Lymphatic targeting of zidovudine using surface-engineered liposomes.
TL;DR: The SE liposomes appeared to be promising novel vesicular system for enhanced targeting of ZDV to lymphatics, in AIDS chemotherapy.
Abstract: The present investigation was aimed at lymphatic targeting of zidovudine (ZDV)-loaded surface-engineered liposomes (SE liposomes). Surface of liposomes was engineered by incorporation of charges (positive or negative) and site-specific ligand (mannose) in order to enhance localization to lymphatics, specifically to lymph node and spleen. Positively and negatively charged nanosized SE liposomes (120 +/- 10 nm) were prepared using stearylamine (SA) and dicetyl phosphate (DCP), respectively, while ligand-coated SE liposomes were prepared using mannose-terminated SA (mannose conjugate). The SE liposomes were characterized for shape and surface morphology, size, entrapment efficiency, and in vitro drug release. All the SE liposomes formulations showed biphasic ZDV release, whereas mannose-coated liposomes (MAN-Lip) significantly reduced (p negatively charged > positively charged > Lip. Thus, the SE liposomes appeared to be promising novel vesicular system for enhanced targeting of ZDV to lymphatics, in AIDS chemotherapy.
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TL;DR: The current progress and challenges in synthesizing nanoparticle platforms for delivering various antimicrobial drugs are reviewed and the need to unite the shared interest between nanoengineers and microbiologists in developing nanotechnology for the treatment of microbial diseases is called attention.
Abstract: This review focuses on the development of nanoparticle systems for antimicrobial drug delivery. Numerous antimicrobial drugs have been prescribed to kill or inhibit the growth of microbes such as bacteria, fungi and viruses. Even though the therapeutic efficacy of these drugs has been well established, inefficient delivery could result in inadequate therapeutic index and local and systemic side effects including cutaneous irritation, peeling, scaling and gut flora reduction. Nanostructured biomaterials, nanoparticles in particular, have unique physicochemical properties such as ultra small and controllable size, large surface area to mass ratio, high reactivity, and functionalizable structure. These properties can be applied to facilitate the administration of antimicrobial drugs, thereby overcoming some of the limitations in traditional antimicrobial therapeutics. In recent years, encapsulation of antimicrobial drugs in nanoparticle systems has emerged as an innovative and promising alternative that enhances therapeutic effectiveness and minimizes undesirable side effects of the drugs. Here the current progress and challenges in synthesizing nanoparticle platforms for delivering various antimicrobial drugs are reviewed. We also call attention to the need to unite the shared interest between nanoengineers and microbiologists in developing nanotechnology for the treatment of microbial diseases.
721 citations
TL;DR: A technology platform that provides a wide range of synthetic nanostructures that may be controlled as a function of size, shape and surface chemistry and scale to these nanotechnical dimensions will be a critical first step in developing appropriate tools and a scientific basis for understanding nanoparticles.
Abstract: The core objective of nanoparticles is to control and manipulate biomacromolecular constructs and supramolecular assemblies that are critical to living cells in order to improve the quality of human health. By definition, these constructs and assemblies are nanoscale and include entities such as drugs, proteins, DNA/RNA, viruses, cellular lipid bilayers, cellular receptor sites and antibody variable regions critical for immunology and are involved in events of nanoscale proportions. The emergence of such nanotherapeutics/diagnostics will allow a deeper understanding of human longevity and human ills that include cancer, cardiovascular disease and genetic disorders. A technology platform that provides a wide range of synthetic nanostructures that may be controlled as a function of size, shape and surface chemistry and scale to these nanotechnical dimensions will be a critical first step in developing appropriate tools and a scientific basis for understanding nanoparticles.
425 citations
TL;DR: Determinants of absorption after SC administration are summarized including compound properties such as charge or molecular weight and scale-up of animal data to humans is discussed, including the current shortcomings of empirical scaling approaches and the lack of suitable mechanistic approaches.
Abstract: The subcutaneous (SC) route is of growing interest for the administration of biotherapeutics. Key products on the biotherapeutic market such as insulins, but also several immunoglobulins or Fc-fusion proteins, are administered SC. Despite the importance of the SC route, the available knowledge about the processes involved in the SC absorption of biotherapeutics is limited. This review summarizes available information on the physiology of the SC tissue and on the pharmacokinetic processes after SC administration including “first pass catabolism” at the administration site as well as transport in the extracellular matrix of the SC tissue, followed by absorption into the blood circulation or the lymphatic system. Both monoclonal antibodies and other biotherapeutics are discussed. Determinants of absorption after SC administration are summarized including compound properties such as charge or molecular weight. Scale-up of animal data to humans is discussed, including the current shortcomings of empirical scaling approaches and the lack of suitable mechanistic approaches.
255 citations
TL;DR: A detailed review of novel lipid-based nanoformulations and their lymphatic delivery via different routes, as well as the in vivo and in vitro models used to study drug transport in the lymphatic system are provided.
