RESUMO
In recent years, the scientific community has tried to address the treatment of complex diseases such as cancer in a more appropriate and promising way. Regarding this and benefiting from the unique optical properties of gold nanoprisms (AuNPRs), the physicochemical properties of thermosensitive liposomes (TSLs), and the tunable drug encapsulation and release properties of silica nanoparticles (BioSi@NPs), this study has developed two nanoformulations. These nanoformulations have the potential to integrate chemotherapy and photothermal therapy within a single entity. Once their components were synthesized and characterized separately, two strategies were taken in order to develop these multifunctional nanoformulations: (1) covalent binding of AuNPRs to TSLs and (2) co-encapsulation of both components within BioSi@NPs, without modifying the optical and physicochemical properties of AuNPRs and TSLs. Finally, the suitability of both nanoformulations to carry and release hydrophilic drugs when triggered by a 1064 nm NIR laser has been explored by using the fluorescent probe 5(6)-carboxyfluorescein (CF) as a hydrophilic drug model. Different laser power and time of exposure were also tested evidencing that hydrophilic drugs were only released from TSLs in the presence of AuNPRs and that the drug release profile was dependent on the type of nanoformulation and irradiation conditions used. In conclusion, these multifunctional nanoformulations exhibit promising potential for controlled drug delivery in combined chemotherapy and phototherapy, with the capability to precisely control the release kinetics based on specific therapeutic needs.
RESUMO
Poly(methyl vinyl ether-alt-maleic anhydride) (PMVEMA) of 119 and 139 molecular weights (P119 and P139, respectively) were electrospun to evaluate the resulting fibers as a topical delivery vehicle for (L-)menthol. Thus, electrospinning parameters were optimized for the production of uniform bead-free fibers from 12% w/w PMVEMA (±2.3% w/w menthol) solutions, and their morphology and size were characterized by field emission scanning electron microscopy (FESEM). The fibers of P119 (F119s) and P139 (F139s) showed average diameter sizes of approximately 534 and 664 nm, respectively, when unloaded, and 837 and 1369 nm when loaded with menthol. The morphology of all types of fibers was cylindrical except for F139s, which mostly displayed a double-ribbon-like shape. Gas chromatography-mass spectrometry (GC-MS) analysis determined that not only was the menthol encapsulation efficiency higher in F139s (92% versus 68% in F119s) but also that its stability over time was higher, given that in contrast with F119s, no significant losses in encapsulated menthol were detected in the F139s after 10 days post-production. Finally, in vitro biological assays showed no significant induction of cytotoxicity for any of the experimental fibers or in the full functionality of the encapsulated menthol, as it achieved equivalent free-menthol levels of activation of its specific receptor, the (human) transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8).
RESUMO
In this study, we employed the copolymer poly(methyl vinyl ether-alt-maleic monoethyl ester) (PMVEMA-Es) and three fluorene-based cationic conjugated polyelectrolytes to develop fluorescent nanoparticles with emission in the blue, green and red spectral regions. The size, Zeta Potential, polydispersity, morphology, time-stability and fluorescent properties of these nanoparticles were characterized, as well as the nature of the interaction between both PMVEMA-Es and fluorescent polyelectrolytes. Because PMVEMA-Es contains a carboxylic acid group in its structure, the effects of pH and ionic strength on the nanoparticles were also evaluated, finding that the size is responsive to pH and ionic strength, largely swelling at physiological pH and returning to their initial size at acidic pHs. Thus, the developed fluorescent nanoparticles can be categorized as pH-sensitive fluorescent nanogels, since they possess the properties of both pH-responsive hydrogels and nanoparticulate systems. Doxorubicin (DOX) was used as a model drug to show the capacity of the blue-emitting nanogels to hold drugs in acidic media and release them at physiological pH, from changes in the fluorescence properties of both nanoparticles and DOX. In addition, preliminary studies by super-resolution confocal microscopy were performed, regarding their potential use as image probes.
Assuntos
Portadores de Fármacos/síntese química , Fluorenos/química , Anidridos Maleicos/química , Polivinil/química , Antibióticos Antineoplásicos/farmacologia , Cor , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Ésteres/química , Transferência Ressonante de Energia de Fluorescência/métodos , Humanos , Concentração de Íons de Hidrogênio , Éteres Metílicos/química , Nanogéis/química , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Compostos de Vinila/químicaRESUMO
The interaction of temozolomide (TMZ) (the main chemotherapeutic agent for brain tumors) with blood components has not been studied at the molecular level to date, even though such information is essential in the design of dosage forms for optimal therapy. This work explores the binding of TMZ to human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), as well as to blood cell-mimicking membrane systems. Absorption and fluorescence experiments with model membranes indicate that TMZ does not penetrate into the lipid bilayer, but binds to the membrane surface with very low affinity. Fluorescence experiments performed with the plasma proteins suggest that in human plasma, most of the bound TMZ is attached to HSA rather than to AGP. This interaction is moderate and likely mediated by hydrogen-bonding and hydrophobic forces, which increase the hydrolytic stability of the drug. These experiments are supported by docking and molecular dynamics simulations, which reveal that TMZ is mainly inserted in the subdomain IIA of HSA, establishing π-stacking interactions with the tryptophan residue. Considering the overexpression of albumin receptors in tumor cells, our results propose that part of the administered TMZ may reach its target bound to plasma albumin and suggest that HSA-based nanocarriers are suitable candidates for designing biomimetic delivery systems that selectively transport TMZ to tumor cells.
Assuntos
Glicoproteínas/metabolismo , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Temozolomida/farmacologia , Sítios de Ligação , Materiais Biomiméticos/química , Materiais Biomiméticos/metabolismo , Dicroísmo Circular , Glicoproteínas/química , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Temozolomida/químicaRESUMO
Multifunctional nanoparticles have been attracting growing attention in recent years because of their capability to integrate materials with different features in one entity, which leads them to be considered as the next generation of nanomedicine. In this work, we have taken advantage of the interesting properties of conjugated polyelectrolytes to develop multicolor fluorescent nanoparticles with integrating imaging and therapeutic functionalities. With this end, thermosensitive liposomes were coated with three recently synthesized polyfluorenes: copoly-((9,9-bis(6'-N,N,N-trimethylammonium)hexyl)-2,7-(fluorene)-alt-1,4-(phenylene)) bromide (HTMA-PFP), copoly-((9,9-bis(6'-N,N,N-trimethylammonium)hexyl)-2,7-(fluorene)-alt-4,7-(2- (phenyl)benzo(d) (1,2,3) triazole)) bromide (HTMA-PFBT) and copoly-((9,9-bis(6'-N,N,N- trimethylammonium)hexyl)-2,7-(fluorene)-alt-1,4-(naphtho(2,3c)-1,2,5-thiadiazole)) bromide (HTMA-PFNT), in order to obtain blue, green and red fluorescent drug carriers, respectively. The stability, size and morphology of the nanoparticles, as well as their thermotropic behavior and photophysical properties, have been characterized by Dynamic Light Scattering (DLS), Zeta Potential, transmission electron microscope (TEM) analysis and fluorescence spectroscopy. In addition, the suitability of the nanostructures to carry and release their contents when triggered by hyperthermia has been explored by using carboxyfluorescein as a hydrophilic drug model. Finally, preliminary experiments with mammalian cells demonstrate the capability of the nanoparticles to mark and visualize cells with different colors, evidencing their potential use for imaging and therapeutic applications.