Current Drug Metabolism - Volume 23, Issue 9, 2022

Liposomes nowadays have become a preferential drug delivery system since they provide facilitating properties to drugs, such as improved therapeutic index of encapsulated drug, target and controlled drug delivery, and less toxicity. However, conventional liposomes have shown some disadvantages, such as less drug loading capacity, poor retention, clearance by kidney or reticuloendothelial system, and less release of hydrophilic drugs. Thus, to overcome these disadvantages recently, scientists have explored new approaches and methods, viz., ligand conjugation, polymer coating, and liposome hybrids, including surface-modified liposomes, biopolymer-incorporated liposomes, guest-in-cyclodextrin-in-liposome, liposome-in-hydrogel, liposome-in-film, liposome-in-nanofiber, etc. These approaches have been shown to improve the physiochemical and pharmacokinetic properties of encapsulated drugs. Lately, pharmacokinetic-pharmacodynamic (PK-PD) computational modeling has emerged as a beneficial tool for analyzing the impact of formulation and system-specific factors on the target disposition and therapeutic efficacy of liposomal drugs. There has been an increasing number of liposome-based therapeutic drugs, both FDA approved and those undergoing clinical trials, having application in cancer, Alzheimer's, diabetes, and glaucoma. To meet the continuous demand of health sectors and to produce the desired product, it is important to perform pharmacokinetic studies. This review focuses on the physical, physicochemical, and chemical factors of drugs that influence the target delivery of drugs. It also explains various physiological barriers, such as systemic clearance and extravasation. A novel approach, liposomal-hybrid complex, an innovative approach as a vesicular drug delivery system to overcome limited membrane permeability and bioavailability, has been discussed in the review. Moreover, this review highlights the pharmacokinetic considerations and challenges of poorly absorbed drugs along with the applications of a liposomal delivery system in improving PKPD in various diseases, such as cancer, Alzheimer's, diabetes, and glaucoma.

Introduction: Nanovesicle technology is making a huge contribution to the progress of treatment studies for various diseases, including Alzheimer’s disease (AD). AD is the leading neurodegenerative disorder characterized by severe cognitive impairment. Despite the prevalence of several forms of anti-AD drugs, the accelerating pace of AD incidence cannot becurbed, and for rescue, nanovesicle technology has grabbed much attention. Methodology: Comprehensive literature search was carried out using relevant keywords and online database platforms. The main concepts that have been covered included a complex pathomechanism underlying increased acetylcholinesterase (AchE) activity, β-amyloid aggregation, and tau-hyperphosphorylation forming neurofibrillary tangles (NFTs) in the brain, which are amongst the major hallmarks of AD pathology. Therapeutic recommendations exist in the form of AchE inhibitors, along with anti-amyloid and anti-tau therapeutics, which are being explored at a high pace. The degree of the therapeutic outcome, however, gets restricted by the pharmacological limitations. Susceptibility to peripheral metabolism and rapid elimination, inefficiency to cross the blood-brain barrier (BBB) and reach the target brain site are the factors that lower the biostability and bioavailability of anti-AD drugs. The nanovesicle technology has emerged as a route to preserve the therapeutic efficiency of the anti-AD drugs and promote AD treatment. The review hereby aims to summarize the developments made by the nanovesicle technology in aiding the delivery of synthetic and plant-based therapeutics targeting the molecular mechanism of AD pathology. Conclusion: Nanovesicles appear to efficiently aid in target-specific delivery of anti-AD therapeutics and nullify the drawbacks posed by free drugs, besides reducing the dosage requirement and the adversities associated. In addition, the nanovesicle technology also appears to uplift the therapeutic potential of several phyto-compounds with immense anti-AD properties. Furthermore, the review also sheds light on future perspectives to mend the gaps that prevail in the nanovesicle-mediated drug delivery in AD treatment strategies.

Gliomas are the most prevailing intracranial tumors, which account for approximately 36% of the primary brain tumors of glial cells. Glioblastoma multiforme (GBM) possesses a higher degree of malignancy among different gliomas. The blood-brain barrier (BBB) protects the brain against infections and toxic substances by preventing foreign molecules or unwanted cells from entering the brain parenchyma. Nano-carriers such as liposomes, nanoparticles, dendrimers, etc. boost the brain permeability of various anticancer drugs or other drugs. The favorable properties like small size, better solubility, and the modifiable surface of dendrimers have proven their broad applicability in the better management of GBM. However, in vitro and in vivo toxicities caused by dendrimers have been a significant concern. The presence of multiple functionalities on the surface of dendrimers enables the grafting of target ligand and/or therapeutic moieties. Surface engineering improves certain properties like targeting efficiency, pharmacokinetic profile, therapeutic effect, and toxicity reduction. This review will be focused on the role of different surface-modified dendrimers in the effective management of GBM

