Lipid-based Drug Carriers Research Articles

Archaeal lipids in oral delivery of therapeutic peptides

Archaea contain membrane lipids that differ from those found in the other domains of life (Eukarya and Bacteria). These lipids consist of isoprenoid chains attached via ether bonds to the glycerol carbons at the sn-2,3 positions. Two types of ether lipids are known, polar diether lipids and bipolar tetraether lipids. The inherent chemical stability and unique membrane-spanning characteristics of tetraether lipids render them interesting for oral drug delivery purposes. Archaeal lipids form liposomes spontaneously (archaeosomes) and may be incorporated in conventional liposomes (mixed vesicles). Both types of liposomes are promising to protect their drug cargo, such as therapeutic peptides, against the acidic environment of the stomach and proteolytic degradation in the intestine. They appear to withstand lipolytic enzymes and bile salts and may thus deliver orally administered therapeutic peptides to distant sections of the intestine or to the colon, where they may be absorbed, eventually by the help of absorption enhancers. Archaeal lipids and their semisynthetic derivatives may thus serve as biological source for the next generation oral drug delivery systems.The aim of this review is to present a systematic overview over existing literature on archaea carrying diether and tetraether lipids, lipid diversity, means of lipid extraction and purification, preparation and in vitro stability studies of archaeal lipid-based liposomal drug carriers and in vivo proof-of concepts studies.

Targeting and modulating infarct macrophages with hemin formulated in designed lipid-based particles improves cardiac remodeling and function

Uncontrolled activation of pro-inflammatory macrophages after myocardial infarction (MI) accelerates adverse left ventricular (LV) remodeling and dysfunction. Hemin, an iron-containing porphyrin, activates heme oxygenase-1 (HO-1), an enzyme with anti-inflammatory and cytoprotective properties. We sought to determine the effects of hemin formulated in a macrophage-targeted lipid-based carrier (denoted HA-LP) on LV remodeling and function after MI.Hemin encapsulation efficiency was ~100% at therapeutic dose levels. In vitro, hemin/HA-LP abolished TNF-α secretion from macrophages, whereas the same doses of free hemin and drug free HA-LP had no effect. Hemin/HA-LP polarized peritoneal and splenic macrophages toward M2 anti-inflammatory phenotype. We next induced MI in mice and allocated them to IV treatment with hemin/HA-LP (10mg/kg), drug free HA-LP, free hemin (10mg/kg) or saline, one day after MI. Active in vivo targeting to infarct macrophages was confirmed with HA-LP doped with PE-rhodamine. LV remodeling and function were assessed by echocardiography before, 7, and 30days after treatment. Significantly, hemin/HA-LP effectively and specifically targets infarct macrophages, switches infarct macrophages toward M2 anti-inflammatory phenotype, improves angiogenesis, reduces scar expansion and improves infarct-related regional function.In conclusion, macrophage-targeted lipid-based drug carriers with hemin switch macrophages into an anti-inflammatory phenotype, and improve infarct healing and repair. Our approach presents a novel strategy to modulate inflammation and improve infarct repair.

Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs

Event Abstract Back to Event Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs Elżbieta Pamuła1, Katarzyna Reczyńska1 and Wojciech Chrzanowski2 1 AGH University of Science and Technology, Department of Biomaterials, Faculrty of Materials Science and Ceramics, Poland 2 The University of Sydney, Faculty of Pharmacy, Australia Introduction: Currently the treatment of lung cancer lacks non-invasively targetable and controlled release topical inhalation therapy. Passive targeting using iron-oxide nanoparticles and magnetic field and their ability to induce localised hyperthermia under oscillating magnetic field could potentially enable both goals in one system. This study developed temperature sensitive lipid-based drug carriers containing superparamagnetic iron-oxide nanoparticles (SPIONs) that are: inhalable, targetable and temperature-sensitive. This system exploits combined effects of pharmaceutics and hyperthermia to enhance synergistically efficacy of the cancer therapy. Materials and Methods: Fatty acids (lauric, palmitic and stearic as well as their mixtures) with melting temperature of 40 - 45oC (hyperthermia conditions) were chosen. Paclitaxel (PAX) and SPIONs were dissolved/dispersed in a melted lipid phase at different SPION/lipid ratios and solid lipid particles were produced using oil in water emulsification. The particle size, thermal properties, chemical composition were assessed using Raman spectroscopy, SEM,EDX, AFM, DSC and drug release tests. Results and Discussion: Developed particles were spherical shape, with an average diameter of 2-6 μm. Thermal and chemical analyses confirmed the presence of PAX and SPIONs inside the lipid matrix. Thermal properties of lipid microparticles, thus their ability to release the drug at specific temperature, were tuned by the formation of eutectic composition obtained by mixing different types of fatty acids. The lipid formulations were shown to have slow release profile at body temperature, but fast release at hyperthermic conditions (45°C), suggesting a potentially powerful controlled release therapy of lung cancer. Conclusion: (i) PAX and SPIONs loaded lipid microparticles of desired size and physical-chemical characteristics were fabricated using oil in water emulsification technique; (ii) the lipid system was thermo-sensitive, allowing controlled release of PAX; (iii) the system holds a promise as an effective drug vehicle in targeted and controlled inhalation therapy. This study was supported by Polish National Science Center (No 2014/14/M/ST5/00649). Keywords: Drug delivery, stimuli-response, targeting delivery, Nano/micro particle Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Biomaterials for therapeutic delivery Citation: Pamuła E, Reczyńska K and Chrzanowski W (2016). Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02822 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski Google Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski Google Scholar Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski PubMed Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Lipid-based drug carriers for prodrugs to enhance drug delivery.

The combination of lipid drug delivery systems with prodrugs offers several advantages including improved pharmacokinetics, increased absorption, and facilitated targeting. Lipidization and use of lipid carriers can increase the pharmacological half-life of the drug, thus improving pharmacokinetics and allowing less frequent dosing. Lipids also offer advantages such as increased absorption through the intestines for oral drug absorption and to the CNS for brain delivery. Furthermore, the use of lipid delivery systems can enhance drug targeting. Endogenous proteins bind lipids in the blood and carry them to the liver to enable targeting of this organ. Drugs with significant side effects in the stomach can be specifically delivered to enterocytes by exploiting lipases for prodrug activation. Finally, lipids can be used to target the lymphatic system, thus bypassing the liver and avoiding first-pass metabolism. Lymphatic targeting is also important for antiviral drugs in the protection of B and T lymphocytes. In this review, both lipid-drug conjugates and lipid-based carriers will be discussed. An overview, including the chemistry and assembly of the systems, as well as examples from the clinic and in development, will be provided.

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drug Fenofibrate: Effects of Digestion

Lipid-based drug carriers are likely to have influence on bioavailability through enhanced solubilization of the drug in the gastrointestinal tract. The study was designed to investigate the lipid formulation digestibility in the simulated gastro intestinal media. Fenofibrate was formulated in representative Type II, IIIA, IIIB and IV self-emulsifying/microemulsifying lipid delivery systems (SEDDS and SMEDDS designed for oral administration) using various medium-chain glyceride components, non-ionic surfactants and cosolvents as excipients. Soybean oil was used only as an example of long-chain triglycerides to compare the effects of formulation with their counterparts. The formulations were subjected to in vitro digestion specifically to predict the fate of the drug in the gastro intestinal tract after exposure of the formulation to pancreatic enzymes and bile. In vitro digestion experiments were carried out using a pH-stat maintained at pH7.5 for 30min using intestinal fluids simulating the fed and fasted states. The digestion rate was faster and almost completed in Type II and IIIA systems. Most of the surfactants used in the studies are digestible. However, the high concentration of surfactant and/or cosolvent used in Type IIIB or IV systems lowered the rate of digestion. The digestion of medium-chain triglycerides was faster than long-chain triglycerides, but kept comparatively less drug in the post digestion products. Medium-chain mixed glycerides are good solvents for fenofibrate as rapidly digested but to improve fenofibrate concentration in post digestion products the use of long-chain mixed glycerides are suggested for further investigations.

