility, allow microrobots to penetrate tissues and reach cancers more efficiently. Here, we highlight how different microrobots, ranging from tailor-made motile bacteria and tiny bubble-propelled microengines to hybrid spermbots, can be engineered to integrate sophisticated features optimised for precision-targeting of a wide range of cancers. Towards this, we highlight the importance of integrating clinicians, the public and cancer patients early on in the development of these novel technologies.


Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Robótica , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Humanos , Comunicação Interdisciplinar , Nanomedicina , Robótica/classificação
9.
Int J Nanomedicine ; 15: 8151-8166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132699

RESUMO

Conventional taxanes are used as cornerstone of the chemotherapeutical treatment for a variety of malignancies. Nevertheless, a large proportion of patients do not benefit from their treatment while they do suffer from severe adverse events related to the solvent or to the active compound. Cremophor EL and polysorbate 80 free formulations, conjugates, oral formulations and different types of drug delivery systems are some examples of the several attempts to improve the treatment with taxanes. In this review article, we discuss recent clinical developments of nanomediated drug delivery systems of taxanes for the treatment of cancer. Targeting mechanisms of drug delivery systems and characteristics of the most commonly used taxane-containing drug delivery systems in the clinical setting will be discussed in this review.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/administração & dosagem , Taxoides/administração & dosagem , Animais , Antineoplásicos/uso terapêutico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias/tratamento farmacológico , Taxoides/farmacocinética , Taxoides/uso terapêutico
10.
Int J Nanomedicine ; 15: 8553-8568, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173292

RESUMO

Purpose: Zolmitriptan (ZT) is a selective serotonin agonist that is used for the treatment of migraine. It belongs to BCS class III with high solubility and low permeability. Besides, the drug is subjected to pre-systemic metabolism. Accordingly, new Zolmitriptan/chitosan nanostructured lipid carriers (ZT/CT NLCs) coated with Tween 80 (stealthy layer) have been developed to overcome such demerits. Methods: The NLCs were developed by combining ultrasonication and double emulsion (w/o/w) techniques. The lipids were Gelucire and Labrasol. Herein, the quality by design (23 full factorial design) was scrupulously followed, where critical process parameters and critical quality attributes were predefined. The optimized formulation (F8) was fully characterized with respect to entrapment efficiency (%EE), percentage yield (% yield), particle size, size distribution (PDI), zeta potential (ZP), morphological appearance (TEM). In vitro release, stability study and pharmacodynamic evaluations were also assessed. The optimized freeze dried formula was dispensed in in situ gelling hard gelatin capsule encompassing pectin and guar gum for further in vitro and pharmacodynamic evaluations. Results: The optimized spherical nanoparticles experienced high percentage EE and yield (78.14% and 60.19%, respectively), low particle size and PDI (343.87 nm and 0.209, respectively), as well as high negative ZP (-25.5 mV). It showed good physical stability at refrigerated conditions. The NLCs dispensed in in situ gelling hard gelatin capsule comprising pectin and guar gum experienced sustained release for 30 h and significantly maintained the pharmacological effect in mice up to 8 h (p < 0.001). Conclusion: ZT, a BCS class III drug that suffers from poor permeability and pre-systemic metabolism, was successfully maneuvered as nanostructured lipid carrier particles (NLCs). The incorporation of the NLCs in in situ gelling hard gelatin capsules fulfilled a dual function in increasing permeability, as well as sustaining the pharmacodynamic effect. This result would open new vistas in improving the efficacy of other class III drugs.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Lipídeos/química , Nanoestruturas/química , Oxazolidinonas/farmacocinética , Triptaminas/farmacocinética , Animais , Cápsulas , Quitosana/química , Portadores de Fármacos/administração & dosagem , Emulsões/química , Gelatina/química , Masculino , Camundongos , Nanopartículas/química , Oxazolidinonas/administração & dosagem , Oxazolidinonas/química , Tamanho da Partícula , Pectinas/química , Polissorbatos/química , Solubilidade , Triptaminas/administração & dosagem , Triptaminas/química , Ultrassom/métodos
11.
Int J Nanomedicine ; 15: 8673-8696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192061

