RESUMO
Ferroptosis has attracted significant attention as a new mechanism of cell death. Sorafenib (SRF) is widely considered a prototypical ferroptosis-inducing drug, particularly for liver cancer treatment. However, the low solubility and hydrophobic nature of SRF, along with the absence of synergistic therapeutic strategies, still limit its application in cancer treatment. Herein, we report a dual therapeutic method incorporating photothermal therapy and ferroptosis by using Fe-doped mesoporous polydopamine nanoparticles (Fe-mPDA@SRF-TPP) as a carrier for loading SRF and targeting triphenylphosphine (TPP). SRF molecules are efficiently encapsulated within the polydopamine nanospheres with a high loading ratio (80%) attributed to the porosity of Fe-mPDA, and the inherent biocompatibility and hydrophilicity of Fe-mPDA@SRF-TPP facilitate the transport of SRF to the target cancer cells. Under the external stimuli of acidic environment (pH 5.0), glutathione (GSH), and laser irradiation, Fe-mPDA@SRF-TPP shows sustained release of SRF and Fe ions with the ratio of 72 and 50% within 48 h. Fe-mPDA@SRF-TPP nanoparticles induce intracellular GSH depletion, inhibit glutathione peroxidase 4 (GPX4) activity, and generate hydroxyl radicals, all of which are essential components of the therapeutic ferroptosis process for killing MDA-MB-231 cancer cells. Additionally, the excellent near-infrared (NIR) light absorption of Fe-mPDA@SRF-TPP nanoparticles demonstrates their capability for photothermal therapy and further enhances the therapeutic efficiency. Therefore, this nanosystem provides a multifunctional therapeutic platform that overcomes the therapeutic limitations associated with standalone ferroptosis and enhances the therapeutic efficacy of SRF for breast cancer.
Assuntos
Ferroptose , Neoplasias Hepáticas , Nanopartículas , Neoplasias , Humanos , Sorafenibe/farmacologia , Terapia Fototérmica , Ferro , Nanopartículas/química , Neoplasias/terapia , Concentração de Íons de Hidrogênio , Linhagem Celular TumoralRESUMO
Multidrug resistance (MDR) is currently a big challenge in cancer therapy and limits its success in several patients. Tumors use the MDR mechanisms to colonize the host and reduce the efficacy of chemotherapeutics that are injected as single agents or combinations. MDR mechanisms are responsible for inactivation of drugs and formbiological barriers in cancer like the drug efflux pumps, aberrant extracellular matrix, hypoxic areas, altered cell death mechanisms, etc. Nanocarriers have some potential to overcome these barriers and improve the efficacy of chemotherapeutics. In fact, they are versatile and can deliver natural and synthetic biomolecules, as well as RNAi/DNAi, thus providing a controlled release of drugs and a synergistic effect in tumor tissues. Biocompatible and safe multifunctional biopolymers, with or without specific targeting molecules, modify the surface and interface properties of nanocarriers. These modifications affect the interaction of nanocarriers with cellular models as well as the selection of suitable models for in vitro experiments. MDR cancer cells, and particularly their 2D and 3D models, in combination with anatomical and physiological structures of tumor tissues, can boost the design and preparation of nanomedicines for anticancer therapy. 2D and 3D cancer cell cultures are suitable models to study the interaction, internalization, and efficacy of nanocarriers, the mechanisms of MDR in cancer cells and tissues, and they are used to tailor a personalized medicine and improve the efficacy of anticancer treatment in patients. The description of molecular mechanisms and physio-pathological pathways of these models further allow the design of nanomedicine that can efficiently overcome biological barriers involved in MDR and test the activity of nanocarriers in 2D and 3D models of MDR cancer cells.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Resistência a Múltiplos Medicamentos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nanomedicina , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
In vitro cell-based characterization methods of nanoparticles are generally static and require the use of secondary analysis techniques and labeling agents. In this study, bare niosomes and chitosan-coated niosomes (chitosomes) and their interactions with intestinal cells are studied under dynamic conditions and without fluorescent probes, using surface plasmon resonance (SPR)-based cell sensing. Niosomes and chitosomes were synthesized by using Tween 20 and cholesterol in a 15 mM:15 mM ratio and then characterized by dynamic light scattering (DLS). DLS analysis demonstrated that bare niosomes had average sizes of â¼125 nm, polydispersity index (PDI) below 0.2, and a negative zeta (ζ)-potential of -35.6 mV. In turn, chitosomes had increased sizes up to â¼180 nm, with a PDI of 0.2-0.3 and a highly positive ζ-potential of +57.9 mV. The viability of HT29-MTX, Caco-2, and Caco-2/HT29-MTX cocultured cells showed that both niosomes and chitosomes are cytocompatible up to concentrations of 31.6 µg/mL for at least 240 min. SPR analysis demonstrated that chitosomes interact more efficiently with HT29-MTX, Caco-2, and Caco-2/HT29-MTX cocultures compared to bare niosomes. The resulting SPR measurements were further supported by confocal microscopy and flow cytometry studies, which demonstrated that this method is a useful complementary or even alternative tool to directly characterize the interactions between niosomes and in vitro cell models in label-free and real-time conditions.
