Lipid-core nanocapsules (LNC) are formed by an organogel surrounded by poly(epsilon-caprolactone) and stabilized by polysorbate 80. LNCs increase the concentration of drugs in the brain after oral or ...intravenous administration. We proposed to determine whether the drug is released from the LNC to cross the blood brain barrier (BBB) or the drug-loaded LNCs can cross the BBB to release the drug. We synthesized a Rhodamine B-polymer conjugate to prepare a fluorescent-labeled LNC formulation, and intravital microscopy was used to determine the ability of the LNCs to cross the brain barrier using different administration routes in C57BI/6 mice. A glioblastoma model was used to determine the impact of the LNC as a shuttle for treatment. After pial vessel exposure, intense fluorescence was detected inside the vessels 10 min after intravenous or 20 min after intraperitoneal injections of fluorescent-labeled LNC. The fluorescence was observed in the perivascular tissue after 30 and 60 min, respectively. Increased tissue fluorescence was detected 240 min after oral administration. The integrity of the barrier was determined during the experiments. Normal leukocyte and platelet adhesion to the vessel wall indicated that Rhodamine B-labeled LNC did not cause pial vessel alterations. After intravenous or oral administration, Rhodamine B-labeled LNC-containing co-encapsulated indomethacin and indomethacin ethyl ester exhibited similar behavior in pial vessels, being more efficient in the treatment of mice with glioblastoma than indomethacin in solution. Therefore, we demonstrated that LNCs act as drug shuttles through the BBB, delivering drugs in brain tissue with high efficiency and reducing glioblastoma after intravenous or oral administration.
Nanotechnology in pharmaceutics has the potential to improve drug efficacy by influencing drug distribution in tissues. Nanocarriers have been developed as drug delivery systems to be administered by ...different biological routes. To ensure the nanotechnological properties, pre-formulation studies are especially critical in determining the influence of the process parameters on the size and polydispersity of particles. Thus, the objective of this work was to establish the mechanism of self-assembly, by determining the influence of the critical aggregation concentration of the materials in the organic phase on the final average particle size and polydispersity of polymeric lipid-core nanocapsules obtained by interfacial deposition of polymer. Measurements of the surface tension and viscosity of the organic and aqueous phases were correlated with the particle size and the concentration of raw materials. We demonstrated that the lipid-core nanocapsules are formed on the nanoscopic scale as unimodal distributions, if the aggregation state of raw materials in the organic phase tends to infinite dilution. The strategy for controlling the particle size distribution is a valuable tool in producing lipid-core nanocapsule formulations with different loading capacities intended for therapeutics.
Model of the mechanism of the self-assembly of lipid-core nanocapsules.
The quantitative relative stability of the submicrometric particles was assessed by determining the values of an enthalpic term (A′ΔH°) involved in the agglomeration process. The higher are the A′ΔH° ...values, the lower is the physical stability of the formulations.
•Stability rank of liquid colloidal dispersions was assessed by a new approach.•The VTMLS approach was used to compare the physical stability of nanocapsules.•The agglomeration process was quantitatively estimated.•The reversible agglomeration was resolved from the irreversible aggregation.•The new approach is a non-destructive method.
In this work, we propose the variable temperature multiple light scattering (VTMLS) as a novel method to determine an enthalpic term of the agglomeration process of submicrometric colloidal systems such as polymeric nanocapsules (NCs) and lipid-core nanocapsules (LNCs). Four different aqueous suspensions were prepared using a linear polyester, triacylglycerol, octyl methoxycinnamate and polysorbate 80 in the presence (individually and combined) or absence of the surfactants: phosphatidylcholine and sorbitan monostearate. Backscattering (BS) signals were monitored applying a temperature gradient from 23°C to 56°C (increase of 3°C at 5-min intervals). Considering the Indefinite Self-Association Model, a relation between the BS signal and the equilibrium constant of the agglomeration process was established. The values of A′ΔH°, obtained by VTMLS for each colloidal aqueous suspension, were predictive of the system physical stability when compared to long-term stability studies. The use of phosphatidylcholine decreased the physical stability of either LNC or NC. The approach enabled to differentiate the first step of the physical destabilization, which corresponds to a reversible surfactant desorption. In conclusion, the new non-destructive analysis can be used to quickly compare the relative physical stability of colloidal systems representing a valuable tool to develop new formulations of dispersed systems.