RESUMO

Polymeric nanomaterials have become a prominent area of research in the field of drug delivery. Their application in nanomedicine can improve bioavailability, pharmacokinetics, and, therefore, the effectiveness of various therapeutics or contrast agents. There are many studies for developing new polymeric nanocarriers; however, their clinical application is somewhat limited. In this review, we present new complex and multifunctional polymeric nanocarriers as promising and innovative diagnostic or therapeutic systems. Their multifunctionality, resulting from the unique chemical and biological properties of the polymers used, ensures better delivery, and a controlled, sequential release of many different therapeutics to the diseased tissue. We present a brief introduction of the classical formulation techniques and describe examples of multifunctional nanocarriers, whose biological assessment has been carried out at least in vitro. Most of them, however, also underwent evaluation in vivo on animal models. Selected polymeric nanocarriers were grouped depending on their medical application: anti-cancer drug nanocarriers, nanomaterials delivering compounds for cancer immunotherapy or regenerative medicine, components of vaccines nanomaterials used for topical application, and lifestyle diseases, ie, diabetes.


Assuntos
Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/química , Administração Tópica , Animais , Antineoplásicos/administração & dosagem , Humanos , Nanomedicina/métodos , Nanoestruturas/administração & dosagem , Polímeros/química , Medicina Regenerativa/métodos
12.
PLoS One ; 15(10): e0240535, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33045028

RESUMO

Acute otitis media (AOM) is the main indication for pediatric antibiotic prescriptions, accounting for 25% of prescriptions. While the use of topical drops can minimize the administered dose of antibiotic and adverse systemic effects compared to oral antibiotics, their use has limitations, partially due to low patient compliance, high dosing frequency, and difficulty of administration. Lack of proper treatment can lead to development of chronic OM, which may require invasive interventions. Previous studies have shown that gel-based drug delivery to the ear is possible with intratympanic injection or chemical permeation enhancers (CPEs). However, many patients are reluctant to accept invasive treatments and CPEs have demonstrated toxicity to the tympanic membrane (TM). We developed a novel method of delivering therapeutics to the TM and middle ear using a topical, thermoresponsive gel depot containing antibiotic-loaded poly(lactic-co-glycolic acid) microspheres. Our in vitro and ex vivo results suggest that the sustained presentation can safely allow therapeutically relevant drug concentrations to penetrate the TM to the middle ear for up to 14 days. Animal results indicate sufficient antibiotic released for treatment from topical administration 24h after bacterial inoculation. However, animals treated 72h after inoculation, a more clinically relevant treatment practice, displayed spontaneous clearance of infection as is also often observed in the clinic. Despite this variability in the disease model, data suggest the system can safely treat bacterial infection, with future studies necessary to optimize microsphere formulations for scaled up dosage of antibiotic as well as further investigation of the influence of spontaneous bacterial clearance and of biofilm formation on effectiveness of treatment. To our knowledge, this study represents the first truly topical drug delivery system to the middle ear without the use of CPEs.


Assuntos
Administração Tópica , Antibacterianos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Otite Média/tratamento farmacológico , Doença Aguda , Animais , Ceftriaxona/administração & dosagem , Chinchila , Ciprofloxacino/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Composição de Medicamentos , Géis , Cobaias , Microesferas
13.
Int J Nanomedicine ; 15: 7415-7431, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116479

