Novel Poly (glycerol-adipate) Polymers Used for Nanoparticle Making: A Study of Surface Free Energy

Abstract Nanoparticles made of biodegradable polymers has become the best approach for nanoparticle making due to their compatibility with the human body. New glycerol adipate polymers with hydroxyl group substituted with different percent of acyl group, sited as figures within the abbreviated name in the text, and triptophan were synthesized and proposed to be used in the preparction of dexamethason phosphate loaded nanoparticles, using the evaporation-deposition technique. The particle forming ability, size and distribution of the nanoparticles might be related to more important physicochemical characteristics, such as the surface properties of the polymers. In this study surface free energies of five derivatives (0%, 20%, 40%, 100% and triptophan 5%) were determined by means of contact angle measurement carried out on films formed on the glass slides KSC Cam 100 instrument. The results were then incorporated into the Fowkes equation, toobtion the surface energy of the polymers. Also, different concentrations of methanol were used to obtion contact angles, which in turn were used to give the critical surface tension (γ c ) of the polymers, using the Zizman's method. The results of surface characteristics indicated that the 40% C 8 polymer was probably the most consistent, compared to the others during the preparation stage, in order to form smaller sized particles with a narrower distribution, correlating with the other works carried out on the loaded particles. In conclusion, it seems that this method could be used to predict characteristics of polymers used for the selection of the best polymer in this series and probably other polymers for nanoparticle making, particularly for the loading of ionized drugs

Cholesterol level affects surface charge of lipid membranes in saline solution

Peer reviewe

Nanomedicines and nanotoxicology: some physiological principles

Nanosized materials have been investigated as potential medicines for several decades. Consequently, a great deal of work has been conducted on how to exploit constructs of this size range in a beneficial way. Similarly, a number of the consequences from the use of these materials have already been considered. Nanosized materials do behave differently to low-molecular-weight drugs, the biological properties of nanomaterials being mainly dependent on relevant physiology and anatomy, which are reviewed in this article. Biodistribution, movement of materials through tissues, phagocytosis, opsonization and endocytosis of nanosized materials are all likely to have an impact on potential toxicity. In turn these processes are most likely to depend on the nanoparticle surface. Evidence from the literature is considered which suggests that our understanding of these areas is incomplete, and that biodistribution to specific sites can occur for nanoparticles with particular characteristics. However, our current knowledge does indicate which areas are of concern and deserve further investigation to understand how individual nanoparticles behave and what toxicity may be expected from them

Solubility of drugs in the presence of gelatin: effect of drug lipophilicity and degree of ionization

The solubility of seven drugs (nitrofurantoin, chlorothiazide, phenobarbital, prednisolone, griseofulvin, diazepam and piroxicam) in the absence and presence of gelatin was measured, at three different pH values (3.7, 5.0 and 7.0) at 37 degreesC. Drugs studied had different physicochemical properties (log P, pK(a), aqueous solubility) and their solubility in presence of 0.1 and 0.5%, (w/v) hydrolyzed land in some cases common) gelatin was estimated. Results show that the solubility of all drugs is significantly enhanced, especially in the presence of 0.5%;, gelatin. This gelatin-induced enhancement in drug solubility is higher in the pH in which acidic drugs are less ionized, especially for the less lipophilic acidic drugs (nitrofurantoin, chlorothiazide). In all cases, drug solubility in presence of gelatin is correlated with their aqueous solubility. Therefore, the established relationships between aqueous and gelatin solubility can be employed to derive an estimate of the drug solubility in presence of gelatin once its aqueous solubility is known. With the exception of piroxicam which is highly ionized and phenobarbital which is relatively soluble, there seems to be a tendency for larger gelatin-induced increases in solubility as drug lipophilicity increases or aqueous solubility decreases

Probing the perturbation of lecithin bilayers by unmodified C60 fullerenes using experimental methods and computational simulations