Melanoma is a severe metastatic skin cancer with poor prognosis and no effective treatment. Therefore, novel therapeutic approaches using nanotechnology have been proposed to improve therapeutic ...effectiveness. Lipid-core nanocapsules (LNCs), prepared with poly(ε-caprolactone), capric/caprylic triglyceride, and sorbitan monostearate and stabilized by polysorbate 80, are efficient as drug delivery systems. Here, we investigated the effects of acetyleugenol-loaded LNC (AcE-LNC) on human SK-Mel-28 melanoma cells and its therapeutic efficacies on melanoma induced by B16F10 in C57B6 mice. LNC and AcE-LNC had z-average diameters and zeta potential close to 210 nm and -10.0 mV, respectively. CytoViva(®) microscopy images showed that LNC and AcE-LNC penetrated into SK-Mel-28 cells, and remained in the cytoplasm. AcE-LNC in vitro treatment (18-90×10(9) particles/mL; 1 hour) induced late apoptosis and necrosis; LNC and AcE-LNC (3-18×10(9) particles/mL; 48 hours) treatments reduced cell proliferation and delayed the cell cycle. Elevated levels of nitric oxide were found in supernatant of LNC and AcE-LNC, which were not dependent on nitric oxide synthase expressions. Daily intraperitoneal or oral treatment (days 3-10 after tumor injection) with LNC or AcE-LNC (1×10(12) particles/day), but not with AcE (50 mg/kg/day, same dose as AcE-LNC), reduced the volume of the tumor; nevertheless, intraperitoneal treatment caused toxicity. Oral LNC treatment was more efficient than AcE-LNC treatment. Moreover, oral treatment with nonencapsulated capric/caprylic triglyceride did not inhibit tumor development, implying that nanocapsule supramolecular structure is important to the therapeutic effects. Together, data herein presented highlight the relevance of the supramolecular structure of LNCs to toxicity on SK-Mel-28 cells and to the therapeutic efficacy on melanoma development in mice, conferring novel therapeutic mechanisms to LNC further than a drug delivery system.
Biodegradable nanoparticles have been widely studied as drug carriers in order to increase drug solubility in aqueous media, modify biodistribution, target tissues and organs or control the drug ...release. Those nanoparticles are, in general, produced as liquid formulations to act as final dosage forms or as intermediate for solid or semi-solid products. Considering the dermatological applications, as medicines or cosmetics, different nanoparticles have been proposed to control the skin penetration of encapsulated lipophilic substances. A point rarely investigated is the penetration of the carrier itself into the skin, independent of the drug penetration profile. In this way, our objective was to correlate the flexibility of the biodegradable nanoparticles to the depth of their skin penetration. To minimize the impact of the chemical composition, the surface chemistry or the shape and size distribution on the results, two kinds of polymeric nanocapsules presenting diverse mechanical properties were produced using almost the same materials and their concentrations. The nanocapsules (NC) and the lipid-core nanocapsules (LNC) were prepared by solvent displacement using Rhodamine B-labeled polymer, oil and surfactants. The only difference in composition between them is the presence of sorbitan monostearate in the latter which was used to have a more rigid nanoparticle as previously reported. NC and LNC had, respectively, mean diameters of 178 and 180 nm and zeta potentials of -11 and -9 mV. The in vitro skin penetration was carried out using Franz cells (pig skin as membrane). Skin samples were observed by confocal laser scanning microscopy (CLSM). NC reached the dermis, while LNC was retained at the outermost layers of the skin. The result was in accordance with the flexibility previously determined for those nanocapsules, in a way that higher flexibility gives deeper penetration. NC can reach the dermis and LNC can act as reservoir systems at the epidermis.
Poly(hydroxybutyrate-
co-hydroxyvalerate) (PHBHV) nanospheres and oily nanocapsules were prepared by emulsification–diffusion technique. Controlled particle sizes were obtained employing binary ...mixtures of solvents (chloroform:ethanol) in the organic phase. Ethanol was chosen because of its dipole–dipole interaction with chloroform and its hydrogen bond with water. The smallest particles (from 253 to 493
nm) were obtained using a mixture of solvents composed of 70% ethanol and 30% chloroform (v/v) in the organic phase, while the largest particles (from 896 to 1568
nm) were obtained using chloroform exclusively. Independently of the organic phase composition, the nanoparticles showed unimodal distributions. Optical microscopy showed that the size of the primary emulsion droplets of the nanosphere formulations decreased with increasing ethanol concentrations in the organic phase. A simple empirical equation was developed correlating the nanoparticle diameters with the surface tension gradient coefficient multiplied by the ethanol molar concentration in the organic phase. The strategy showed that the control of the nanoparticle diameters, using emulsification–diffusion technique, could be achieved by adjusting the surface tension of the organic phase.
