Amir Azadi

Hydrogel nanoparticles in drug delivery

Hydrogel nanoparticles have gained considerable attention in recent years as one of the most promising nanoparticulate drug delivery systems owing to their unique potentials via combining the characteristics of a hydrogel system (e.g., hydrophilicity and extremely high water content) with a nanoparticle (e.g., very small size). Several polymeric hydrogel nanoparticulate systems have been prepared and characterized in recent years, based on both natural and synthetic polymers, each with its own advantages and drawbacks. Among the natural polymers, chitosan and alginate have been studied extensively for preparation of hydrogel nanoparticles and from synthetic group, hydrogel nanoparticles based on poly (vinyl alcohol), poly (ethylene oxide), poly (ethyleneimine), poly (vinyl pyrrolidone), and poly-N-isopropylacrylamide have been reported with different characteristics and features with respect to drug delivery. Regardless of the type of polymer used, the release mechanism of the loaded agent from hydrogel nanoparticles is complex, while resulting from three main vectors, i.e., drug diffusion, hydrogel matrix swelling, and chemical reactivity of the drug/matrix. Several crosslinking methods have been used in the way to form the hydrogel matix structures, which can be classified in two major groups of chemically- and physically-induced crosslinking.

Pharmacokinetic Consequences of Pegylation

Pegylation, generally described as the molecular attachment of polyethylene glycols (PEGs) with different molecular weights to active drug molecules or surface treatment of drug-bearing particles with PEGs, is one of the most promising and extensively studied strategies with the goal of improving the pharmacokinetic behavior of the therapeutic drugs. A variety of PEGs, both linear and branched, with different molecular weights have been exploited successfully for use in this procedure in the form of reactive PEG species. Both reversible and irreversible PEG-drug conjugates have been prepared with relative advantages/disadvantages. The main pharmacokinetic outcomes of pegylation are summarized as changes occurring in overall circulation life-span, tissue distribution pattern, and elimination pathway of the parent drug/particle. Based on these favorable pharmacokinetic consequences leading to desired pharmacodynamic outcomes, a variety of proteins/peptides as well as small molecule drugs have been pegylated and evaluated successfully. Also a number of corresponding products have been approved by the U.S. FDA for specific clinical indications and some others are underway. In this article, the chemistry, rationale, strategies, pharmacokinetic outcomes, and therapeutic possibilities of pegylated drugs are reviewed with pharmacokinetic aspects presented with more details.

Methotrexate-loaded chitosan nanogels as ‘Trojan Horses’ for drug delivery to brain: Preparation and in vitro/in vivo characterization

Methotrexate-loaded hydrogel nanoparticles were prepared and after in vitro characterization, their transport across blood-brain barrier was investigated in vivo in intact animals in this study. The ionic gelation method was used for preparation of drug-loaded nanogels, after optimized by a systematic multi-objective optimization approach. After surface-modification with polysorbate 80, nanoparticles with the final particle size, poly-dispersity index (PDI), loading efficiency (LE) and loading capacity (LC) of 118.54 ± 15.93 nm, 0.35 ± 0.05, 61.82 ± 6.84%, and 53.68 ± 3.09% were obtained, respectively. The in vitro drug release study indicated non-Fickian diffusion kinetic, apparently governed by both diffusion of the drug out of the nanoparticles and swelling/disintegration of the polymeric network as characterized by a Weibull model for both surface-treated and untreated nanogels. After intravenous administration of surface-modified and unmodified nanogels compared to the free drug, all with the same dose of 25 mg/kg, remarkably higher brain concentrations of methotrexate were achieved with the nanogel formulations in comparison to the free drug (in some cases, more than 10-fold); but there were no significant differences between the surface-modified and unmodified nanogels in all the time points tested.