Gadolinium Containing Photochromic Micelles as Potential Magnetic Resonance Imaging Traceable Drug Carriers

Novel photochromic amphipathic molecules, KMR-AZn (Gd-DTPA-AZCn), composed of hydrophilic Gd-DTPA and hydrophobic alkylated azobenzene were prepared. In aqueous environment, KMR-AZn indicated self-assembly. The resulting aggregates were demonstrated to be able to include a hydrophobic drug substitute (hydrophobic fluorescent dye) into the internal core, and to release the included compound upon photoirradiation within 10 min through the influence of azobenzene photoisomerization. This micellar MRI contrast agent exhibited three- to four-fold higher r(1) relaxivity (r(1) = 14.5-16.5 mM(-1) s(-1), 0.47 T at 40°C) than the widely applied small molecule contrast agent Gd-DTPA (Magnevist(®) r(1) = 4.1 mM(-1) s(-1), 0.47 T at 40°C). This dual functionality of encapsulated compound release and increased MR imaging contrast indicates that KMR-AZn is a potential candidate for application as a lipid-based MRI-traceable drug carrier.

Lipid-Based Drug Delivery Systems for Cancer Treatment

It is a fact that chemotherapy agents have little specificity for cancer cells, this leading to low concentrations into the tumor interstititum and severe side effects on healthy tissues. The formulation of lipid-based nanomedicines against cancer has been hypothesized to improve drug localization into the tumor tissue and to increase the anticancer efficacy of concentional drugs, while minimizing their systemic adverse effects. In this review, special attention is devoted to the analysis of the state-of-the-art in the development of lipid-based drug carriers against cancer. Specifically, the most significant in vitro and in vivo results on the use of niosomes, liposomes, and solid lipid nanoparticles are revised. It is concluded that biodistribution profiles of chemotherapy agents can be controlled by their loading to such nanoplatforms. Lipid-based nanomedicines offer an interesting approach to the delivery of anticancer drugs to brain tumors, and to reverse multi-drug resistance of cancer cells. Finally, a deep evaluation of the applicability of drug delivery strategies in the formulation of lipid-based nanoplatforms is carried out. They involve active drug targeting (including ligand-mediated delivery, and stimuli-sensitive carriers), and passive drug targeting (through the enhanced permeability and retention effect) to tumors.

Size control of lipid-based drug carrier by drug loading

A phospholipid-protein hybrid nanostructure was found to reveal various hydrodynamic diameters dependent on the amount of the drugs incorporated, which could be over 10 times larger than that of the starting nanostructure. This observation was likely related to the thermal stabilization of the nanostructure during incorporation of the drugs by using the increased amount of phospholipids for the preparation. Furthermore, hydrophobicity or molecular weight of drugs is at least needed for size control.

Gemini Surfactant Based Carriers in Gene and Drug Delivery

Lipid-based drug carriers, such as liposomes or drug/lipid complexes, have been extensively investigated in a large number of therapeutic protocols such as gene therapy, drug delivery, drug targeting and antibacterial treatments, in preclinical and clinical trials. Many formulations composed of natural and/or synthetic amphiphiles have been studied. Many synthetic lipids and surfactants have been designed and tested in order to improve liposomes and lipid complexes performances, such as fusion with cellular membrane, cellular uptake, target selectivity, transfection efficiency, low toxicity. Among these, gemini surfactants have been shown to be highly effective in delivering genetic material to cells, and also have been shown promising as synthetic additives in liposome formulations for drug delivery. The encouraging results obtained in gene therapy have given impulse to chemist creativity: an extensive selection of pH sensitive, sugar-, aminoacid- , and peptide-based gemini surfactants have been developed, many of which have shown good biological features. This review focuses on recent progress in gemini surfactant based formulations and their applications in different therapeutic protocols.

