Nanomedicine is an amalgam of nanotechnology and medicine that uses advances from the former in the latter discipline. Liposomes can be subjected to various modifications in order to change the physiological course of the metabolic process.
Nanomedicine market
Liposomes
When phospholipids are dissolved in an aqueous medium, a rearrangement of the water molecules occurs, so that the free energy increases. To minimize this energy cost, the hydrophobic part of the phospholipids is grouped so that the number of charged water molecules is minimal.
Monoclonal antibodies
A further classification of monoclonal antibodies can be made according to the use made of them. Rituximab (MabThera®), cetuximab (Erbitux®) and bevacizumab (Avastin®) also belong to this group of monoclonal antibodies.
Metallic nanoparticles
However, there are limitations that all types of monoclonal antibody-based therapy have in common, regardless of the type of active ingredient chosen. Clinical trials such as linking tumor necrosis factor α to colloidal gold to cure sarcoma are already underway.
Search strategy
Also, what are the data needed to create a pharmacokinetic model to create in silico studies. The goal was to collect as much data as possible to help with the creation of new nanodrugs.
Selection criteria
Thus, normalization of the vasculature can be used to improve extravasation by reducing IFP in the tumor. The results showed that deposition of nanoparticles was found in the stratum corneum.
PHARMACOKINETICS OF LIPOSOMES
Pharmacokinetics
The two parts of the nanomedicine (the liposome and the associated chemical compound) may follow different kinetics. When we have an immediate (or rather rapid) release from the carrier, we can study the kinetics of the drug, whereas when we have a latency release, we only study the kinetics of the associated carrier.
Absorption
- Route of administration
- Effect of liposome size
- Effect of liposome composition and dose
As mentioned before, the release rate of the drug from their liposomal carrier affects its systemic absorption. Only 5% of the original amount of liposomes was found circulating in the blood and then removed by the mononuclear system.
Distribution
- Distribution of stabilized and classical liposomes
- Effect of liposome size
- Effect of liposome composition
There is also a small increased distribution of stabilized liposomes in some other tissues including carcass, skin, kidneys, lymph nodes, bone marrow [20,22] and tissues of pathology such as tumor tissues. In the first demonstration of in vivo targeting of stabilized liposomes (SL), as much as 50% of an injected dose of L-α-phosphatidylcholine (eggPC) with CHOL:GM1 immunoliposomes, conjugated to a monoclonal antibody against a glycoprotein -antigen expressed on capillary endothelial cells, has been shown to localize in lungs [37].
Clearance and elimination of stabilized and classical liposomes
- Clearance kinetics
- Effect of dose
In this model, as in the tumor models above, it is thought that increased distribution of SL at the site of infection was related to permeability changes in the capillaries of the infected region. One of the main differences between stabilized and classical liposomes is the kinetics of their disposition. It results when CL saturates the high-affinity and low-capacity uptake mechanisms of the mononuclear system [21].
The non-linear pharmacokinetics of CL results in an unpredictable way to calculate the bioavailability of the liposome-associated drug, as clearance is not continuous over the clinical concentration range. Initially, a high-affinity, low-capacity, saturable system probably corresponds to the recognition and association of liposomes by the organs of the mononuclear system.
Drug metabolism
The first low capacity process, during which there is rapid saturation of receptors involved in macrophage phagocytosis and endocytosis and the second, high capacity process includes either a clear receptor and / or the slow saturation of the liver cell population [44]. 45] since there was no reduction in splenic or hepatic uptake of empty CL after a predose of stabilized liposomes containing monosialotetrahexosylganglioside, when the predose of those liposomes contained entrapped doxorubicin, a subsequent dose of empty classical liver reduced uptake and increased splenic recording. 30 also possible when the liposome-entrapped drug is absorbed away from a site, the free drug may provoke toxicity.
Pharmacokinetic–Pharmacodynamic Relationships
- Physiologically-Based Pharmacokinetic Modeling and Simulation
- Simplified PBPK model
- Whole-Body PBPK Model
- PK–PD Modeling System with Spatiotemporal Characterization
The binding of a large molecule, such as a monoclonal antibody, to a specific receptor located on top of the cell membrane acts as a trigger. On the other hand, specific binding occurs through the Fab region of the antibody. A clear but simplified representation of the various secretion pathways is shown in Figure 7.
Liposomes can be subjected to various modifications to alter the physiological flow of the metabolic process. As presented, addition of phospholipids such as cholesterol increases the fluidity of the liposome, providing better.
PHARMACOKINETICS OF MONOCLONAL-ANTIBODIES
Pharmacokinetic characteristics of monoclonal antibodies
- Absorption
- Distribution
- Elimination
- Antigen binding
Since the flow rate from the lymphatic system is low, mAbs absorption can be considered delayed release [64]. First, those cases include the presentation of a soluble factor by the part of the antigen such as the tumor necrosis factor (TNF) that can be targeted by infliximab. Next, the activator enzyme must be located on the surface of the target cell and present a receptor or an enzyme.
Both the mAb and the ligand can bind to the antigen, but at different sites on the latter. The overall result depends on the concentrations of the mAb and the physiologically presented ligand and the rate of antigen expression.