Assuntos
Quitosana , Lipossomos , Humanos , Células CACO-2 , IntestinosRESUMO
Neuroblastoma is a biologically heterogeneous extracranial tumor, derived from the sympathetic nervous system, that affects most often the pediatric population. Therapeutic strategies relying on aggressive chemotherapy, surgery, radiotherapy, and immunotherapy have a negative outcome in advanced or recurrent disease. Here, spherical polymeric nanomedicines (SPN) are engineered to co-deliver a potent combination therapy, including the cytotoxic docetaxel (DTXL) and the natural wide-spectrum anti-inflammatory curcumin (CURC). Using an oil-in-water emulsion/solvent evaporation technique, four SPN configurations were engineered depending on the therapeutic payload and characterized for their physico-chemical and pharmacological properties. All SPN configurations presented a hydrodynamic diameter of â¼ 185 nm with a narrow size distribution. A biphasic release profile was observed for all the configurations, with almost 90 % of the total drug mass released within the first 24 h. SPN cytotoxic potential was assessed on a panel of human neuroblastoma cells, returning IC50 values in the order of 1 nM at 72 h and documenting a strong synergism between CURC and DTXL. Therapeutic efficacy was tested in a clinically relevant orthotopic model of neuroblastoma, following the injection of SH-SY5Y-Luc+ cells in the left adrenal gland of athymic mice. Although â¼ 2 % of the injected SPN per mass tissue reached the tumor, the overall survival of mice treated with CURC/DTXL-SPN was extended by 50 % and 25 % as compared to the untreated control and the monotherapies, respectively. In conclusion, these results demonstrate that the therapeutic potential of the DTXL/CURC combination can be fully exploited only by reformulating these two compounds into systemically injectable nanoparticles.
Assuntos
Antineoplásicos , Curcumina , Nanopartículas , Neuroblastoma , Criança , Humanos , Camundongos , Animais , Docetaxel/farmacologia , Neuroblastoma/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/química , Polímeros/química , Linhagem Celular TumoralRESUMO
Many PEGylated nanoparticles activate the complement system, which is an integral component of innate immunity. This is of concern as uncontrolled complement activation is potentially detrimental and contributes to disease pathogenesis. Here, it is demonstrated that, in contrast to carboxyPEG2000-stabilized poly(lactic-co-glycolic acid) nanoparticles, surface camouflaging with appropriate combinations and proportions of carboxyPEG2000 and methoxyPEG550 can largely suppress nanoparticle-mediated complement activation through the lectin pathway. This is attributed to the ability of the short, rigid methoxyPEG550 chains to laterally compress carboxyPEG2000 molecules to become more stretched and assume an extended, random coil configuration. As supported by coarse-grained molecular dynamics simulations, these conformational attributes minimize statistical protein binding/intercalation, thereby affecting sequential dynamic processes in complement convertase assembly. Furthermore, PEG pairing has no additional effect on nanoparticle longevity in the blood and macrophage uptake. PEG pairing significantly overcomes nanoparticle-mediated complement activation without the need for surface functionalization with complement inhibitors.