A novel lipid-based drug carrier targeted to the non-parenchymal cells, including hepatic stellate cells, in the fibrotic livers of bile duct ligated rats

In fibrotic livers, collagen producing hepatic stellate cells (HSC) represent a major target for antifibrotic therapies. We designed liposomes with surface-coupled mannose 6-phosphate (M6P) modified human serum albumin (HSA) to target HSC via the M6P receptor. In this study we determined the pharmacokinetics and target specificity of M6P-HSA-liposomes in a rat model of liver fibrosis. Ten minutes after injection of [ 3H]-M6P-HSA-liposomes 90% of the dose has cleared the circulation. The blood elimination of these liposomes was counteracted by free M6P-HSA and polyinosinic acid, a competitive inhibitor of scavenger receptors. The M6P-HSA-liposomes accumulated in HSC. However, also Kupffer cells and endothelial cells contributed to the uptake of M6P-HSA-liposomes in the fibrotic livers. Polyinosinic acid inhibited the accumulation of the liposomes in Kupffer cells and liver endothelial cells, but not in HSC. PCR analysis revealed that cultured HSC express scavenger receptors. This was confirmed by Western blotting, although activation of HSC diminishes scavenger receptor protein expression. In conclusion, in a rat model for liver fibrosis M6P-HSA-liposomes can be efficiently targeted to non-parenchymal cells, including HSC. M6P receptors and scavenger receptors are involved in the cellular recognition of these liposomes, allowing multiple pharmacological interference in different pathways involved in the fibrosis.

Effects of a New Bioactive Lipid-Based Drug Carrier on Cultured Hepatic Stellate Cells and Liver Fibrosis in Bile Duct-Ligated Rats

In the fibrotic liver, hepatic stellate cells (HSC) produce large amounts of collagen and secrete variety of mediators that promote development of fibrosis in this organ. Therefore, these cells are considered an attractive target for antifibrotic therapies. We incorporated the bioactive lipid dilinoleoylphosphatidylcholine (DLPC) into the membrane of liposomes, and then we evaluated its effect on hepatic stellate cell activation and liver fibrosis. To target DLPC-liposomes to HSC, human serum albumin modified with mannose 6-phosphate (M6P-HSA) was coupled to the surface of these liposomes. In vitro, the effects of the carrier were determined in primary cultures of HSC, Kupffer cells, and liver endothelial cells using real-time reverse transcription-polymerase chain reaction. In vivo DLPC-liposomes were tested in bile duct-ligated rats. Targeted M6P-HSA-DLPC-liposomes and DLPC-liposomes significantly reduced gene expression levels for collagen 1alpha1, alpha-smooth muscle actin (alpha-SMA), and transforming growth factor-beta (TGF-beta) in cultured HSC. In fibrotic livers, DLPC-liposomes decreased gene expression for TGF-beta and collagen 1alpha1 as well as alpha-SMA and collagen protein expression. In contrast, M6P-HSA-DLPC-liposomes enhanced expression of profibrotic and proinflammatory genes in vivo. In cultured Kupffer and endothelial cells M6P-HSA liposomes influenced the expression of proinflammatory genes. Both types of liposomes increased hepatocyte glycogen content in fibrotic livers, indicating improved functionality of the hepatocytes. We conclude that DLPC-containing liposomes attenuate activation of cultured HSC. In fibrotic livers, M6P-HSA-mediated activation of Kupffer and endothelial cells probably counteracts this beneficial effect of DLPC-liposomes. Therefore, these bioactive drug carriers modulate the activity of all liver cells during liver fibrosis.

Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)

Synthesis of a radiolabeled diglyceride, 3-[(18)F]fluoro-1,2-dipalmitoylglycerol [[(18)F]fluorodipalmitin ([(18)F]FDP)], and its potential as a reagent for radiolabeling long-circulating liposomes were investigated. The incorporation of (18)F into the lipid molecule was accomplished by nucleophilic substitution of the p-toluenesulfonyl moiety with a decay-corrected yield of 43+/-10% (n=12). Radiolabeled, long-circulating polyethylene-glycol-coated liposomes were prepared using a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] ammonium salt (61:30:9) and [(18)F]FDP with a decay-corrected yield of 70+/-8% (n=4). PET imaging and biodistribution studies were performed with free [(18)F]FDP and liposome-incorporated [(18)F]FDP. Freely injected [(18)F]FDP had the highest uptake in the liver, spleen and lungs. Liposomal [(18)F]FDP remained in blood circulation at near-constant levels for at least 90 min, with a peak concentration near 2.5%ID/cc. Since [(18)F]FDP was incorporated into the phospholipid bilayer, it could potentially be used for radiolabeling a variety of lipid-based drug carriers.

