Remote navigation and targeted delivery of biologically active compounds is one of the current challenges in the development of drug delivery systems. Modern methods of micro- and nanofabrication give us new opportunities to produce particles and capsules bearing cargo to deploy and possess magnetic properties to be externally navigated. In this work we explore multilayer composite magnetic microcapsules as targeted delivery systems in vitro and in vivo studies under natural conditions of living organism. Herein, we demonstrate magnetic addressing of fluorescent composite microcapsules with embedded magnetite nanoparticles in blood flow environment. First, the visualization and capture of the capsules at the defined blood flow by the magnetic field are shown in vitro in an artificial glass capillary employing a wide-field fluorescence microscope. Afterward, the capsules are visualized and successfully trapped in vivo into externally exposed rat mesentery microvessels. Histological analysis shows that capsules infiltrate small mesenteric vessels whereas large vessels preserve the blood microcirculation. The effect of the magnetic field on capsule preferential localization in bifurcation areas of vasculature, including capsule retention at the site once external magnet is switched off is discussed. The research outcome demonstrates that microcapsules can be effectively addressed in a blood flow, which makes them a promising delivery system with remote navigation by the magnetic field.
A new application of the photodynamic treatment (PDT) is presented for the opening of blood-brain barrier (BBB) and the brain clearing activation that is associated with it, including the use of gold nanoparticles as emerging photosensitizer carriers in PDT. The obtained results clearly demonstrate 2 pathways for the brain clearing: (1) using PDT-opening of BBB and intravenous injection of FITC-dextran we showed a clearance of this tracer via the meningeal lymphatic system in the subdural space; (2) using optical coherence tomography and intraparenchymal injection of gold nanorods, we observed their clearance through the exit gate of cerebral spinal fluid from the brain into the deep cervical lymph node, where the gold nanorods were accumulated. These data contribute to a better understanding of the cerebrovascular effects of PDT and shed light on mechanisms, underlying brain clearing after PDT-related opening of BBB, including clearance from nanoparticles as drug carriers.
Photodynamic treatment (PDT) causes a significant increase in the permeability of the blood-brain barrier (BBB) in healthy mice. Using different doses of laser radiation (635 nm, 10-40 J/cm) and photosensitizer (5-aminolevulinic acid - 5-ALA, 20 and 80 mg/kg, i.v.), we found that the optimal PDT for the reversible opening of the BBB is 15 J/cm and 5-ALA, 20 mg/kg, exhibiting brain tissues recovery 3 days after PDT. Further increases in the laser radiation or 5-ALA doses have no amplifying effect on the BBB permeability, but are associated with severe damage of brain tissues. These results can be an informative platform for further studies of new strategies in brain drug delivery and for better understanding of mechanisms underlying cerebrovascular effects of PDT-related fluorescence guided resection of brain tumor.
Lactoferrin (Lf) has considerable potential as a functional ingredient in food, cosmetic and pharmaceutical applications. However, the bioavailability of Lf is limited as it is susceptible to digestive enzymes in gastrointestinal tract. The shells comprising alternate layers of bovine serum albumin (BSA) and tannic acid (TA) were tested as Lf encapsulation system for oral administration. Lf absorption by freshly prepared porous 3 μm CaCO3 particles followed by Layer-by-Layer assembly of the BSA-TA shells and dissolution of the CaCO3 cores was suggested as the most efficient and harmless Lf loading method. The microcapsules showed high stability in gastric conditions and effectively protected encapsulated proteins from digestion. Protective efficiency was found to be 76 ± 6% and 85 ± 2%, for (BSA-TA)4 and (BSA-TA)8 shells, respectively. The transit of Lf along the gastrointestinal tract (GIT) of mice was followed in vivo and ex vivo using NIR luminescence. We have demonstrated that microcapsules released Lf in small intestine allowing 6.5 times higher concentration than in control group dosed with the same amount of free Lf. Significant amounts of Lf released from microcapsules were then absorbed into bloodstream and accumulated in liver. Suggested encapsulation system has a great potential for functional foods providing lactoferrin.
paper presents the synthesis of highly biocompatible and biodegradable
poly(lactide-co-glycolide) (PLGA) microchamber arrays
sensitive to low-intensity therapeutic ultrasound (1 MHz, 1–2
W, 1 min). A reliable method was elaborated that allowed the microchambers
to be uniformly filled with epinephrine hydrochloride (EH), with the
possibility of varying the cargo amount. The maximum load of EH was
4.5 μg per array of 5 mm × 5 mm (about 24 pg of EH per
single microchamber). A gradual, spontaneous drug release was observed
to start on the first day, which is especially important in the treatment
of acute patients. Ultrasound triggered a sudden substantial release
of EH from the films. In vivo real-time studies using a laser speckle
contrast imaging system demonstrated changes in the hemodynamic parameters
as a consequence of EH release under ultrasound exposure. We recorded
a decrease in blood flow as a vascular response to EH release from
a PLGA microchamber array implanted subcutaneously in a mouse. This
response was immediate and delayed (1 and 2 days after the implantation
of the array). The PLGA microchamber array is a new, promising drug
depot implantable system that is sensitive to external stimuli.
Although new drug delivery systems have been intensely developed in the past decade, no significant increase in the efficiency of drug delivery by nanostructure carriers has been achieved. The reasons are the lack of information about acute toxicity, the influence of the submicron size of the carrier and difficulties with the study of biodistribution in vivo. Here we propose, for the first time in vivo, new nanocomposite submicron carriers made of bovine serum albumin (BSA) and tannic acid (TA) and containing magnetite nanoparticles with sufficient content for navigation in a magnetic field gradient on mice. We examined the efficacy of these submicron carriers as a delivery vehicle in combination with magnetite nanoparticles which were systemically administered intravenously. In addition, the systemic toxicity of this carrier for intravenous administration was explicitly studied. The results showed that (BSA/TA) carriers in the given doses were hemocompatible and didn’t cause any adverse effect on the respiratory system, kidney or liver functions. A combination of gradient-magnetic-field controllable biodistribution of submicron carriers with fluorescence tomography/MRI imaging in vivo provides a new opportunity to improve drug delivery efficiency.
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