Assuntos
Ativação do Complemento , Nanopartículas , PolietilenoglicóisRESUMO
Extracellular vesicles (EVs) play a crucial role in the intercellular crosstalk. Mesenchymal stem cell-derived EVs (MSC-EVs), displaying promising therapeutic roles, contribute to the strong rationale for developing EVs as an alternative therapeutic option. EV analysis still represents one of the major issues to be solved in order to translate the use of MSC-EV detection in clinical settings. Even if flow cytometry (FC) has been largely applied for EV studies, the lack of consensus on protocols for FC detection of EVs generated controversy. Standard FC procedures, based on scatter measurements, only allows the detection of the "tip of the iceberg" of all EVs. We applied an alternative FC approach based on the use of a trigger threshold on a fluorescence channel. The EV numbers obtained by the application of the fluorescence triggering resulted significantly higher in respect to them obtained from the same samples acquired by placing the threshold on the side scatter (SSC) channel. The analysis of EV concentrations carried out by three different standardized flow cytometers allowed us to achieve a high level of reproducibility (CV < 20%). By applying the here-reported method highly reproducible results in terms of EV analysis and concentration measurements were obtained.
Assuntos
Vesículas Extracelulares/metabolismo , Citometria de Fluxo/métodos , Células-Tronco Mesenquimais/citologia , Animais , Células Cultivadas , Difusão Dinâmica da Luz , Separação Imunomagnética , Células-Tronco Mesenquimais/metabolismoRESUMO
Extracellular vesicles (EVs) are released by shedding during different physiological processes and are increasingly thought to be new potential biomarkers. However, the impact of pre-analytical processing phases on the final measurement is not predictable and for this reason, the translation of basic research into clinical practice has been precluded. Here we have optimized a simple procedure in combination with polychromatic flow cytometry (PFC), to identify, classify, enumerate, and separate circulating EVs from different cell origins. This protocol takes advantage of a lipophilic cationic dye (LCD) able to probe EVs. Moreover, the application of the newly optimized PFC protocol here described allowed the obtainment of repeatable EVs counts. The translation of this PFC protocol to fluorescence-activated cell sorting allowed us to separate EVs from fresh peripheral blood samples. Sorted EVs preparations resulted particularly suitable for proteomic analyses, which we applied to study their protein cargo. Here we show that LCD staining allowed PFC detection and sorting of EVs from fresh body fluids, avoiding pre-analytical steps of enrichment that could impact final results. Therefore, LCD staining is an essential step towards the assessment of EVs clinical significance.
Assuntos
Biomarcadores , Vesículas Extracelulares/metabolismo , Citometria de Fluxo , Biópsia Líquida , Animais , Citometria de Fluxo/métodos , Humanos , Biópsia Líquida/métodos , Tamanho da Partícula , Plasma , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Bacteria generate membrane vesicles, which are structures known as extracellular vesicles (EVs), reported to be involved in different pathogenic mechanisms, as it has been demonstrated that EVs participate in biofilm formation, cell-to-cell communication, bacteria-host interactions, and nutrients supply. EVs deliver nucleic acids, proteins, and polysaccharides. It has been reported that Helicobacter pylori (H. pylori) and Lactobacillus reuteri (L. reuteri), of both planktonic and biofilm phenotypes, produce EVs carrying extracellular DNA (eDNA). Here, we used polychromatic flow cytometry (PFC) to identify, enumerate, and characterize EVs as well as the eDNA-delivering EV compartment in the biofilm and planktonic phenotypes of H.pylori ATCC 43629 and L. reuteri DSM 17938. Biofilm formation was demonstrated and analyzed by fluorescence microscopy, using a classical live/dead staining protocol. The enumeration of EVs and the detection of eDNA-associated EVs were performed by PFC, analyzing both whole samples (cells plus vesicles) and EVs isolated by ultracentrifugation confirm EVs isolated by ultracentrifugation. PFC analysis was performed relying on a known-size beaded system and a mix of three different fluorescent tracers. In detail, the whole EV compartment was stained by a lipophilic cationic dye (LCD), which was combined to PKH26 and PicoGreen that selectively stain lipids and DNA, respectively. Fluorescence microscopy results displayed that both H. pylori and L. reuteri produced well-structured biofilms. PFC data highlighted that, in both detected bacterial species, biofilms produced higher EVs counts when paralleled to the related planktonic phenotypes. Furthermore, the staining with PicoGreen showed that most of the generated vesicles were associated with eDNA. These data suggest that the use of PFC, set according to the parameters here described, allows for the study of the production of eDNA-associated EVs in different microbial species in the same or several phases of growth, thus opening new perspectives in the study of microbial derived EVs in clinical samples.