Addressing Liver Fibrosis with Liposomes Targeted to Hepatic Stellate Cells

Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of liver fibrosis is mainly based on the removal of the underlying cause of the disease and liver transplantation, which is the only treatment for patients with advanced fibrosis. Hepatic stellate cells (HSC) are considered to be key players in the development of liver fibrosis. Chronically activated HSC produces large amounts of extracellular matrix and enhance fibrosis by secreting a broad spectrum of cytokines that exert pro-fibrotic actions in other cells, and in an autocrine manner perpetuate their own activation. Therefore, therapeutic interventions that inhibit activation of HSC and its pro-fibrotic activities are currently under investigation worldwide. In the present study we applied targeted liposomes as drug carriers to HSC in the fibrotic liver and explored the potential of these liposomes in antifibrotic therapies. Moreover, we investigated effects of bioactive compounds delivered by these liposomes on the progression of liver fibrosis. To our knowledge, this is the first study demonstrating that lipid-based drug carriers can be selectively delivered to HSC in the fibrotic liver. By incorporating the bioactive lipid DLPC, these liposomes can modulate different processes such as inflammation and fibrogenesis in the fibrotic liver. This dual functionality of liposomes as a drug carrier system with intrinsic biological effects may be exploited in new approaches to treat liver fibrosis.

Investigation of dynamic processes in lipid-based nanoparticulate drug carrier systems with small and wide angle X-ray diffraction

Colloidal lipid-based particles offer interesting possibilities in drug delivery, in particular for the administration of poorly water soluble drugs, e.g. into the bloodstream. Such particles can be prepared by high-pressure homogenisation of the respective lipids in an aqueous phase with adequate stabilizers. Since thematerial properties of thematrix lipids in the colloidal state may differ significantly from those of the raw materials adequate characterization of the prepared particles is a very important part of the development work on such systems to ensure the formation of the desired particle properties. X-ray diffraction (XRD) in combinationwith complementarymethods such as, e.g., differential scanning calorimetry (DSC) and electron microscopy, has proven to be a very effective tool for this purpose. Examples will be shown from three different types of lipid drug carrier systems: solid lipid nanoparticles, supercooled smectic nanoparticles and nanoparticles of cubic phase. When solid lipid nanoparticles are prepared via triglyceride melts, a pronounced supercooling effect is often observed which may impair the formation of the desired solid state. Certain emulsifiers can increase the crystallization temperature and thus improve the solidification behaviour of the nanoparticles but their use is often accompanied by additional thermal events prior to triglyceride crystallization. According to XRD these additional thermal events correspond to the crystallization of a surfactant layer at the particle surface which may also include some of the triglyceride in dependence on the composition. The emulsifiers may also modify the polymorphic transitions of the triglycerides after crystallization. Generally, polymorphic transitions are faster in the nanoparticles than in the bulk and sometimes a more stable modification than observed for the bulk material is reached. Also within the colloidal size range different transition rates can be observed with smaller particles transforming faster than larger ones. For small nanoparticles from saturated monoacid triglycerides, a structured melting event is observed in DSC that is not caused by polymorphism but has to be attributed to a particle size effect according to XRD. An influence of the type of emulsifier is also observed for the crystallization behaviour of nanoparticles based on supercooled smectic phase cholesterol esters. The typical bimodal crystallization process observed in phospholipid-containing cholesteryl myristate dispersions is not due to polymorphism as confirmed by XRD but probably reflects the crystallization properties of particles with different shapes. The temperature dependence of different preparation processes for cubic phase nanoparticles based on aqueous monoolein/poloxamer systems seems to be related to the phase behaviour as indicated by results from small angle XRD. m37.o05

322 A novel lipid-based drug carrier targeted to the non-parenchymal cells, including hepatic stellate cells, in the fibrotic livers of bile duct ligated rats

322 A novel lipid-based drug carrier targeted to the non-parenchymal cells, including hepatic stellate cells, in the fibrotic livers of bile duct ligated rats

Investigation on particle self-assembly in solid lipid-based colloidal drug carrier systems.

