Abstract:A new self-assembled formulation of methylprednisolone succinate (MPS) based on a carboxylated trifunctional block copolymer of ethylene oxide and propylene oxide (TBC-COOH) was developed. TBC-COOH and MPS associated spontaneously at increased concentrations in aqueous solutions to form almost monodisperse mixed micelles (TBC-COOH/MPS) with a hydrodynamic diameter of 19.6 nm, zeta potential of -27.8 mV and optimal weight ratio ∼1:6.3. Conditions for the effective formation of TBC-COOH/MPS were elucidated by co… Show more
“…Moreover, the area under the curve (AUC) of RBC-MPSS-CSNPs group was 861.85 ng·h/mL, which was significantly higher than that of the MPSS-CSNPs group (334.32 ng/ml·h) and the MPSS injection group (281.78 ng/ml·h). The half-life of MPSS was approximately 0.5 h; therefore, the drug was unmeasurable shortly after the administration of MPSS injection [ 43 , 44 ]. Fig.…”
Hyper-inflammation associated with cytokine storm syndrome causes high mortality in patients with COVID-19. Glucocorticoids, such as methylprednisolone sodium succinate (MPSS), effectively inhibit this inflammatory response. However, frequent and chronic administration of glucocorticoids at high doses leads to hormone dependence and serious side effects. The aim of the present study was to combine nanoparticles with erythrocytes for the targeted delivery of MPSS to the lungs. Chitosan nanoparticles loading MPSS (MPSS-CSNPs) were prepared and adsorbed on the surface of red blood cells (RBC-MPSS-CSNPs) by non-covalent interaction.
In vivo
pharmacokinetic study indicated that RBC-hitchhiking could significantly reduce the plasma concentration of the drug and prolong the circulation time. The mean residence time (MRT) and area under the curve (AUC) of the RBC-MPSS-CSNPs group were significantly higher than those of the MPSS-CSNPs group and the MPSS injection group. Moreover,
in vivo
imaging and tissue distribution indicated that RBC-hitchhiking facilitated the accumulation of nanoparticles loading fluorescein in the lung, preventing uptake of these nanoparticles by the liver. Furthermore, compared with the MPSS-CSNPs and MPSS treatment groups, treatment with RBC-MPSS-CSNPs considerably inhibited the production of inflammatory cytokines such as TNF-α and IL-6, and consequently attenuated lung injury induced by lipopolysaccharide in rats. Therefore, RBC-hitchhiking is a potentially effective strategy for the delivery of nanoparticles to the lungs for the treatment of acute lung injury and acute respiratory distress syndrome.
“…Moreover, the area under the curve (AUC) of RBC-MPSS-CSNPs group was 861.85 ng·h/mL, which was significantly higher than that of the MPSS-CSNPs group (334.32 ng/ml·h) and the MPSS injection group (281.78 ng/ml·h). The half-life of MPSS was approximately 0.5 h; therefore, the drug was unmeasurable shortly after the administration of MPSS injection [ 43 , 44 ]. Fig.…”
Hyper-inflammation associated with cytokine storm syndrome causes high mortality in patients with COVID-19. Glucocorticoids, such as methylprednisolone sodium succinate (MPSS), effectively inhibit this inflammatory response. However, frequent and chronic administration of glucocorticoids at high doses leads to hormone dependence and serious side effects. The aim of the present study was to combine nanoparticles with erythrocytes for the targeted delivery of MPSS to the lungs. Chitosan nanoparticles loading MPSS (MPSS-CSNPs) were prepared and adsorbed on the surface of red blood cells (RBC-MPSS-CSNPs) by non-covalent interaction.
In vivo
pharmacokinetic study indicated that RBC-hitchhiking could significantly reduce the plasma concentration of the drug and prolong the circulation time. The mean residence time (MRT) and area under the curve (AUC) of the RBC-MPSS-CSNPs group were significantly higher than those of the MPSS-CSNPs group and the MPSS injection group. Moreover,
in vivo
imaging and tissue distribution indicated that RBC-hitchhiking facilitated the accumulation of nanoparticles loading fluorescein in the lung, preventing uptake of these nanoparticles by the liver. Furthermore, compared with the MPSS-CSNPs and MPSS treatment groups, treatment with RBC-MPSS-CSNPs considerably inhibited the production of inflammatory cytokines such as TNF-α and IL-6, and consequently attenuated lung injury induced by lipopolysaccharide in rats. Therefore, RBC-hitchhiking is a potentially effective strategy for the delivery of nanoparticles to the lungs for the treatment of acute lung injury and acute respiratory distress syndrome.