Assuntos
Membrana Celular/química , DNA Bacteriano/análise , Vesículas Extracelulares/química , Citometria de Fluxo , Helicobacter pylori/química , Limosilactobacillus reuteri/químicaRESUMO
Solid lipid nanoparticles carrying a chemotherapeutic payload (i.e., temozolomide, TMZ) were synthesized using ghee, a clarified butter commonly used in traditional medicine and food products. Ghee solid lipid nanoparticles (GSLN) were characterized through dynamic light scattering, scanning electron microscopy, and UV-visible spectrometry. Formulations were generated with varying ratios of surfactant to lipid, resulting in a maximum TMZ entrapment efficiency of Ë70%. Optimal formulations were found to have an average size and polydispersity of Ë220 nm and 0.340, respectively. Release kinetics revealed TMZ-loaded GSLN (TMZ@GSLN) retained 10% of its pay-load at 2 h with Ë53% released in 5 h. Metabolic activity on human umbilical vein endothelial cells (HUVEC) revealed GSLN treatment resulted in an increase in viability following 3 d while treatment of glioblastoma LN-229 cells with TMZ@GSLN resulted in a significant decrease. Evaluation of diffusion of TMZ across a reconstructed HUVEC monolayer demonstrated TMZ@GSLN resulted in a significantly higher diffusion of drug when compared to free TMZ. This data suggests GSLN pose a promising delivery vehicle for TMZ-based therapeutics. Collectively, this data demonstrates GSLN exhibit favorable drug carrier properties with anti-proliferative properties in glioblastoma cancer cells.
Assuntos
Portadores de Fármacos , Ghee , Nanopartículas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/química , Dacarbazina/farmacocinética , Dacarbazina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Células Endoteliais da Veia Umbilical Humana , Humanos , TemozolomidaRESUMO
Elastic and ultradeformable liposomes were synthesized and physicochemically characterized to make suitable topical formulations for delivering the anti-inflammatory and anticancer compound 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid. The average sizes of elastic and ultradeformable liposomes are below 300 nm, while the size distribution and Z-potential are below 0.3 and - 25 mV, respectively. The presence of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid does not affect the physicochemical parameters of nanovesicles. Elastic and ultradeformable liposomes show a zero order release kinetic and are stable at room temperature for a long time with or without 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid. The ultradeformable liposomes are more deformable than elastic liposomes. These differences may depend on sodium cholate derivatives making nanoformulations. The 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid-loaded elastic and ultradeformable liposomes can provide innovative nanotherapeutics-based natural compounds for the potential treatment of cutanous inflammation.
Assuntos
Antineoplásicos/administração & dosagem , Diterpenos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Propionatos/administração & dosagem , Rutaceae/química , Administração Tópica , Antineoplásicos/farmacologia , Diterpenos/farmacologia , Sistemas de Liberação de Medicamentos , Medicamentos de Ervas Chinesas/farmacocinética , Lipossomos , Propionatos/farmacologiaRESUMO
This paper reports the MEPS-HPLC-DAD method for the simultaneous determination of 12 azole drugs (bifonazole, butoconazole, clotrimazole, econazole, itraconazole, ketoconazole, miconazole, posaconazole, ravuconazole, terconazole, tioconazole and voriconazole) administered to treat different systemic and topical fungal infections, in biological samples. Azole drugs separation was performed in 36 min. The analytical method was validated in the ranges as follows: 0.02-5 µg mL-1 for ravuconazole; 0.2-5 µg mL-1 for terconazole; 0.05-5 µg mL-1 for the other compounds. Human plasma and urine were used as biological samples during the analysis, while benzyl-4-hydroxybenzoate was used as an internal standard. The precision (RSD%) and trueness (Bias%) values fulfill with International Guidelines requirements. To the best of our knowledge, this is the first HPLC-DAD procedure coupled to MEPS, which provides the simultaneous analysis of 12 azole drugs, available in the market, in human plasma and urine. Moreover, the method was successfully applied for the quantitative determination of two model drugs (itraconazole and miconazole) after oral administration in real samples.
