Stearylated cycloarginine nanosystems for intracellular delivery – simulations, formulation and proof of concept

Dhawan, Vivek; Magarkar, Aniket; Joshi, Ganesh; Makhija, Dinesh T.; Jain, Arvind Kumar; Shah, J.; Reddy, B. V. V. G.; Krishnapriya, M.; Bunker, Alex; Jagtap, Aarti; Nagarsenker, Mangal S.

doi:10.1039/c6ra16432c

Cited by 17 publications

(6 citation statements)

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“…For a recent review of lipid diversity, please read refs − . In spite of this variety, artificial lipids are actively developed for pharmaceutical applications − or as research tools. − For reviews, see refs − .…”

Section: Biomembranes As the Target Of Simulations: Native Membranes ...mentioning

confidence: 99%

Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance

et al. 2019

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Biological membranes are tricky to investigate. They are complex in terms of molecular composition and structure, functional over a wide range of time scales, and characterized by nonequilibrium conditions. Because of all of these features, simulations are a great technique to study biomembrane behavior. A significant part of the functional processes in biological membranes takes place at the molecular level; thus computer simulations are the method of choice to explore how their properties emerge from specific molecular features and how the interplay among the numerous molecules gives rise to function over spatial and time scales larger than the molecular ones. In this review, we focus on this broad theme. We discuss the current state-of-the-art of biomembrane simulations that, until now, have largely focused on a rather narrow picture of the complexity of the membranes. Given this, we also discuss the challenges that we should unravel in the foreseeable future. Numerous features such as the actin-cytoskeleton network, the glycocalyx network, and nonequilibrium transport under ATP-driven conditions have so far received very little attention; however, the potential of simulations to solve them would be exceptionally high. A major milestone for this research would be that one day we could say that computer simulations genuinely research biological membranes, not just lipid bilayers.

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Section: Biomembranes As the Target Of Simulations: Native Membranes ...mentioning

confidence: 99%

Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance

et al. 2019

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“…An organ with the highest cholesterol content is the brain, particularly the myelin sheets insulating the axons . There are also various cholesterol-rich biomaterial applications mimicking nature, such as liposomes used in drug delivery, where high cholesterol content prevents leakage of encapsulated drugs. − This is a common strategy in currently approved therapies based on liposomes as drug carriers. , …”

Section: Introductionmentioning

confidence: 99%

Tail-Oxidized Cholesterol Enhances Membrane Permeability for Small Solutes

et al. 2020

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Cholesterol renders mammalian cell membranes more compact by reducing the amount of voids in the membrane structure. Because of this, cholesterol is known to regulate the ability of cell membranes to prevent the permeation of water and water-soluble molecules through the membranes. Meanwhile, it is also known that even seemingly tiny modifications in the chemical structure of cholesterol can lead to notable changes in membrane properties. The question is, how significantly do these small changes in cholesterol structure affect the permeability barrier function of cell membranes? In this work, we applied fluorescence methods as well as atomistic molecular dynamics simulations to characterize changes in lipid membrane permeability induced by cholesterol oxidation. The studied 7β-hydroxycholesterol (7β-OH-chol) and 27-hydroxycholesterol (27-OH-chol) represent two distinct groups of oxysterols, namely, ring- and tail-oxidized cholesterols, respectively. Our previous research showed that the oxidation of the cholesterol tail has only a marginal effect on the structure of a lipid bilayer; however, oxidation was found to disturb membrane dynamics by introducing a mechanism that allows sterol molecules to move rapidly back and forth across the membrane—bobbing. Herein, we show that bobbing of 27-OH-chol accelerates fluorescence quenching of NBD-lipid probes in the inner leaflet of liposomes by dithionite added to the liposomal suspension. Systematic experiments using fluorescence quenching spectroscopy and microscopy led to the conclusion that the presence of 27-OH-chol increases membrane permeability to the dithionite anion. Atomistic molecular dynamics simulations demonstrated that 27-OH-chol also facilitates water transport across the membrane. The results support the view that oxysterol bobbing gives rise to successive perturbations to the hydrophobic core of the membrane, and these perturbations promote the permeation of water and small water-soluble molecules through a lipid bilayer. The observed impairment of permeability can have important consequences for eukaryotic organisms. The effects described for 27-OH-chol were not observed for 7β-OH-chol which represents ring-oxidized sterols.