In this study, we aimed to use physicochemical and theoretical tools to understand fundamental problems of the interaction between lipid bilayers (Egg-PC liposomes) and unmodified C60 fullerenes. The morphology, the size, and the electrokinetic properties of plain and C60-loaded liposomes were investigated by means of atomic force microscopy, dynamic light scattering, and ?-potential studies, respectively. The incorporation of C60 molecules into the liposomes increases their size; however, there was no effect on their electrokinetic properties. Visualization studies revealed that the presence of C60 in the membranes induced distortion in vesicle morphology, resulting in nonspherical vesicles. To elucidate further the impact of C60 molecules on lipid bilayers, we assessed their miscibility by fluorescence spectroscopy measurements. Fluorescence measurements showed that the presence of C60 in liposomes causes a pronounced effect on the Nile red emission spectrum due to alterations to the packing of the lipid membrane. The release of vesicle-encapsulated calcein was used as a measure of the integrity of the liposomes. Plain liposomes were found to be more stable compared with C60-loaded (PC) liposomes, suggesting that C60 ruptures the liposome membrane. Toxicity studies of C60 in liposomes were carried out on cultured cells [rodent fibroblasts (3T3)] to assess further their toxicity. The results suggest that fullerene cytotoxic effect was reduced significantly after its incorporation into the liposomal bilayer after 24 h of incubation with the rodent fibroblasts (3T3). Finally, energy minimization studies were employed to underpin the experimental observations. The theoretical calculations show that low concentration of fullerene molecules present in the membrane had no effect on the membrane integrity; however, at high concentrations of fullerenes significant enlargement of the surface area is observed, supporting the experimental finding

Stability of SUV liposomes in the presence of cholate salts and pancreatic lipases: effect of lipid composition

The effect of bile salts (sodium cholate and sodium taurocholate), and pancreatic lipases on the structural integrity of SW liposomes of different lipid compositions was studied. Liposomal membrane integrity was judged by bile salt or pancreatin-induced release of vesicle encapsulated 5,6-carboxyfluorescein, and vesicle size distribution before and after incubations. Bile salt concentration was 10 mM, while a saturated solution of pancreatin (mixed with equal volume of liposomes) was utilized. Results agree with earlier studies, demonstrating the instability of liposomes composed of lipids with low transition temperatures (PC and DMPC) in presence of cholates. Addition of cholesterol (1:1 lipid:chol molar ratio) does not substantially increase the encapsulated molecule retention. Nevertheless, liposomes composed of lipids with high transition temperatures (DPPC, DSPC and SM), retain significantly higher amounts of encapsulated material, under all conditions studied. Furthermore, the vesicles formed by mixing cholesterol with these lipids will possibly be sufficiently stable in the gastrointestinal tract for long periods of time. Sizing results reveal that in most cases release of encapsulated molecules is mainly caused by their leakage through holes formed on the Lipid bilayer. However, in stearylamine containing DPPC and DSPC vesicles, the cholate-induced drastic decrease in vesicle size suggests total liposome disruption as the possible mechanism of encapsulated material immediate release. (C) 2000 Elsevier Science B.V. All rights reserved

Arsenic trioxide liposomes: Encapsulation efficiency and in vitro stability

The use of arsenic-containing compounds in cancer therapy is currently being reconsidered, after the recent approval of arsenic trioxide (Trisenox(R)) for the treatment of relapsed promyelocytic leukemia (PML). In an attempt to prepare a carrier system to minimize the toxicity of this drug, the aim of this study is to prepare and characterize liposomes encapsulating arsenic trioxide (ATO). For this, we prepared different types of liposomes entrapping ATO: large multilamellar (MLV), sonicated (SUV) and dried reconstituted vesicles (DRV). The techniques used were: thin film hydration, sonication and the DRV method, respectively. Two lipid compositions were studied for each liposome type, EggPC/Chol (1: 1) and DSPC/Chol (1: 1). After liposome preparation, drug encapsulation was evaluated, by measuring arsenic in liposomes. For this, energy-dispersive X-ray fluorescence spectroscopy or atomic absorption was used. In addition, the retention of the drug in the liposomes was evaluated after incubating the liposomes in buffer at 37degreesC. The experimental results reveal that encapsulation of ATO in liposomes ranges between 0.003 and 0.506 mol/ mol of lipid, and is highest in the DRV vesicles and lowest in the small unilamellar vesicles, as anticipated. Considering the in vitro stability of ATO-encapsulating liposomes: 1) For the PC/Chol liposomes (DRV and MLV), after 24 hours of incubation, more than 70% (or 90% in some cases) of the initially encapsulated amount of ATO was released. 2) The liposomes composed of DSPC/Chol could retain substantially higher amounts of ATO, especially the DRV liposomes (54% retained after 24 h). 3) In the case of PC/Chol, temperature of incubation has no effect on the ATO release after 24 hours, but affects the rate of ATO release in the MLV liposomes, while for the DSPC/Chol liposomes there is a slight increase (statistically insignificant) of ATO release at higher temperature