In this study, a novel method to determine the cloud point temperature variation in aqueous solutions of thermoresponsive homo- and copolymers was developed. Poly(N-vinylcaprolactam) (PVCL) and ...triblock copolymers of poly(t-butyl acrylate-co-acrylic acid)-b-poly(N-vinylcaprolactam)-b-(t-butyl acrylate-co-acrylic acid) (P(tBA-co-AA)-b-PVCL-b-P(tBA-co-AA) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and used as models. The incorporation of AA units (hydrophilic segments) into the polymeric chain of PVCL influenced the phase transition, increasing the cloud point temperature of the final copolymer. The cloud point temperatures of the PVCL and the triblock copolymer P(tBA-co-AA)-b-PVCL-b-P(tBA-co-AA) were determined by measuring the transmittance of aqueous solutions of the polymers in a Turbiscan Lab instrument in the range of 29 to 40 C. This is the first study in which Turbiscan Lab is used to determine the cloud point temperature.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A strategy was developed to estimate the intrinsic dialysis flux of poorly water soluble substance in aqueous solution allowing the evaluation of the effect of nanoencapsulation on the release rate ...of a lipophilic substance.
•Strategy to estimate intrinsic dialysis flux (J0) of lipophilic substance in water.•Correlates the apparent flux against hydroethanolic mediums with the ethanol ratio.•Comparison of the J0 with the release flux from LNCs without further interferences.•Evaluation of the nanoencapsulation effect on the lipophilic substance release rate.
In studies on the release of drugs, antioxidants, vitamins, etc., from submicrometric particles, the released portion cannot be separated from that which remains entrapped in the carrier using conventional filtration methods due to the membrane cut-off. Thus, other methods, for example, ultrafiltration–centrifugation or dialysis with dialysis bags, which enable this separation are used. However, as the substances vehiculated in colloidal aqueous solutions are usually poorly water soluble substances, it is not easy to obtain their intrinsic flux (J0) value in aqueous solution. In this context, our objective was to develop a strategy to obtain the J0 value of a poorly water soluble substance dialysate from an aqueous solution aiming to compare it with its apparent flux (Japp) from an aqueous colloidal system allowing the evaluation of the effect of nanoencapsulation on the release rate of a lipophilic substance. Different hydroethanolic solutions of a poorly water soluble substance (benzophenone-3 (BZ3)) were dialyzed against hydroethanolic media using dynamic dialysis with bags. The Japp value of BZ3 in each system was plotted as a function of the proportion of organic solvent and the exponential mathematical equation of this relation was used to calculate the J0 value of the substance in aqueous solution. BZ3-loaded lipid-core nanocapsule suspensions (BZ3-LNC) were used as a model for colloidal nanocarriers. The Japp value obtained for the release from the BZ3-LNC suspension was around 14-fold lower than the J0 value, indicating that the encapsulation of BZ3 into the LNC system was able to slows its diffusion. The strategy developed allows the use of the J0 values of poorly water soluble substances in aqueous solutions to verify whether the nanoencapsulation can prolong, for example, the substance delivery on the biological environment.
In this work we present a simple model for the kinetics of agglomeration and aggregation of colloidal particles. We consider that particles agglomerate rapidly and endothermically forming oligomers. ...These oligomers can, in turn, aggregate irreversibly, in a process that leads to the destabilization of the colloidal system. As these two processes have very different relative energy activations, they occur in different time-scales: the first step is faster and reaches a state of quasi‑equilibrium. Because of this, the enthalpy change during the agglomeration can be experimentally determined through the variable temperature multiple light scattering (VTMLS) method. Interestingly, this value is related to the relative kinetic stability of the system and can be used to evaluate the stability of new colloidal compositions. Our results are in qualitative agreement with experimental data of low concentration colloidal dispersions consisted of polymer particles and/or surfactant-coated particles.
Vegetable oils might be alternatives to mineral or synthetic oils used in nanostructured systems for cutaneous application, due to their advantages with regard to skin care and protection. In this ...study, we propose the use of vegetable oils (Brazil nut, sunflower seed, olive, rose hip, grape seed and carrot oils) as oily core of Eudragit RS100® nanocapsules and determine their influence on the physicochemical properties of those nanoparticles, in comparison with nanocapsules with capric/caprylic triglycerides as oily core. The formulations containing vegetable oils as core presented pH values suitable for topical application, average diameter close to 280 nm (SPAN around 2.5) and zeta potential close to +7 mV, due to the cationic properties of the polymer. Their viscosities were not affected by the type of oil used as core. By means of multiple light scattering, a reversible particle creaming phenomenon was observed for all the formulations. The nanocapsules prepared using Brazil nut, sunflower seed, olive, grape seed, rose-hip and carrot oils presented some distinct physicochemical properties when compared to nanocapsules obtained with capric/caprylic triglycerides: a higher size and SPAN value, a lower number of particles and a higher tendency to reversible creaming. Those findings are probably related to the lower density and higher viscosity of the vegetable oils.
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