RESUMO

Introduction: AT101, the R-(-)-enantiomer of the cottonseed-derived polyphenol gossypol, is a promising drug in glioblastoma multiforme (GBM) therapy due to its ability to trigger autophagic cell death but also to facilitate apoptosis in tumor cells. It does have some limitations such as poor solubility in water-based media and consequent low bioavailability, which affect its response rate during treatment. To overcome this drawback and to improve the anti-cancer potential of AT101, the use of cubosome-based formulation for AT101 drug delivery has been proposed. This is the first report on the use of cubosomes as AT101 drug carriers in GBM cells. Materials and Methods: Cubosomes loaded with AT101 were prepared from glyceryl monooleate (GMO) and the surfactant Pluronic F-127 using the top-down approach. The drug was introduced into the lipid prior to dispersion. Prepared formulations were then subjected to complex physicochemical and biological characterization. Results: Formulations of AT101-loaded cubosomes were highly stable colloids with a high drug entrapment efficiency (97.7%) and a continuous, sustained drug release approaching 35% over 72 h. Using selective and sensitive NMR diffusometry, the drug was shown to be efficiently bound to the lipid-based cubosomes. In vitro imaging studies showed the high efficiency of cubosomal nanoparticles uptake into GBM cells, as well as their marked ability to penetrate into tumor spheroids. Treatment of GBM cells with the AT101-loaded cubosomes, but not with the free drug, induced cytoskeletal rearrangement and shortening of actin fibers. The prepared nanoparticles revealed stronger in vitro cytotoxic effects against GBM cells (A172 and LN229 cell lines), than against normal brain cells (SVGA and HMC3 cell lines). Conclusion: The results indicate that GMO-AT101 cubosome formulations are a promising basic tool for alternative approaches to GBM treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos/química , Glioblastoma/tratamento farmacológico , Gossipol/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Disponibilidade Biológica , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Coloides/química , Coloides/farmacologia , Citoesqueleto/efeitos dos fármacos , Preparações de Ação Retardada/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/patologia , Glicerídeos/química , Gossipol/administração & dosagem , Gossipol/farmacocinética , Gossipol/farmacologia , Humanos , Lipídeos/química , Espectroscopia de Ressonância Magnética/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Poloxâmero/química , Solubilidade
14.
Int J Nanomedicine ; 15: 7491-7507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116484

RESUMO

Background: Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The poor response to antitubercular agents necessitates the long-term use of high drug doses, resulting in low patient compliance, which is the main reason for chemotherapy failure and contributes to the development of multidrug-resistant TB. Patient non-compliance has been a major obstacle in the successful management of TB. The aim of this work was to develop and characterise rifapentine (RPT)-loaded PLGA-based nanoparticles (NPs) for reducing dosing frequency. Methods: RPT-loaded PLGA and PLGA-PEG NPs were prepared using premix membrane homogenisation combined with solvent evaporation method. The resulting NPs were characterised in terms of physicochemical characteristics, toxicity, cellular uptake and antitubercular activity. NPs were further evaluated for pharmacokinetic and biodistribution studies in mice. Results: The resulting NPs showed suitable and safe physicochemical characteristics and could be taken up by macrophages. RPT-loaded NPs were more effective against Mycobacterium tuberculosis than free RPT. In vivo studies revealed that NPs could improve pharmacokinetic parameters, particularly for RPT/PLGA-PEG NPs. Moreover, both formulations had no toxicity to the organs of mice and could reduce hepatotoxicity. Conclusion: The application of PLGA-based NPs as sustained-release delivery vehicles for RPT could prolong drug release, modify pharmacokinetics, increase antitubercular activity and diminish toxicity, thereby allowing low dosage and frequency.


Assuntos
Antituberculosos/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Nanopartículas/administração & dosagem , Rifampina/análogos & derivados , Administração Oral , Animais , Antituberculosos/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Hemólise/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Prostaglandinas A/química , Rifampina/administração & dosagem , Rifampina/farmacocinética , Distribuição Tecidual
15.
Int J Nanomedicine ; 15: 7703-7717, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116496