Assuntos
Imidazóis/análise , Microextração em Fase Sólida , Triazóis/análise , Adsorção , Cromatografia Líquida de Alta Pressão , Estrutura MolecularRESUMO
The use of nanocarriers, which respond to different stimuli controlling their physicochemical properties and biological responsivness, shows a growing interest in pharmaceutical science. The stimuli are activated by targeting tissues and biological compartments, e.g., pH modification, temperature, redox condition, enzymatic activity, or can be physically applied, e.g., a magnetic field and ultrasound. pH modification represents the easiest method of passive targeting, which is actually used to accumulate nanocarriers in cells and tissues. The aim of this paper was to physicochemically characterize pH-sensitive niosomes using different experimental conditions and demonstrate the effect of surfactant composition on the supramolecular structure of niosomes. In this attempt, niosomes, made from commercial (Tween21) and synthetic surfactants (Tween20 derivatives), were physicochemically characterized by using different techniques, e.g., transmission electron microscopy, Raman spectroscopy, and small-angle X-ray scattering. The changes of niosome structure at different pHs depend on surfactants, which can affect the supramolecular structure of colloidal nanocarriers and their potential use both in vitro and in vivo. At pH 7.4, the shape and structure of niosomes have been maintained; however, niosomes show some differences in terms of bilayer thicknesses, water penetration, membrane coupling, and cholesterol dispersion. The acid pH (5.5) can increase the bilayer fluidity, and affect the cholesterol depletion. In fact, Tween21 niosomes form large vesicles with lower curvature radius at acid pH; while Tween20-derivative niosomes increase the intrachain mobility within a more interchain correlated membrane. These results demonstrate that the use of multiple physicochemical procedures provides more information about supramolecular structures of niosomes and improves the opportunity to deeply investigate the effect of stimuli responsiveness on the niosome structure.
Assuntos
Bicamadas Lipídicas/química , Lipossomos/química , Polissorbatos/química , Físico-Química , Colesterol/química , Concentração de Íons de Hidrogênio , Espalhamento a Baixo Ângulo , Análise Espectral Raman , Difração de Raios XRESUMO
We developed and validated an analytical method based on microextraction packed sorbent (MEPS) and high-performance liquid chromatography (HPLC) coupled to photodiode array (PDA) detector to simultaneously quantify multiple nonsteroidal anti-inflammatory drugs (NSAIDs) and fluoroquinolones (FLQs), which may provide as combination several adverse reactions in nephrology and neurology. The linearity range from LOQs (0.1 µg/mL) to 10 µg/mL, and LODs values were 0.03 µg/mL for both NSAIDs and FLQs. The validation was performed according to international guidelines and the accuracy was tested measuring the precision, intermediate precision and trueness. The drugs stability was tested under different storage conditions (+4 °C and -20 °C) and after three different cycles of freezing and thawing. The method can be a suitable tool to simultaneously detect a possible association of drugs in human biological samples and provide several potentialities for clinical applications, bioequivalence studies, pharmacodynamics and toxicodynamics of different pharmaceutical dosage forms showing NSAIDs and FLQs.
Assuntos
Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/urina , Fluoroquinolonas/sangue , Fluoroquinolonas/urina , Microextração em Fase Líquida , Anti-Inflamatórios não Esteroides/administração & dosagem , Cromatografia Líquida de Alta Pressão , Fluoroquinolonas/administração & dosagem , Voluntários Saudáveis , Humanos , Estrutura MolecularRESUMO
CONTEXT: Celastrol, a natural compound derived from the herb Tripterygium wilfordii, is known to have anticancer activity, but is not soluble in water. OBJECTIVE: Formation of celastrol liposomes, to avoid the use of toxic solubilising agents. MATERIALS AND METHODS: Two different formulations of PEGylated celastrol liposomes were fabricated. Liposomal characteristics and serum stability were determined using dynamic light scattering. Drug entrapment efficacy and drug release were measured spectrophotometrically. Cellular internalisation and anticancer activity was measured in prostate cancer cells. RESULTS: Liposomal celastrol displayed efficient serum stability, cellular internalisation and anticancer activity, comparable to that of the free drug reconstituted in dimethyl sulfoxide. DISCUSSION AND CONCLUSION: Liposomal celastrol can decrease the viability of prostate cancer cells, while eliminating the need for toxic solubilising agents.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Tripterygium/química , Triterpenos/administração & dosagem , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Lipossomos , Masculino , Triterpenos Pentacíclicos , Próstata/citologia , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/patologia , Triterpenos/químicaRESUMO
Bacterial infections pose a significant threat to human health and safety, necessitating the urgent resolution of the problem through the development and implementation of highly effective antibacterial agents. However, the emergence of multidrug-resistant bacteria has diminished the satisfactory effectiveness of antibacterial treatments. To overcome this obstacle, we developed effective antibacterial agents by chemical reduction for inhibiting bacterial proliferation and inducing membrane damage. Specifically, four different types of chitosan/Ag nanoparticle (CS-AgNPs-i) (i-1, 2, 3, 4) complexes were synthesized by varying the quantity of chitosan added during the synthesis process. We found that the amount of CS does not affect the morphology and size of CS-AgNPs-i, which remained at approximately 20 nm and all CS-AgNPs were mostly spherical. The zeta potential measurements indicated that the surface of CS-AgNPs carries a positive charge. Notably, elevating the chitosan concentration led to a more pronounced antibacterial impact, particularly evident in its interaction with the peptidoglycan layer on the bacterial surface. Our experimental results undeniably establish the potent antibacterial efficacy of CS-AgNPs against both Escherichia coli and Staphylococcus aureus. Employing live/dead bacterial staining, we reveal the marked capability of CS-AgNPs to effectively hinder bacterial proliferation. Furthermore, our experimental investigations revealed that CS-AgNPs possess broad-spectrum antimicrobial activity. The results of in vitro cytotoxicity experiments substantiated the high biocompatibility of CS-AgNPs with elevated chitosan loading. The study provides valuable insights into the development of nano-antibacterial agents that exhibit significant potential as a substitute to replace traditional antibiotics for medical applications.