Exosomal nanoparticles are cell-derived nano-sized vesicles in the size range of 30-150nm formed by the inward infolding of the cell membrane. They are encased in a lipid bilayer membrane and contain various proteins and nucleic acids according to the characteristics of their parent cell. They are involved in intercellular communication. Their specific structural and inherent properties are helpful in therapeutics and as biomarkers in diagnostics. Since they are biomimetic, these small-sized nanoparticles pose many advantages if used as a drug carrier vehicle. In cancer, the exosomal nanoparticles have both stimulatory and inhibitory activity towards immune responses; hence, they are used in immunotherapy. They can also carry chemotherapeutic agents to the target site minimizing their targetability concerns. Chemoimmunotherapy (CIT) is a synergistic approach in which chemotherapy and immunotherapy are utilized to benefit each other. Exosomal nanoparticles (NPs) are essential in delivering CIT agents into tumor tissues. Most advanced studies in CIT take place in the stimulator of interferon genes (STING) signaling pathway, where the STING activation supported by chemotherapy-induced an increase in immune surveillance through the help of exosomal NPs. Dendritic cell(DC) derived exosomes, as well as Mesenchymal stem cells (MSC), are abundantly used in immunotherapy, and hence their support can be used in chemoimmunotherapy (CIT) for multifaceted benefits.

Epilepsy is a chronic neurological disorder affecting 70 million people globally. One of the fascinating attributes of brain microvasculature is the (BBB), which controls a chain of distinct features that securely regulate the molecules, ions, and cells movement between the blood and the parenchyma. The barrier's integrity is of paramount importance and essential for maintaining brain homeostasis, as it offers both physical and chemical barriers to counter pathogens and xenobiotics. Dysfunction of various transporters in the (BBB), mainly ATP binding cassette (ABC), is considered to play a vital role in hampering the availability of antiepileptic drugs into the brain. ABC (ATP-binding cassette) transporters constitute a most diverse protein superfamily, which plays an essential part in various biological processes, including cell homeostasis, cell signaling, uptake of nutrients, and drug metabolism. Moreover, it plays a crucial role in neuroprotection by out-flowing various internal and external toxic substances from the interior of a cell, thus decreasing their buildup inside the cell. In humans, forty-eight ABC transporters have been acknowledged and categorized into subfamilies A to G based on their phylogenetic analysis. ABC subfamilies B, C, and G, impart a vital role at the BBB in guarding the brain against the entrance of various xenobiotic and their buildup. The illnesses of the central nervous system have received a lot of attention lately Owing to the existence of the BBB, the penetration effectiveness of most CNS medicines into the brain parenchyma is very limited (BBB). In the development of neurological therapies, BBB crossing for medication delivery to the CNS continues to be a major barrier. Nanomaterials with BBB cross ability have indeed been extensively developed for the treatment of CNS diseases due to their advantageous properties. This review will focus on multiple possible factors like inflammation, oxidative stress, uncontrolled recurrent seizures, and genetic polymorphisms that result in the deregulation of ABC transporters in epilepsy and nanotechnology-enabled delivery across BBB in epilepsy.

Anticancer drugs and diagnostics can be transported in nanoscale vesicles that provide a flexible platform. A hybrid nanoparticle, a nano assembly made up of many types of nanostructures, has the greatest potential to perform these two activities simultaneously. Nanomedicine has shown the promise of vesicular carriers based on lipopolymersomes, lipid peptides, and metallic hybrid nano-vesicle systems. However, there are significant limitations that hinder the clinical implementation of these systems at the commercial scale, such as low productivity, high energy consumption, expensive setup, long process durations, and the current cancer therapies described in this article. Combinatorial hybrid systems can be used to reduce the above limitations. A greater therapeutic index and improved clinical results are possible with hybrid nanovesicular systems, which integrate the benefits of many carriers into a single structure. Due to their unique properties, cell-based drug delivery systems have shown tremendous benefits in the treatment of cancer. Nanoparticles (NPs) can benefit significantly from the properties of erythrocytes and platelets, which are part of the circulatory cells and circulate for a long time. Due to their unique physicochemical properties, nanomaterials play an essential role in cell-based drug delivery. Combining the advantages of different nanomaterials and cell types gives the resulting delivery systems a wide range of desirable properties. NPs are nextgeneration core-shell nanostructures that combine a lipid shell with a polymer core. The fabrication of lipid-polymer hybrid NPs has recently undergone a fundamental shift, moving from a two-step to a one-step technique based on the joint self-assembly of polymers and lipids. Oncologists are particularly interested in this method as a combinatorial drug delivery platform because of its two-in-one structure. This article addresses various preparative methods for the preparation of hybrid nano-vesicular systems. It also discusses the cellular mechanism of hybrid nano-vesicular systems and describes the thorough knowledge of various hybrid vesicular systems.