“…Because the retention of a drug at the RW does not lead to a leveling of its concentration along the cochlear spiral (see also Plontke et al, 2007b), different strategies for drug delivery to the cochlear apex should be employed. Stable drug loaded nanocarriers (Zou et al, 2014; Li et al, 2017; Kamalov et al, 2018) which can stay in the ST long enough without being cleared into the surrounding tissue may be a feasible option. When the concentration of nanocarriers along the ST reaches a constant level, the encapsulated drug could be released from the carriers through thermal or light activation (Karimi et al, 2016, 2017; Yuan et al, 2017) to obtain sufficient drug concentrations along the entire cochlear spiral.…”
Intratympanic drug administration depends on the ability of drugs to pass through the round window membrane (RW) at the base of the cochlea and diffuse from this location to the apex. While the RW permeability for many different drugs can be promoted, passive diffusion along the narrowing spiral of the cochlea is limited. Earlier measurements of the distribution of marker ions, corticosteroids, and antibiotics demonstrated that the concentration of substances applied to the RW was two to three orders of magnitude higher in the base compared to the apex. The measurements, however, involved perforating the cochlear bony wall and, in some cases, sampling perilymph. These manipulations can change the flow rate of perilymph and lead to intake of perilymph through the cochlear aqueduct, thereby disguising concentration gradients of the delivered substances. In this study, the suppressive effect of salicylate on cochlear amplification via block of the outer hair cell (OHC) somatic motility was utilized to assess salicylate diffusion along an intact guinea pig cochlea
in vivo
. Salicylate solution was applied to the RW and threshold elevation of auditory nerve responses was measured at different times and frequencies after application. Resultant concentrations of salicylate along the cochlea were calculated by fitting the experimental data using a mathematical model of the diffusion and clearing of salicylate in a tube of variable diameter combined with a model describing salicylate action on cochlear amplification. Concentrations reach a steady-state at different times for different cochlear locations and it takes longer to reach the steady-state at more apical locations. Even at the steady-state, the predicted concentration at the apex is negligible. Model predictions for the geometry of the longer human cochlea show even higher differences in the steady-state concentrations of the drugs between cochlear base and apex. Our findings confirm conclusions that achieving therapeutic drug concentrations throughout the entire cochlear duct is hardly possible when the drugs are applied to the RW and are distributed via passive diffusion. Assisted methods of drug delivery are needed to reach a more uniform distribution of drugs along the cochlea.
“…It was also shown that the complex of TBC and MPS is able to undergo self-assembly to obtain uniform and relatively stable micelles, which are characterized by high encapsulation efficiency and cellular availability of MPS. The initial study of the preparation demonstrated increased cellular uptake and antiradical activity of the complex compared to free MPS [29]. These data confirmed the possible use of TBC/MPS as a pharmaceutical composition.…”
Section: Discussionmentioning
confidence: 53%
“…The most studied amphiphilic polymers include ethylene oxide (EO) and propylene oxide (PO) block polymers [26,27]. In the aqueous environment, amphiphilic triblock copolymers (TBC) can spontaneously fuse to form polymeric micelles [28,29]. The specific features of delivery systems based on nanomicelles are their small size and preservation of drug stability [30].…”
Spinal cord injuries must be treated as soon as possible. Studies of NASCIS protocols have questioned the use of methylprednisolone therapy. This study aimed to evaluate the effect of local delivery of methylprednisolone succinate in combination with a tri-block copolymer in rats with spinal cord injury. The experiments were conducted in accordance with the bioethical guidelines. We evaluated the state of the motor centers below the level of injury by assessing the amplitude of evoked motor responses in the hind limb muscles of rats during epidural stimulation. Kinematic analysis was performed to examine the stepping cycle in each rat. Trajectories of foot movements were plotted to determine the range of limb motion, maximum foot lift height, and lateral deviation of the foot in rats on the 21st day after spinal cord injury. We have shown that the local application of methylprednisolone succinate in combination with block copolymer leads to recovery of center excitability by 21 days after injury. In rats, they recovered weight-supported locomotion, directional control of walking, and balance. The proposed assessment method provides valuable information on gait disturbances following injury and can be utilized to evaluate the quality of therapeutic interventions.
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