Assuntos
Quitosana , Nanopartículas Metálicas , Humanos , Prata/farmacologia , Prata/química , Nanopartículas Metálicas/química , Quitosana/farmacologia , Quitosana/química , Antibacterianos/farmacologia , Antibacterianos/química , Staphylococcus aureus , Escherichia coli , Testes de Sensibilidade MicrobianaRESUMO
Nanoparticles (NPs) interact with biological fluids after being injected into the bloodstream. The interactions between NPs and plasma proteins at the nano-bio interface affect their biopharmaceutical properties and distribution in the organ and tissues due to protein corona (PrC) composition, and in turn, modification of the resulting targeting capability. Moreover, lipid and polymer NPs, at their interface, affect the composition of PrC and the relative adsorption and abundance of specific proteins. To investigate this latter aspect, we synthesized and characterized different liposomal formulations (LFs) with lipids and polymer-conjugated lipids at different molar ratios, having different sizes, size distributions and surface charges. The PrC composition of various designed LFs was evaluated ex vivo in human plasma by label-free quantitative proteomics. We also correlated the relative abundance of identified specific proteins in the coronas of the different LFs with their physicochemical properties (size, PDI, zeta potential). The evaluation of outputs from different bioinformatic tools discovered protein clusters allowing to highlight: (i) common as well as the unique species for the various formulations; (ii) correlation between each identified PrC and the physicochemical properties of LFs; (iii) some preferential binding determined by physicochemical properties of LFs; (iv) occurrence of formulation-specific protein patterns in PrC. Investigating specific clusters in PrC will help decode the multivalent roles of the protein pattern components in the drug delivery process, taking advantage of the bio-nanoscale recognition and identification for significant advances in nanomedicine.
RESUMO
PEGylation is currently used for the synthesis of stealth liposomes and to enhance the pharmacokinetic and biopharmaceutical properties of payloads. PEGylated dendron phospholipids can decrease the detachment of polyethylene glycol (PEG) from the liposomal surface owing to an increased hydrophobic anchoring effect on the phospholipid bilayer of liposomes and thus generating super stealth liposomes that are suitable for the systemic delivery of anticancer drugs. Herein, doxorubicin hydrochloride-loaded super stealth liposomes were studied for the treatment of breast cancer lung metastasis in an animal model. The results demonstrated that the super stealth liposomes had suitable physicochemical properties for in vivo administration and could significantly increase the efficacy of doxorubicin in breast cancer lung metastasis tumor-bearing mice compared to the free drug. The super stealth liposomes also increased doxorubicin accumulation inside the tumor tissue. The permanence of PEG on the surface of the super stealth liposomes favored the formation of a depot of therapeutic nanocarriers inside the tumor tissue by improving their permanence after stopping treatment. The doxorubicin-loaded super stealth liposomes increased the survival of the mouse tumor model. These promising results demonstrate that the doxorubicin-loaded super stealth liposomes could be an effective nanomedicine to treat metastatic breast cancer.