Designing PEGylated therapeutic molecules: advantages in ADMET properties

Background: PEGylation, association of poly(ethylene glycol) (PEG) to drug molecules or drug-bearing particles, is one of the most promising techniques on the way to improve the pharmacokinetic features of a drug which, in turn, leads to pharmacodynamic improvements. Objective: The aim of this review is to describe PEGylation as a procedure for alteration of drug molecular structure with the main emphasis on its pharmacokinetic consequences. Methods: After a brief but concise overview of the history and chemistry of PEGylation, the boundary of this literature survey is confined to the findings and reports on the impact of PEGylation on biodistribution and bioelimination of therapeutic molecules. Conclusion: It is concluded, based on the whole body of the data in literature, that the main results of PEGylation on pharmacokinetic properties of the drug include prolongation of lifespan in circulation, alterations in drug elimination pathway(s) and changes in drug biodistribution profile, among others, which all are derived from the structural changes that occur in the drug molecule, mainly reversible attachment of a large polymeric moiety to parent drug.

Preparation and optimization of surface-treated methotrexate-loaded nanogels intended for brain delivery.

Nanogels loaded with methotrexate (MTX) were prepared via an ionic gelation process using chitosan and sodium tripolyphosphate (TPP). The preparation process was optimized by a systematic multi-objective-optimization approach in terms of the size, poly-dispersity index (PDI), loading efficiency (LE) and loading capacity (LC) of the resulting nanocarriers. A combination of the pH of the chitosan solution, the addition time of the TPP solution and temperature effects accounted for nearly 75% of the variation in nanogel size; the TPP initial concentration had a very significant effect on LE (p<0.0001). The final particle size (Z-average (r nm)), PDI, LE and LC corresponding to the optimal conditions were 59.27 nm, 0.34, 61.82% and 53.68%, respectively. As the ultimate goal, the surfaces of the MTX-loaded nanogels were modified by polysorbate 80 for the purpose of brain targeting. The cumulative in vitro release profiles of surfactant-coated and uncoated nanogels were almost identical and showed acceptable performance.

Neuropharmacokinetic evaluation of methotrexate-loaded chitosan nanogels.

Delivery of the hydrophilic drugs to the brain is still a great challenge for the treatment of many CNS-related diseases. Nanogels loaded by methotrexate (MTX) were prepared using the ionic gelation method. After intravenous administration of surface-modified (SMNs) and unmodified nanogels (UMNs) compared to the free drug, the neuropharmacokinetic evaluations were applied mainly by tissue drug uptake and graphic estimation of the uptake clearance methods. In optimized condition, the particle sizes of UMNs and SMNs were 118.54±15.93 nm and 106.68±7.23 nm, respectively. Drug entrapment efficiency and drug loading capacity were 61.82±6.84%, and 53.68±3.09%, respectively. The brain concentrations of MTX were shown to be higher in the case of both types of the nanogels. There were no significant differences between SMNs and UMNs in terms of the brain concentrations and AUCs of brain concentration-time profiles. Meanwhile, the brain uptake clearance of the drug loaded in SMNs were significantly higher than UMN ones (i.e. about 3- and 1.6-times for the high and low MTX doses, respectively). It can be concluded that, while the drug loading in both forms of nanogels have a significant increasing effect on the brain penetration of MTX, surface treatment of nanogels exerts an additional effect on the plasma volume cleared from MTX via brain tissue in time unit.

Nanostructure L-asparaginase-fatty acid bioconjugate: synthesis, preformulation study and biological assessment.

The present study aims to develop a novel L-asparaginase fatty acid bioconjugates and characterize their applicability for intravenous delivery of L-asparaginase. These bioconjugates were achieved by covalent linkage of fatty acids having different chain lengths (C12, C16 and C22) to the native enzyme. To determine the optimum conditions of bioconjugation, the effect of lipid:protein ratios, reaction time and medium composition on enzyme activity and conjugation degree were evaluated. The native and bioconjugates have been characterized by activity, conjugation degree, particle size, and zeta potential. The results showed that bioconjugated L-asparaginase were more resistant to proteolysis, more stable at different pH, and had prolonged plasma half-life, compared to the native form. From partition coefficient study, the modified enzymes showed approximately 15-fold increase in hydrophobicity. Secondary structure analysis using circular dichroism revealed alteration after lipid conjugation. In addition, the Michaelis constant of the native enzyme was 3.38 mM, while the bioconjugates showed the higher affinity to the substrate L-asparagine. These findings indicate that new lipid bioconjugation could be a very useful strategy for intravenous delivery of L-asparaginase.

