The aim of our study was to develop a novel method for the preparation of polymeric core-shell nanoparticles loaded with various actives for biomedical applications. Poly(caprolactone) (PCL), poly(lactic acid) (PLA) and poly(lactide-co-glycolide) (PLGA) nanoparticles were prepared using the spontaneous emulsification solvent evaporation (SESE) method. The model active substance, Coumarin-6, was encapsulated into formed polymeric nanoparticles, then they were modified/functionalized by multilayer shells’ formation. Three types of multilayered shells were formed: two types of polyelectrolyte shell composed of biocompatible and biodegradable polyelectrolytes poly-L-lysine hydrobromide (PLL), fluorescently-labeled poly-L-lysine (PLL-ROD), poly-L-glutamic acid sodium salt (PGA) and pegylated-PGA (PGA-g-PEG), and hybrid shell composed of PLL, PGA, and SPIONs (superparamagnetic iron oxide nanoparticles) were used. Multilayer shells were constructed by the saturation technique of the layer-by-layer (LbL) method. Properties of our polymeric core-shell nanoparticle were optimized for bioimaging, passive and magnetic targeting.
BackgroundThe functionalization of a nanoparticle surface with PEG (polyethylene glycol) is an approach most often used for extending nanomaterial circulation time, enhancing its delivery and retention in the target tissues, and decreasing systemic toxicity of nanocarriers and their cargos. However, because PEGylated nanomedicines were reported to induce immune response including production of anti-PEG antibodies, activation of the complement system as well as hypersensitivity reactions, hydrophilic polymers other than PEG are gaining interest as its replacement in nanomaterial functionalization. Here, we present the results of in vivo evaluation of polyelectrolyte nanocapsules with biodegradable, polyelectrolyte multilayer shells consisting of poly-l-lysine (PLL) and poly-l-glutamic (PGA) acid as a potential drug delivery system. We compared the effects of nanocapsules functionalized with two different “stealth” polymers as the external layer of tested nanocapsules was composed of PGA (PGA-terminated nanocapsules, NC-PGA) or the copolymer of poly-l-lysine and polyethylene glycol (PEG-terminated nanocapsules, NC-PEG).MethodsNanocapsules pharmacokinetics, biodistribution and routes of eliminations were analysed postmortem by fluorescence intensity measurement. Toxicity of intravenously injected nanocapsules was evaluated with analyses of blood morphology and biochemistry and by histological tissue analysis. DNA integrity was determined by comet assay, cytokine profiling was performed using flow cytometer and detection of antibodies specific to PEG was performed by ELISA assay.ResultsWe found that NC-PGA and NC-PEG had similar pharmacokinetic and biodistribution profiles and both were eliminated by hepatobiliary and renal clearance. Biochemical and histopathological evaluation of long-term toxicity performed after a single as well as repeated intravenous injections of nanomaterials demonstrated that neither NC-PGA nor NC-PEG had any acute or chronic hemato-, hepato- or nephrotoxic effects. In contrast to NC-PGA, repeated administration of NC-PEG resulted in prolonged increased serum levels of a number of cytokines.ConclusionOur results indicate that NC-PEG may cause undesirable activation of the immune system. Therefore, PGA compares favorably with PEG in equipping nanomaterials with stealth properties. Our research points to the importance of a thorough assessment of the potential influence of nanomaterials on the immune system.
The
aim of our study was to develop a novel method for nanocarriers’
preparation as a fluorine magnetic resonance imaging (
19
F MRI)-detectable drug delivery system. The novelty of the proposed
approach is based on the application of fluorinated polyelectrolyte
Nafion as a contrast agent since typical MRI contrast agents are based
on paramagnetic gadolinium or ferro/superparamagnetic iron oxide compounds.
An advantage of using an
19
F-based tracer comes from the
fact that the
19
F image is detected at a different resonance
frequency than the
1
H image. In addition, the close to
zero natural concentration of
19
F nuclei in the human body
makes fluorine atoms a promising MRI marker without any natural background
signal. That creates the opportunity to localize and identify only
exogenous fluorinated compounds with 100% specificity. The nanocarriers
were formed by the deposition of polyelectrolytes on nanoemulsion
droplets via the layer-by-layer technique with the saturation approach.
The polyelectrolyte multilayer shell was composed of Nafion, the fluorinated
ionic polymer used for labeling by
19
F nuclei, and poly-
l
-lysine (PLL). The surface of such prepared nanocarriers was
further pegylated by adsorption of pegylated polyanion, poly-
l
-glutamic acid (PGA). The
19
F MRI-detectable hydrophobic
nanocarriers with an average size of 170 nm and a sufficient signal-to-noise
ratio have been developed and optimized to be used for passive tumor
targeting and drug delivery.
Clozapine (CLO), an atypical antipsychotic used in the clinic for treatment of schizophrenia, has a well-known efficacy, but its general use in clinical practice is limited because of the risk of serious side effects. Therefore, in the present work, we focused on the encapsulation of CLO into polymeric polycaprolactone nanoparticles (PCL NPs) and studies of interactions of this nanoformulation with model cells. Two types of clozapine PCL NPs (CLO-PCL NPs), pegylated and non-pegylated, were obtained by nanoemulsion templating method. The complex interactions of these NPs with three model cell lines (HEK 293, human embryonic kidney cell line; RAW 264.7, murine macrophage cell line; hCMEC/D3, model of blood-brain barrier, BBB) were studied. Cell viability, cellular uptake of NPs, NO release, expression of proinflammatory agents and transcytosis experiments were performed. Pegylated CLO-PCL NPs showed better results in the tests performed in the present study, in comparison to non-pegylated ones: they are not toxic to model cells; pegylated outer surface protected from their fast uptake by macrophages; they were not immunogenic; transcytosis experiments pointed to their ability to cross a model BBB. The results obtained in the present study indicate that pegylated CLO-PCL NPs are promising carrier for antipsychotic drugs directed to cross BBB. The experiments were conducted using only in vitro models but they provide valuable data in the field of nanotechnology which can be used in novel molecular pharmacology.
Cancer is one of the most important health problems of our population, and one of the common anticancer treatments is chemotherapy. The disadvantages of chemotherapy are related to the drug’s toxic effects, which act on cancer cells and the healthy part of the body. The solution of the problem is drug encapsulation and drug targeting. The present study aimed to develop a novel method of preparing multifunctional 5-Fluorouracil (5-FU) nanocarriers and their in vitro characterization. 5-FU polyaminoacid-based core@shell nanocarriers were formed by encapsulation drug-loaded nanocores with polyaminoacids multilayer shell via layer-by-layer method. The size of prepared nanocarriers ranged between 80–200 nm. Biocompatibility of our nanocarriers as well as activity of the encapsulated drug were confirmed by MTT tests. Moreover, the ability to the real-time observation of developed nanocarriers and drug accumulation inside the target was confirmed by fluorine magnetic resonance imaging (19F-MRI).
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