Abstract: The delivery of drugs and bioactive compounds via the lymphatic system is complex and dependent on the physiological uniqueness of the system. The lymphatic route plays an important role in transporting extracellular fluid to maintain homeostasis and in transferring immune cells to injury sites, and is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism. The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system. Lymphatic imaging is useful in evaluating disease states and treatment plans for progressive diseases of the lymph system. Novel lipid-based nanoformulations, such as solid lipid nanoparticles and nanostructured lipid carriers, have unique characteristics that make them promising candidates for lymphatic delivery. These formulations are superior to colloidal carrier systems because they have controlled release properties and provide better chemical stability for drug molecules. However, multiple factors regulate the lymphatic delivery of drugs. Prior to lymphatic uptake, lipid-based nanoformulations are required to undergo interstitial hindrance that modulates drug delivery. Therefore, uptake and distribution of lipid-based nanoformulations by the lymphatic system depends on factors such as particle size, surface charge, molecular weight, and hydrophobicity. Types of lipid and concentration of the emulsifier are also important factors affecting drug delivery via the lymphatic system. All of these factors can cause changes in intermolecular interactions between the lipid nanoparticle matrix and the incorporated drug, which in turn affects uptake of drug into the lymphatic system. Two lipid-based nanoformulations, ie, solid lipid nanoparticles and nanostructured lipid carriers, have been administered via multiple routes (subcutaneous, pulmonary, and intestinal) for targeting of the lymphatic system. This paper provides a detailed review of novel lipid-based nanoformulations and their lymphatic delivery via different routes, as well as the in vivo and in vitro models used to study drug transport in the lymphatic system. Physicochemical properties that influence lymphatic delivery as well as the advantages of lipid-based nanoformulations for lymphatic delivery are also discussed.
242 citations
TL;DR: This review presents an overview of different applications of glycosylated carriers, with a focus on their applicability in development of a nanoconstruct with GRAS status.
229 citations
References
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TL;DR: It is found that as the surface charge of the lipid lamellae is increased, the amount of cation per μmle of lipid increases, and the phospholipid liquid crystalline structures appear to “bind” or “capture” cations.
4,341 citations
"Lymphatic targeting of zidovudine u..." refers background or methods in this paper
...1985), surface modification with ligands (Oussoren and Storm 2001), coating of polymers (Bangham et al. 1965), and using highly lipophilic compounds....
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...The lymphatic uptake could be enhanced by reducing particle size (Tumer et al. 1983; Bergqvist et al. 1984), charge incorporation (Hirano et al. 1985), surface modification with ligands (Oussoren and Storm 2001), coating of polymers (Bangham et al. 1965), and using highly lipophilic compounds....
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...Conventional and SE liposomes were prepared using cast film method (Bangham et al. 1965)....
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TL;DR: Overall, it is increasingly evident that both the tropism and burden of HIV infection correlate closely with the manifestations of disease.
Abstract: Many questions have been posed about acquired immunodeficiency syndrome (AIDS) pathogenesis. Is human immunodeficiency virus (HIV) both necessary and sufficient to cause AIDS? Is AIDS essentially an autoimmune disease, triggering apoptosis, or is virus infection the cause of T helper lymphocyte depletion? What is the significance of HIV tropism and the role of macrophages and dendritic cells in AIDS? Is there viral latency and why is there usually a long period between infection and AIDS? Is HIV variation a crucial aspect of its pathogenesis and, if so, do virulent strains emerge? Although this article provides few definitive answers, it aims to focus commentary on salient points. Overall, it is increasingly evident that both the tropism and burden of HIV infection correlate closely with the manifestations of disease.
700 citations
"Lymphatic targeting of zidovudine u..." refers background in this paper
...The human immunodeficiency viruses (HIV) generally encompasses two broad categories HIV-1, the predominant AIDS causing virus in the world, and HIV-2, a biologically distinct second type of AIDS virus, identified in 1986 and generally restricted in West Africa (Weiss 1993)....
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TL;DR: Liposomes can be separated from low molecular weight solutes on minicolumns of Sephadex G-50 made from the barrels of 1- or 5-ml plastic syringes by centrifugation, which has advantages over other methods for separating extraliposomal solutes from liposomes.
444 citations
TL;DR: It is shown that phagocytosis by macrophages is the most important mechanism for lymph node uptake of liposomes and this has stimulated research on lymphatic targeting ofliposomes for diagnostic and therapeutic applications.
319 citations
"Lymphatic targeting of zidovudine u..." refers background in this paper
...Moreover, studies on the intranodal fate of liposomes demonstrated that phagocytosis by macrophages was the most important mechanism of lymphatic uptake (Oussoren and Storm 2001)....
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...1985), surface modification with ligands (Oussoren and Storm 2001), coating of polymers (Bangham et al....
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...The lymphatic uptake could be enhanced by reducing particle size (Tumer et al. 1983; Bergqvist et al. 1984), charge incorporation (Hirano et al. 1985), surface modification with ligands (Oussoren and Storm 2001), coating of polymers (Bangham et al. 1965), and using highly lipophilic compounds....
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TL;DR: The largest liposomes were retained most by lymph nodes, and would be the best prototypical carrier of the group if increased therapeutic availability within both lymph and lymph nodes is desired, and the results implicate other, unexplored physical and physiological variables as potentially of equal importance.
154 citations
"Lymphatic targeting of zidovudine u..." refers background in this paper
...1984), charge incorporation (Hirano et al. 1985), surface modification with ligands (Oussoren and Storm 2001), coating of polymers (Bangham et al....
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...The surface modification by imparting charge is expected to enhance lymphatic localization (Hirano et al. 1985)....
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...The lymphatic uptake could be enhanced by reducing particle size (Tumer et al. 1983; Bergqvist et al. 1984), charge incorporation (Hirano et al. 1985), surface modification with ligands (Oussoren and Storm 2001), coating of polymers (Bangham et al. 1965), and using highly lipophilic compounds....
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