Susan Hua

Advances and Challenges of Liposome Assisted Drug Delivery

The application of liposomes to assist drug delivery has already had a major impact on many biomedical areas. They have been shown to be beneficial for stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo. This enables effective delivery of encapsulated compounds to target sites while minimizing systemic toxicity. Liposomes present as an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address different delivery considerations. Despite considerable research in the last 50 years and the plethora of positive results in preclinical studies, the clinical translation of liposome assisted drug delivery platforms has progressed incrementally. In this review, we will discuss the advances in liposome assisted drug delivery, biological challenges that still remain, and current clinical and experimental use of liposomes for biomedical applications. The translational obstacles of liposomal technology will also be presented.

Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue.

UNLABELLED Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohns disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. FROM THE CLINICAL EDITOR Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations.

The use of lipid-based nanocarriers for targeted pain therapies

Sustained delivery of analgesic agents at target sites remains a critical issue for effective pain management. The use of nanocarriers has been reported to facilitate effective delivery of these agents to target sites while minimizing systemic toxicity. These include the use of biodegradable liposomal or polymeric carriers. Of these, liposomes present as an attractive delivery system due to their flexible physicochemical properties which allow easy manipulation in order to address different delivery considerations. Their favorable toxicity profiles and ease of large scale production also make their clinical use feasible. In this review, we will discuss the concept of using liposomes as a drug delivery carrier, their in vitro characteristics as well as in vivo behavior. Current advances in the targeted liposomal delivery of analgesic agents and their impacts on the field of pain management will be presented.

A role for acute-phase serum amyloid A and high-density lipoprotein in oxidative stress, endothelial dysfunction and atherosclerosis.

Abstract The acute-phase protein serum amyloid A (SAA) is a clinically useful marker of inflammation and associates strongly with increased risk of cardiovascular events. Chronically elevated SAA concentrations may contribute to physiological processes that lead to atherosclerosis, including endothelial dysfunction, an early and predictive event in the development of cardiovascular disease. Accumulating data suggest that SAA can be a direct mediator in the development and progression of atherogenesis and atherothrombosis. SAA may affect key events underlying acute coronary syndromes, including cholesterol transport, contribute to endothelial dysfunction, promote thrombosis, and enhance leukocyte trafficking and activation. This review summarizes the evidence supporting a role for SAA as a potential regulator of inflammation and endothelial dysfunction, which underlie the adverse outcomes that complicate coronary artery disease. The findings suggest that novel therapeutic strategies to reduce SAA levels and/or oppose the actions of SAA may have beneficial effects in patients with coronary artery disease.

Targeting sites of inflammation: intercellular adhesion molecule-1 as a target for novel inflammatory therapies

Targeted drug delivery to sites of inflammation will provide effective, precise, and safe therapeutic interventions for treatment of diverse disease conditions, by limiting toxic side effects and/or increasing drug action. Disease-site targeting is believed to play a major role in the enhanced efficacy observed for a variety of drugs when formulated inside lipid vesicles. This article will focus on the factors and mechanisms involved in drug targeting to sites of inflammation and the importance of cell adhesion molecules, in particular intercellular adhesion molecule-1, in this process.

Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions.

Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors.

Lipid-based nano-delivery systems for skin delivery of drugs and bioactives.

Topical drug delivery across the skin can offer many advantages, such as confer sustained drug release, lower fluctuations in plasma drug levels, circumvent first-pass metabolism, improve patient compliance, and provide local (dermal), or systemic (transdermal) effects (Schafer-Korting et al., 2007; El Maghraby et al., 2008). However, the barrier function of the skin, exerted by the horny layer of the stratum corneum, impairs the penetration and absorption of drugs (Bouwstra and Ponec, 2006). This layer prevents the penetration of hydrophilic compounds much more efficiently as compared to lipophilic compounds (Bouwstra et al., 2003; Bouwstra and Ponec, 2006). Therefore, there has been wide interest in exploring new techniques to increase drug absorption through the skin. Novel topical drug delivery systems, with the use of nanotechnology in dosage form design, have been used to facilitate overcoming the skin barrier. This article will summarize recent findings of lipid-based nano-delivery systems for skin delivery of drugs and bioactives agents.

The acute-phase protein serum amyloid A induces endothelial dysfunction that is inhibited by high-density lipoprotein.