Evaluation of poly (glycerol-adipate) nanoparticle uptake in an In Vitro 3-D brain tumor co-culture model

Despite the inherent problems associated with in vivo animal models of tumor growth and metastases, many of the current in vitro brain tumor models also do notaccurately mimic tumor-host brain interactions. Therefore, there is a need to develop such co-culture models to study tumor biology and, importantly, the efficacy of drug delivery systems targeting the brain. So far, few investigations of this nature have been published. In this paper we describe the development of a new model system and its application to drug delivery assessment. For our new model, a co-culture of DAOY cell brain tumor aggregates and organo-typic brain slices was developed. Initially, the DAOY aggregates attached to cerebellum slices and invaded as a unit. Single cells in the periphery of the aggregate detached from the DAOY aggregates and gradually replaced normal brain cells. This invasive behavior of DAOY cells toward organotypic cerebellum slices shows a similar pattern to that seen in vivo. A er validation of the co-culture model using transmission electron microscopy, nanoparticle (NP) uptake was then evaluated. Confocal micrographs illustrated that DAOY cells in this co-culture model took up most of the NPs, but few NPs were distributed into brain cells. This finding corresponded with results of NP uptake in DAOY and brain aggregates reported elsewhere

Characterization, Stability and In - Vivo Distribution of Asialofetuin Glycopeptide Incorporating DSPC/CHOL Liposomes Prepared by Mild Cholate Incubation

In this study, a small triantennary asialoglycopeptide of fetuin (A-F-2) was used as a ligand to direct liposomes to hepatocytes. A-F2 was cleaved from asialofetuin, purified, conjugated with fatty acids and incorporated into pre-formed sonicated DSPC/Chol (2:1) liposomes. A mild cholate incubation method for incorporating the A-F2 ligand on pre-formed vesicles was used. In preliminary in vivo experiments In-111(3+) encapsulated in A-F-2/palmityl liposomes was seen to accumulate in the liver of mice significantly faster than when encapsulated in non-ligand bearing liposomes of the same lipid composition (studied before), justifying further investigation of this system. The presence of the A-F-2/fatty acid conjugate in a functional form on the vesicle surface was confirmed by their reversible agglutination in the presence of Ricinus communis agglutinin (RCA(120)). Effects of ligand incorporation on the vesicle size distribution, z-potential, membrane integrity and stability were monitored. The results demonstrate that highest ligand incorporation was achieved when liposomes and ligand were co-incubated in the presence of 1mM sodium cholate. Incorporation increased with the length of the fatty acid used for A-F2 conjugation. Ligand-bearing liposomes were demonstrated to be smaller in diameter (about 30%) with a more positive z-potential in comparison to control vesicles while ligand incorporation did not influence the liposome membrane integrity. The size of the ligand-incorporating vesicles was maintained after 24 hours of incubation in isotonic buffer, proving that the vesicles do not aggregate. Although the preliminary biodistribution results may suggest that ligand bearing liposomes are accumulating in the liver, further cell culture in vivo distribution and especially liver fractionation studies are required in order to clarify the intrahepatic localization of these liposomes and the ability to target liver hepatocytes in vivo