Chitosan-based hydrogel nanoparticle amazing behaviors during transmission electron microscopy.

Nanogels are potential polymeric nanoparticulate systems of interest in biomedical applications, including time-controlled drug delivery and active drug targeting. With the aim of preparation of a nanocarrier for brain enhancement of the BBB-restricted hydrophilic drugs, nanogel loaded with the antineoplasm drug, methotrexate was prepared using an ionic gelation process. During transmission electron microscopy imaging, hydrogel nanoparticles were found as a polymeric matrix containing aqueous vacuoles. With emitting the electrons and increase in energy intake, the vacuoles were interconnected and form a large one. Then the volume of the new vacuole grew and subsequently decreased over the time. The behavior was in good agreement with drug release kinetic findings. These results provide important guidelines for designing top-down fabricated hydrogel nanoparticles with specific drug release kinetic mechanisms for enhancing and predicting the drug delivery efficacy.

Traditional neurotherapeutics approach intended for direct nose to brain delivery

ETHNOPHARMACOLOGICAL RELEVANCE Nasal delivery systems have a significant role in Persian traditional medicine. Most of them were utilized for central nervous system (CNS)-related disorders. In modern medicine, nasal drug delivery systems for brain delivery are highly regarded. AIM OF THE STUDY Despite recent advances in drug delivery to the (CNS), delivery of therapeutics to the brain remains a major challenge because of the blood brain barrier (BBB). There are several mechanisms which regulate the drug transfer across the BBB. Local administration methods of therapeutic agents are often associated with adverse events, while the intranasal pathway has been suggested as a non-invasive alternative route to deliver drugs to the brain. This route can bypass the BBB and deliver drug molecules directly to the CNS. There are different nasal formulations have been addressed in Persian traditional pharmacopeias. The present review attempt to explore the famous and practical Qarabadin to find ancient nasal dosage forms. MATERIALS AND METHODS With an explore on traditional herbs in google scholar, scopus and science direct, we have found some original and review articles which have demonstrated our findings on the use of traditional herbs for CNS disorders. Four encyclopedia of multi-component formulations, including Qarabadin Salehi (1766), Qarabadin kabir (1781),Qarabadin Ghaderi (18th century), and Qarabadin Azam (1853), were searched for nasal formulations having CNS-related indications. Formulations were categorized based on dosage forms, and also, diseases which they were suggested for. While the names of illnesses were in ancient terminology of Traditional Medicine, they were translated to modern medical terminology by comparing their definitions, signs, and symptoms from two medical systems. Typical samples of each dosage form have been mentioned with details like amount of ingredients, scientific names of plants, and considerations pertaining to preparation or usage. RESULTS Among all traditional nasal formulations, seven types were found that is used for sicknesses relating to CNS including Saoot, Nafookh, Atoos, Nashoogh, Shamoom, Lakhlakheh, and Bakhoor. CONCLUSIONS The findings of this study reveal the physicochemical characteristics of each formulation, route of administration, and type of disease which they are suitable and also present some famous formulations.

Promising horizon to alleviate Alzeheimer’s disease pathological hallmarks via inhibiting mTOR signaling pathway: A new application for a commonplace analgesic

Alzheimers disease (AD) is a very prevalent and burdensome disease of elderlies but albeit extensive studies, mechanisms underlying its pathology and consequently its definite treatment is ambiguous. Intra and extra-cellular aggregation of abnormal proteins and impaired autophagy machinery, two closely related events taking place in AD brains proposed to be directly controlled by mTOR signaling pathway. On the other hand, tramadol that is a very well tolerated opioid analgesic has been revealed to inhibit mTOR upstream controllers through interaction with specific types of muscarinic, serotonergic, nicotinic and NMDA receptors, although it seems to induce the opposite effect via µ-opioid receptor. Putting all the pieces of experimental evidence together, we hypothesize that tramadol might alleviate AD pathological hallmarks at least in cellular level through decreasing activity of PI3K-AKT and ERK and also mTOR signaling pathways respectively and results in autophagy activation as well as tau-dephosphorylation.