Drug interaction studies
- Differences in pharmacokinetics between mAbs and nano drugs
Another parameter that can influence the production of antibodies that combat the mAb therapy is the dose frequency. Last but not least, genes from each patient may elicit a faster response from the human immune system to contrast the monoclonal therapy, especially when the patient has an autoimmune disease or has previously been treated with monoclonal therapy. The problem with this immunological response is that binding with the therapeutic monoclonal antibodies can induce an irreversible binding, which leads to an inevitable removal from the body, rendering the therapy insufficient and drastically altering the kinetics and dynamics of the administered mAbs.
The target binding of nanomedicines can be modified, but the binding of mAbs is most of the time irreversible. Finally, regarding their pharmacokinetic profile, nanodrugs show a non-linear profile, which is the profile that mAbs mostly follow [ 72 ].
Modelling monoclonal antibodies
- Non-compartmental-analysis
- Compartmental analysis
- Population-based analysis
Population analysis has evolved over the past 20 years with the help of technology that made this process faster and more accurate than it used to be. In this kind of analysis, it is quite important to have different information about the people studied, such as their dosage and administration, but also a big role is played by their different characteristics (such as age, gender and race). The abandonment of the non-linear model appears to confirm the previous calculation by adding this additional elimination pathway.
Accordingly, clearance following the nonlinear model at low concentrations of mAbs shows higher clearance and appears to be independent of blood concentration. This trend can be explained by the fact that linear clearance is the description of proteolytic degradation in liver cells.
METALLIC NANOPARTICLES
Introduction
Pharmacokinetics
- Gold nanoparticles
- Silver nanoparticles
The most studied Ag-Nps are those whose surface has been treated with the pegylation technique. Next, they experimented with injecting the same dose but different sizes of PEG-Ag-Nps (4, 13 and 100 nm). With these results, we can conclude that the pharmacokinetics of Ag-Nps also depends on the animal species used, as T1/2 was found to be 3-4 times shorter in rats than in rabbits.
They injected 120 mg/kg Ag-Np agglomerates (90.5 nm) into both male and female rats. Findings regarding the Vd of Ag-Nps in rats (31.9 mL/g for female rats and 21.7 mL/g for male rats) suggest extensive tissue accumulation as it was at least twice that of the total body fluid of rats (≈15 ml).
Absorption
- Gold nanoparticles
- Silver nanoparticles
To study the variation of pharmacokinetics caused by dose and route of administration, Park et al. To identify the depth of disposition of a group of certain given Au-Nps, Schlel et al used radiolabeled Au-Nps with 22nm diameter and continued for a 2 hour inhalation process to understand how surfactant pulmonary protein D affects the results [87]. To determine the importance of the translocation across the lung to circulation, Balasubramanian et al investigated the concentration in blood and in other organs of gold nanoparticles [87].
Initially, the nanoparticles showed an inverse proportional relationship that can be simplified as "the smaller the passage easier". According to Hillyer et al., after esophageal instillation performed in rats using radiolabeled gold nanoparticles, the data extracted showed a minimal absorption across the intestinal lumen [91].
Distribution
- Gold nanoparticles
- Silver nanoparticles
They administered 90mg/kg of 19 nm uncoated or 16 nm coated poly-vinyl-pyrrolidone Ag-Nps and AgNO3 with silver resulting in 9 mg/kg dose. The presence of Ag-Nps was noted in all types of liver cells, such as Küpffer cells, hepatocytes and sinusoidal endothelial cells. Ag-Nps of 20nm showed higher deposition to liver cells, but 110nm Ag-Nps showed preference to the spleen cells followed by the pulmonary and liver.
From these studies we conclude that size can affect the delivery target of Ag-Nps and creates considerations on toxicity and health risks. According to studies (Takenaka et al., Garza-Ocanas et al., van der Zande et al.) ≤ 100nm Ag-Nps demonstrate a high brain distribution, even when the route of administration changes.
Metabolism
- Gold nanoparticles
- Silver nanoparticles
At all fixed periods, concentration of Ag in liver, spleen, kidney, lung and brain was significantly higher in 20nm groups, regardless of their similar distribution profiles. However, it is not really clear whether they succeeded in crossing the blood-brain barrier, since in most studies it is quite unclear whether the concentration of Ag in the brain is the result of endothelial cells or neuronal tissue accumulation. Through in vitro experiments, it is known that peptide-coated Au-Nps can be internalized and then degraded by protein cathepsin L in the endosomal compartments [111].
Unfortunately, there are no data regarding in vivo experiments regarding the metabolism of Au-Nps. After per os administration, the pH of the gastric fluid (≈1.5) rapidly oxidizes Ag-Nps to cationic Ag in a percentage of 97% within 6 h.
Elimination
- Gold nanoparticles
- Silver nanoparticles
63 a large fraction of gold nanoparticles can be retained in primary organs such as liver and lymph. Air-blood barrier translocation of tracheally inspired gold nanoparticles is inversely dependent on particle size. Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration.
Distribution of silver in rats after 28 days of repeated oral exposure to silver nanoparticles or silver acetate. Twenty-eight-day oral toxicity, genotoxicity, and sex-related tissue distribution of silver nanoparticles in Sprague-Dawley rats. Biodistribution and long-term fate of silver nanoparticles functionalized with bovine serum albumin in rats.
Fate of intravenously administered gold nanoparticles in hair follicles: follicular release, pharmacokinetic interpretation and excretion.