RESUMO

Background: Thymoquinone (TQ), an active compound isolated from Nigella sativa, has been proven to exhibit various biological properties such as antioxidant. Although oral delivery of TQ is valuable, it is limited by poor oral bioavailability and low solubility. Recently, TQ-loaded nanostructured lipid carrier (TQ-NLC) was formulated with the aim of overcoming the limitations. TQ-NLC was successfully synthesized by the high-pressure homogenization method with remarkable physiochemical properties whereby the particle size is less than 100 nm, improved encapsulation efficiency and is stable up to 24 months of storage. Nevertheless, the pharmacokinetics and biodistribution of TQ-NLC have not been studied. This study determined the bioavailability of oral and intravenous administration of thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) in rats and its distribution to organs. Materials and Methods: TQ-NLC was radiolabeled with technetium-99m before the administration to the rats. The biodistribution and pharmacokinetics parameters were then evaluated at various time points. The rats were imaged at time intervals and the percentage of the injected dose/gram (%ID/g) in blood and each organ was analyzed. Results: Oral administration of TQ-NLC exhibited greater relative bioavailability compared to intravenous administration. It is postulated that the movement of TQ-NLC through the intestinal lymphatic system bypasses the first metabolism and therefore enhances the relative bioavailability. However, oral administration has a slower absorption rate compared to intravenous administration where the AUC0-∞ was 4.539 times lower than the latter. Conclusion: TQ-NLC had better absorption when administered intravenously compared to oral administration. However, oral administration showed greater bioavailability compared to the intravenous route. This study provides the pharmacokinetics and biodistribution profile of TQ-NLC in vivo which is useful to assist researchers in clinical use.


Assuntos
Benzoquinonas/administração & dosagem , Benzoquinonas/farmacocinética , Portadores de Fármacos/química , Nanoestruturas/química , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Lipídeos/química , Masculino , Nanoestruturas/administração & dosagem , Tamanho da Partícula , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual
16.
Int J Nanomedicine ; 15: 7719-7743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116497

RESUMO

Objective: The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy. Methods: An ion-pairing complex of OP with a permeation enhancer, N α-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF). Results: The optimized powder formulation was sized in the nanoscale range (133±1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls. Conclusion: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacocinética , Administração Metronômica , Administração Oral , Animais , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Feminino , Glicerídeos/química , Humanos , Absorção Intestinal/efeitos dos fármacos , Lisina/análogos & derivados , Lisina/química , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Poloxâmero/química , Ratos Sprague-Dawley
17.
Int J Nanomedicine ; 15: 6737-6748, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982230

RESUMO

Purpose: Chemotherapy of colon cancer needs improvement to mitigate the severe adverse effects (AEs) associated with the cytotoxic drugs. The aim of this study is to develop a novel targeted drug delivery system (TDDS) with practical application potential for colon cancer treatment. Methods: The TDDS was built by loading docetaxel (DTX) in albumin nanoparticles (NPs) that were functionalized with nucleolin-targeted aptamers (AS1411). Results: The TDDS (Apt-NPs-DTX) had an average size of 62 nm and was negatively charged with a zeta potential of -31.2 mV. DTX was released from the albumin NP with a typical sustained release profile. Aptamer-guided NPs were preferentially ingested by nucleolin-expressing CT26 colon cancer cells vs the control cells. In vitro cytotoxicity study showed that Apt-NPs-DTX significantly enhanced the killing of CT26 colon cancer cells. Importantly, compared with non-targeted drug delivery, Apt-NPs-DTX treatment significantly improved antitumor efficacy and prolonged the survival of CT26-bearing mice, without raising systemic toxicity. Conclusion: The results suggest that Apt-NPs-DTX has potential in the targeted treatment of colon cancer.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Docetaxel/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Oligodesoxirribonucleotídeos/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Células CHO , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Cricetulus , Docetaxel/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Oligodesoxirribonucleotídeos/química , Soroalbumina Bovina/química
18.
PLoS One ; 15(9): e0238823, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970684

RESUMO

Mucoadhesive polymeric nanocapsules have attracted interest of researchers from different fields from natural sciences because of their ability to interact with the mucosa and increase drug permeation. Anesthesia by immersion causes absorption through the skin and gills of fish, so it is important to evaluate the exposure of these organs to drug nanosystems. Benzocaine (BENZ) is one of the most popular anesthetic agents used in fish anesthesia, but it has drawbacks because of its low bioavailability, resulting in weak absorption after immersion. Here we describe method developed for preparing and characterizing chitosan-coated PLGA mucoadhesive nanoparticles containing BENZ (NPMAs) for zebrafish immersion anesthesia. We determined the lowest effective concentration, characterized the interaction of the mucoadhesive system with fish, measured the anesthetic efficacy, and evaluated possible toxic effects in embryos and adults exposed to the nanoformulations. This study opens perspectives for using nanoformulations prepared with BENZ in aquaculture, allowing reduction of dosage as well as promoting more effective anesthesia and improved interaction with the mucoadhesive system of fish.