The effect of spontaneous particle self-assembly into stack-like structures occurring in dispersions of melt-homogenized tripalmitin nanocrystals (solid lipid nanoparticles; SLNs) was studied in dependence of lipid concentration, stabilizer type, stabilizer concentration, and particle size. Tripalmitin nanosuspensions with concentrations ranging from 20 to 200 mg/g were prepared by high-pressure melt homogenization. The formulations were characterized by synchrotron small-angle X-ray scattering (SAXS), photon correlation spectroscopy (PCS), and freeze-fracture transmission electron microscopy (TEM). Dispersions of partly self-assembled particles could be derived both with anionic or cationic surfactants. Particle self-assemblies were observed in such formulations when the tripalmitin concentration exceeds 40 mg/g. Further increase of the lipid concentration enhances particle self-assembly. The tendency to form self-assemblies is also influenced by the particle shape. The interparticle distances in stacked lamellae are determined by the tripalmitin concentration and by the surfactant concentration. Parallel alignment of tripalmitin nanoplatelets is a completely reversible and concentration-dependent effect that can be attributed to the overlap of the exclusion volumes of the anisometric particles. The usefulness of this effect might be explored for the formulation of drug delivery systems.

Lipid association increases the potency against primary medulloblastoma cells and systemic exposure of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats.

To reduce the systemic toxicity and prolong the systemic presence of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), a lipid-based drug carrier was designed and characterized. The degree of CCNU association with lipid vesicles composed of 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) (1:1, m/m) was characterized and the drug decomposition rates of lipid-drug complexes were monitored. Effects of lipid association on drug potency against medulloblastoma cells and total systemic drug exposure in rats were determined. At a CCNU:lipid molar ratio greater than 1:5, more than 90% of the drug was associated with the lipid vesicles. In aqueous suspensions, lipid association significantly reduced the first-order drug decomposition rate. In addition, lipid-associated CCNU exhibited a 4-fold increase in drug sensitivity with medulloblastoma cells. IC50 values for CCNU admixed and encapsulated with lipid vesicles were 18+/-4.9 and 14.0+/-2.2 microM, respectively, compared to 83+/-11.0 microM for free CCNU. When administered to rats, lipid-associated CCNU increased the AUC (area under the concentration-time curve) of CCNU by approximately 2-fold (20.46+/-2.15 compared to 39.59+/-1.87 microg x min/ml), and the terminal half-life (t1/2beta) by almost 9-fold (17+/-9 compared to 147+/-48 min) over free CCNU. Despite the increase in total systemic drug exposure, rats treated with lipid-associated CCNU exhibited a significantly lower frequency of acute neurotoxicity. These data indicate that CCNU associated with lipid vesicles may increase drug stability, potency, and systemic exposure in rats.

Comparative study of the association of itraconazole with colloidal drug carriers

In the present study, the association of a new hydrophobic triazole derivative, itraconazole, with intravenously compatible drug carriers (liposomes, cholesterol complexes, nanospheres) was evaluated and the different association yields compared. We tried to elucidate the mechanism of drug-carrier association by means of dilution and zeta potential measurement in the most promising formulations. The different lipid-based drug carriers yielded low association efficiencies (< 0.6%), whereas itraconazole loading into chemically modified β-cyclodextrin nanospheres reached 6.8% (0.170 mg/mL). The longer the hydrophobic chain linked to the β-cyclodextrin, the higher the association of itraconazole within the nanospheres. The highest association yields, 4.1% (0.510 mg/mL), were obtained with nanospheres composed of the most hydrophobic polymer tested, poly-i-caprolactone, and a negatively charged steroidal surfactant, sodium deoxycholate. Itraconazole seems to be both included in the matrix (40%) and adsorbed at the surface of the nanospheres (60%). This may explain the nanosphere instability with time because of continuous itraconazole desorption from the nanospheres, although the nanosphere mean size remained unchanged. The enhanced association yields observed with sodium deoxycholate were not the result of electrostatic attraction between itraconazole (a weak base) and the negatively charged surfactant but rather to stronger hydrophobic interactions between itraconazole and sodium deoxycholate, and to increased specific area of sodium deoxycholate-coated nanospheres. This latter was due to the smaller mean diameter (80 nm) of the sodium deoxycholate-coated nanospheres compared with non ionic surfactant-coated nanospheres (130 nm). © 1996 Wiley-Liss, Inc.