Assuntos
Neoplasias da Mama , Doxorrubicina , Lipossomos , Polietilenoglicóis , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Animais , Lipossomos/química , Polietilenoglicóis/química , Polietilenoglicóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Camundongos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Humanos , Linhagem Celular Tumoral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Camundongos Endogâmicos BALB C , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinéticaRESUMO
Photothermal therapy combined with chemotherapy has shown great promise in the treatment of cancer. In this synergistic system, a safe, stable, and efficient photothermal agent is desired. Herein, an effective photothermal agent, carbon quantum dots (CQDs), was initially synthesized and then rationally constructed a folic acid (FA)-targeted photothermal multifunctional nanoplatform by encapsulating CQDs and the anticancer drug doxorubicin (DOX) in the liposomes. Indocyanine green (ICG), a near infrared (NIR) photothermal agent, approved by the U.S. Food and Drug Administration, was embedded in the bilayer membrane to further enhance the photothermal effects and facilitate the rapid cleavage of liposomes for drug release. Triggered by the NIR laser, this engineered photothermal multifunctional nanoplatform, not only exhibited an excellent performance with the photothermal conversion efficiency of up to 47.14%, but also achieved controlled release of the payloads. In vitro, and in vivo experiments demonstrated that the photothermal multifunctional nanoplatform had excellent biocompatibility, enhanced tumor-specific targeting, stimuli-responsive drug release, effective cancer cell killing and tumor suppression through multi-modal synergistic therapy. The successful construction of this NIR light-triggered targeted photothermal multifunctional nanoplatform will provide a promising strategy for the design and development of synergistic chemo-photothermal combination therapy and improve the therapeutic efficacy of cancer treatment.
RESUMO
Deformable nanovesicles have a crucial role in topical drug delivery through the skin, due to their capability to pass intact the stratum corneum and epidermis (SCE) and significantly increase the efficacy and accumulation of payloads in the deeper layers of the skin. Namely, lipid-based ultradeformable nanovesicles are versatile and load bioactive molecules with different physicochemical properties. For this reason, this study aims to make oleic acid based nanovesicles (oleosomes) for the codelivery of icariin and sodium naproxen and increase their permeation through the skin. Oleosomes have suitable physicochemical properties and long-term stability for a potential dermal or transdermal application. The inclusion of oleic acid in the lipid bilayer increases 3-fold the deformable properties of oleosomes compared to conventional liposomes and significantly improves the percutaneous permeation of icariin and sodium naproxen through the human SCE membranes compared to hydroalcoholic solutions of both drugs. The tolerability studies on human volunteers demonstrate that oleosomes are safer and speed up the recovery of transepidermal water loss (TEWL) baselines compared to saline solution. These results highlight promising properties of icariin/sodium naproxen coloaded oleosomes for the treatment of skin disorders and suggest the potential future applications of these nanovesicles for further in vivo experiments.
RESUMO
Cerebrovascular impairment represents one of the main causes of death worldwide with a mortality rate of 5.5 million per year. The disability of 50% of surviving patients has high social impacts and costs in long period treatment for national healthcare systems. For these reasons, the efficacious clinical treatment of patients, with brain ischemic stroke, remains a medical need. To this aim, a liposome nanomedicine, with monosialic ganglioside type 1 (GM1), OX26 (an anti-transferrin receptor antibody), and CDP-choline (a neurotrophic drug) (CDP-choline/OX26Lip) was prepared. CDP-choline/OX26Lip were prepared by a freeze and thaw method and then extruded through polycarbonate filters, to have narrow size distributed liposomes of ~80 nm. CDP-choline/OX26Lip were stable in human serum, they had suitable pharmacokinetic properties, and 30.0 ± 4.2% of the injected drug was still present in the blood stream 12 h after its systemic injection. The post-ischemic therapeutic effect of CDP-choline/OX26Lip is higher than CDP-choline/Lip, thus showing a significantly high survival rate of the re-perfused post-ischemic rats, i.e. 96% and 78% after 8 days. The treatment with CDP-choline/OX26Lip significantly decreased the peroxidation rate of ~5-times compared to CDP-choline/Lip; and the resulting conjugated dienes, that was 13.9 ± 1.1 mmol/mg proteins for CDP-choline/Lip and 3.1 ± 0.8 for CDP-choline/OX26Lip. OX26 increased the accumulation of GM1-liposomes in the brain tissues and thus the efficacious of CDP-choline. Therefore, this nanomedicine may represent a strategy for the reassessment of CDP-choline to treat post-ischemic events caused by brain stroke, and respond to a significant clinical need.