Liposomal drug delivery systems: from concept to clinical applications.

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biological barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.

Strategies in the design of nanoparticles for therapeutic applications

Doxil®--the first FDA-approved nano-drug: lessons learned.

The fish gill is a multipurpose organ that, in addition to providing for aquatic gas exchange, plays dominant roles in osmotic and ionic regulation, acid-base regulation, and excretion of nitrogenous wastes Thus, despite the fact that all fish groups have functional kidneys, the gill epithelium is the site of many processes that are mediated by renal epithelia in terrestrial vertebrates Indeed, many of the pathways that mediate these processes in mammalian renal epithelial are expressed in the gill, and many of the extrinsic and intrinsic modulators of these processes are also found in fish endocrine tissues and the gill itself The basic patterns of gill physiology were outlined over a half century ago, but modern immunological and molecular techniques are bringing new insights into this complicated system Nevertheless, substantial questions about the evolution of these mechanisms and control remain

https://people.clas.ufl.edu/devans/files/PRVGill.pdf

The Multifunctional Fish Gill: Dominant Site of Gas Exchange, Osmoregulation, Acid-Base Regulation, and Excretion of Nitrogenous Waste

Advanced strategies in liposomal cancer therapy: problems and prospects of active and tumor specific drug release.

Dynamical order and disorder in lipid bilayers

Methoxy(polyethylene glycol), mPEG, -grafted liposomes are known to exhibit prolonged circulation time in the blood, but their infusion into a substantial percentage of human subjects triggers immediate non-IgE-mediated hypersensitivity reactions. These reactions are strongly believed to arise from anaphylatoxin production through complement activation. Despite the general view that vesicle surface camouflaging with mPEG should dramatically suppress complement activation, here we show that bilayer enrichment of noncomplement activating liposomes [dipalmitoylphosphatidylcholine (DPPC) vesicles] with phospholipid-mPEG conjugate induces complement activation resulting in vesicle recognition by macrophage complement receptors. The extent of vesicle uptake, however, is dependent on surface mPEG density. We have delineated the likely structural features of phospholipid-mPEG conjugate responsible for PEGylated liposome-induced complement activation in normal as well as C1q-deficient human sera, using DPPC vesicles bearing the classical as well as newly synthesized lipid-mPEG conjugates. With PEGylated DPPC vesicles, the net anionic charge on the phosphate moiety of phospholipid-mPEG conjugate played a key role in activation of both classical and alternative pathways of complement and anaphylatoxin production (reflected in significant rises in SC5b-9, C4d, and C3a-desarg levels in normal human sera as well as SC5b-9 in EGTA-chelated/Mg2+ supplemented serum), since methylation of the phosphate oxygen of phospholipid-mPEG conjugate, and hence the removal of the negative charge, totally prevented complement activation. To further corroborate on the role of the negative charge in complement activation, vesicles bearing anionic phospholipid-mPEG conjugates, but not the methylated phospholipid-mPEG, were shown to significantly decrease serum hemolytic activity and increase plasma thromboxane B2 levels in rats. In contrast to liposomes, phospholipid-mPEG micelles had no effect on complement activation, thus suggesting a possible role for vesicular zwitterionic phospholipid head-groups as an additional factor contributing to PEGylated liposome-mediated complement activation. Our findings provide a rational conceptual basis for development of safer vesicles for site-specific drug delivery and controlled release at pathological sites.

Methylation of the phosphate oxygen moiety of phospholipid-methoxy(polyethylene glycol) conjugate prevents PEGylated liposome-mediated complement activation and anaphylatoxin production

A standing hypothesis in membrane biology implies that the collective physical properties of the lipid bilayer component of biological membranes can modulate the activity of membrane-associated proteins. We provide strong support for this hypothesis by exploring a model system, phospholipase A2 catalyzed hydrolysis of one-component phospholipid vesicles. For vesicles of lipids with different chain lengths we observe, as a function of temperature and chain length, a systematic variation of the characteristic lag time for the onset of rapid phospholipase A2 hydrolysis. These results, combined with theoretical results obtained from computer simulation of the gel-to-fluid phase transition in the unhydrolyzed lipid bilayers, enable us to demonstrate a strong correlation between the lag time and the degree of bilayer microheterogeneity in the phase transition region. Insight into the nature of this correlation suggests rational ways of modulating enzyme activity by modifying the physical properties of the lipid bilayer.

Systematic Relationship between Phospholipase A2 Activity and Dynamic Lipid Bilayer Microheterogeneity

Lipid-bilayer membranes are key objects in drug research in relation to (i) interaction of drugs with membrane-bound receptors, (ii) drug targeting, penetration, and permeation of cell membranes, and (iii) use of liposomes in micro-encapsulation technologies for drug delivery. Rational design of new drugs and drug-delivery systems therefore requires insight into the physical properties of lipid-bilayer membranes. This mini-review provides a perspective on the current view of lipid-bilayer structure and dynamics based on information obtained from a variety of recent experimental and theoretical studies. Special attention is paid to trans-bilayer structure, lateral molecular organization of the lipid bilayer, lipid-mediated protein assembly, and lipid-bilayer permeability. It is argued that lipids play a major role in lipid membrane-organization and functionality.

Kent Jørgensen

Papers

Advanced strategies in liposomal cancer therapy: problems and prospects of active and tumor specific drug release.

Dynamical order and disorder in lipid bilayers

Methylation of the phosphate oxygen moiety of phospholipid-methoxy(polyethylene glycol) conjugate prevents PEGylated liposome-mediated complement activation and anaphylatoxin production

Systematic Relationship between Phospholipase A2 Activity and Dynamic Lipid Bilayer Microheterogeneity

A new look at lipid-membrane structure in relation to drug research