Assuntos
Anestesia/veterinária , Benzocaína/administração & dosagem , Nanocápsulas/administração & dosagem , Peixe-Zebra , Animais , Aquicultura , Quitosana/administração & dosagem , Quitosana/toxicidade , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Brânquias/efeitos dos fármacos , Nanocápsulas/toxicidade , Pele/efeitos dos fármacos
19.
Int J Nanomedicine ; 15: 6295-6310, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32943863

RESUMO

Oral administration has been the most common therapeutic regimen in various diseases because of its high safety, convenience, lower costs, and high compliance of patients. However, susceptible in hostile gastrointestinal (GI) environment, many drugs show poor permeability across GI tract mucus and intestinal epithelium with poor oral absorption and limited therapeutic efficacy. In recent years, nanoparticulate drug delivery systems (NDDS) have become a hot research spot because of their unique advantages including protecting drug from premature degrading and interacting with the physiological environment, increasing intracellular penetration, and enhancing drug absorption. However, a slight change in physicochemistry of nanoparticles can significantly impact their interaction with biological pathways and alter the oral bioavailability of drugs. Hence, this review focuses on the factors affecting oral bioavailability from two aspects. On the one hand, the factors are the biochemical and physiological barriers in oral drugs delivery. On the other hand, the factors are the nanoparticle properties including size, surface properties, and shape of nanoparticles.


Assuntos
Portadores de Fármacos/farmacocinética , Nanopartículas/administração & dosagem , Nanopartículas/química , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Tamanho da Partícula , Permeabilidade , Propriedades de Superfície
20.
Int J Nanomedicine ; 15: 6545-6560, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32943867

RESUMO

Background: The metastasis, one of the biggest barriers in cancer therapy, is the leading cause of tumor deterioration and recurrence. The anti.-metastasis has been considered as a feasible strategy for clinical cancer management. It is well known that diosgenin could inhibit tumor metastasis and doxorubicin (DOX) could induce tumor apoptosis. However, their efficient delivery remains challenging. Purpose: To address these issues, a novel pH-sensitive polymer-prodrug based on diosgenin nanoparticles (NPs) platform was developed to enhance the efficiency of DOX delivery (DOX/NPs) for synergistic therapy of cutaneous melanoma, the most lethal form of skin cancer with high malignancy, early metastasis and high mortality. Methods and Results: The inhibitory effect of DOX/NPs on tumor proliferation and migration was superior to that of NPs or free DOX. What is more, DOX/NPs could combine mitochondria-associated metastasis and apoptosis with unique internalization pathway of carrier to fight tumors. In addition, biodistribution experiments proved that DOX/NPs could efficiently accumulate in tumor sites through enhancing permeation and retention (EPR) effect compared with free DOX. Importantly, the data from in vivo experiment revealed that DOX/NPs without heart toxicity significantly inhibited tumor metastasis by exerting synergistic therapeutic effect, and reduced tumor volume and weight by inducing apoptosis. Conclusion: The nanocarrier DOX/NPs with satisfying pharmaceutical characteristics based on the establishment of two different functional agents is a promising strategy for synergistically enhancing effects of cancer therapy.


Assuntos
Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Melanoma/tratamento farmacológico , Nanopartículas/química , Pró-Fármacos/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Diosgenina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Melanoma/patologia , Melanoma/secundário , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Pró-Fármacos/farmacologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundário , Distribuição Tecidual
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