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“…Percent hemolysis values below 10% were considered to be nonhemolytic. 62 It was observed that formulated cationic RL5 caused 1.88% hemolysis, which is under the permissible limit (less than 10% lysis). Hemolysis assay suggests that the concentration of SA used in the formulation of RL5 is blood biocompatible and can be used for in vivo administration.…”

Section: Resultsmentioning

confidence: 96%

“…In the present investigation, RL5 formulation (equivalent to 20 mg/mL RS) and free RS (20 mg/mL) were evaluated for hemolysis as compared to positive control (1% w/v Triton in PBS) and negative control (0.1% v/v DMSO in PBS), as depicted in Figure S2. Percent hemolysis values below 10% were considered to be nonhemolytic . It was observed that formulated cationic RL5 caused 1.88% hemolysis, which is under the permissible limit (less than 10% lysis).…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Evaluation of Resveratrol Loaded Cationic Liposomes for Targeting Hepatocellular Carcinoma

Jagwani

Jalalpure

Dhamecha

et al. 2020

ACS Biomater. Sci. Eng.

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The destructive nature of the disease makes it difficult for clinicians to manage the condition. Hence, there is an urgent need to find new alternatives for HCC, as the role of conventional cytotoxic drugs has reached a plateau to control HCC associated mortality. Antioxidant compounds of plant origin with potential anti-tumor effect have been recognized as alternate modes in cancer treatment and chemoprevention. Resveratrol (RS) is a model natural nonflavonoid drug known for its anti-cancer activity. However, its clinical application is limited due to its poor bioavailability. The current research work aims to formulate, optimize, and characterize RS loaded cationic liposomes (RLs) for specific delivery in HCC. The optimized liposomes formulation (RL5) was spherical with a vesicle size (VS) of 145.78 ± 9.9 nm, ζ potential (ZP) of 38.03 ± 9.12 mV, and encapsulation efficiency (EE) of 78.14 ± 8.04%. In vitro cytotoxicity studies in HepG2 cells demonstrated an improved anti-cancer activity of RL5 in comparison with free RS. These outcomes were supported by a cell uptake study in HepG2 cells, in which RL5 exhibited a higher uptake than free RS. Furthermore, confocal images of HepG2 cells after 3 and 5 h of incubation showed higher internalization of coumarin 6 (C6) loaded liposomes (CL) as compared to those of the free C6. Pharmacokinetic and pharmacodynamic (prophylactic and therapeutic treatment modalities) studies were performed in N-nitrosodiethylamine (NDEA-carcinogen) induced HCC in rats. Pharmacokinetic evaluation of RL5 demonstrated increased localization of RS in cancerous liver tissues by 3.2- and 2.2-fold increase in AUC and Cmax, respectively, when compared to those of the free RS group. A pharmacodynamic investigation revealed a significant reduction in hepatocyte nodules in RL5 treated animals when compared to those of free RS. Further, on treatment with RL5, HCC-bearing rats showed a significant decrease in the liver marker enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, total bilirubin levels, γ-glutamyl transpeptidase, and α-fetoprotein), in comparison with that of the disease control group. Our findings were supported by histopathological analysis, and we were first to demonstrate that NDEA induced detrimental effect on rat livers was successfully reversed with the treatment of RL5 formulation. These results implied that delivery of RS loaded cationic liposomes substantially controlled the severity of HCC and that they can be considered as a promising nanocarrier in the management of HCC.

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Stearylated cycloarginine nanosystems for intracellular delivery – simulations, formulation and proof of concept

Abstract: Novel cationic agent liposomes performed better in silico translating in higher cellular uptake with reduced toxicity.

Cited by 17 publications

References 54 publications

Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance

Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance

Tail-Oxidized Cholesterol Enhances Membrane Permeability for Small Solutes

Pharmacokinetic and Pharmacodynamic Evaluation of Resveratrol Loaded Cationic Liposomes for Targeting Hepatocellular Carcinoma

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