The acute-phase protein serum amyloid A (SAA) is elevated during inflammation and may be deposited in atheroma where it promotes atherosclerosis. We investigated the proatherogenic effects of SAA on the vascular endothelium and their regulation by high-density lipoprotein (HDL). Exposure of human aortic endothelial cells (HAEC) to SAA (0.25-25μg/ml) decreased nitric oxide ((•)NO) synthesis/bioavailability, although the endothelial NO synthase monomer-to-dimer ratio was unaffected. SAA (10μg/ml) stimulated a Ca(2+) influx linked to apocynin-sensitive superoxide radical anion (O(2)(•-)) production. Gene expression for arginase-1, nuclear factor κB (NF-κB), interleukin-8, and tissue factor (TF) increased within 4h of SAA stimulation. Enzymatically active Arg-1/2 was detected in HAEC cultured with SAA for 24h. Therefore, in addition to modulating (•)NO bioavailability by stimulating O(2)(•-) production in the endothelium, SAA modulated vascular l-Arg bioavailability. SAA also diminished relaxation of preconstricted aortic rings induced by acetylcholine, and added superoxide dismutase restored the vascular response. Preincubation of HAEC with HDL (100 or 200, but not 50, μg/ml) before (not after) SAA treatment ameliorated the Ca(2+) influx and O(2)(•-) production; decreased TF, NF-κB, and Arg-1 gene expression; and preserved overall vascular function. Thus, SAA may promote endothelial dysfunction by modulating (•)NO and l-Arg bioavailability, and HDL pretreatment may be protective. The relative HDL to SAA concentrations may regulate the proatherogenic properties of SAA on the vascular endothelium.

The neural cell adhesion molecule antibody blocks cold water swim stress-induced analgesia and cell adhesion between lymphocytes and cultured dorsal root ganglion neurons

BACKGROUND:Opioid-containing immune cells migrate in a site-directed manner into inflamed tissue and adhere to sensory nerve fibers. These cells release opioid peptides in close proximity to these fibers, thereby avoiding localized degradation by peptidases, and delivering opioid peptides proximal to opioid receptors to provide antinociception. METHODS:The effects of the anti–neural-cell-adhesion molecule (anti-NCAM) were assessed on cold water swim stress-induced antinociception in Wistar rats with Freund’s adjuvant-induced inflammation of one hindpaw. Algesiometry was assessed for both thermal and mechanical stimuli. Cell adhesion experiments examining the effects of &bgr;-endorphin and antibodies to NCAM and intercellular cell adhesion molecule-1 and were performed on cultured dorsal root ganglion neurons and isolated lymphocytes. Lymphocyte binding was determined by fluorescence using calcein AM loaded into freshly isolated lymphocytes. RESULTS:The direct adhesion between lymphocytes and cultured sensory neurons was inhibited by anti-NCAM. This adhesion was also demonstrated to be opioid dependent, with lymphocyte adhesion to cultured sensory neurons reduced in the presence of 1 &mgr;M &bgr;-endorphin, which was reversed by 100 &mgr;M naloxone. Moreover, anti-NCAM blocked cold-water-swim-induced analgesia in inflamed paws both to thermal and mechanical stimuli. However, anti-NCAM did not affect fentanyl-induced antinociception. CONCLUSIONS:This study provides insight into the role of cell adhesion molecules in lymphocyte adhesion to sensory neurons and a link to immune-derived antinociception.

Comparison of in vitro dialysis release methods of loperamide-encapsulated liposomal gel for topical drug delivery

Background The purpose of this study was to determine the most appropriate dialysis equilibrium method to assess liposomal gel formulations containing hydrophobic drugs, to give the most accurate indication of drug release. Methods Loperamide hydrochloride-encapsulated liposomes, composed of L-α-phosphatidylcholine and cholesterol (molar ratio of 2:1), were prepared according to the method of dried lipid film hydration. The liposomes were incorporated into a carbopol gel (0.5%, weight/weight). The release of the drug from the nanoparticles was assessed using a number of variations of the dialysis technique, taking into account solubility parameters and formulation. Method 1 (below saturation point) and Method 2 (above saturation point) used a dilution method to evaluate how drug concentration and solubility affects the in vitro drug-release profile of loperamide hydrochloride, while Methods 3 (below saturation point) and 4 (above saturation point) evaluated how drug concentration and the gel base affect the release profile. Results In Method 1, the liposomes showed a rapid release of just over 60% in the first 3 hours and then a slower, sustained release to just over 70% at 24 hours. Method 2 showed a gradual, sustained release profile with the liposomes with 55% release at 24 hours. In Method 3, the liposomes showed a rapid burst release of 98% at 2 hours. In Method 4, the liposomal gel had a rapid release of 60% within 3 hours and then a more gradual, sustained release with 86% release at 24 hours. The free drug suspension in Methods 2 and 4 showed a limited release across the dialysis membrane, in comparison to Methods 1 and 3, which showed a complete release in a timely manner. Conclusion This study has demonstrated that the actual method used for equilibrium dialysis plays a significant role in determining the true characteristics of a topical nanoformulation, with Method 3 providing the most accurate indication of the release of a hydrophobic drug from a topical liposomal formulation.