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Introduction: Targeting of drugs and delivery systems
advanced
drug d&my reviews
ELSEVIER
Introduction:
Advanced
Drug
Delivery
Targeting
Reviews
17 (1995)
l-3
of drugs and delivery systems
“Who shoots at the mid-day sun, though he be sure he shall never hit the mark; yet as sure he is he shall shoot higher than who aims but at a bush ” [Sir Philip Sidney, The Arcadia 21
This monograph is a compilation of state of art reviews which highlight current trends and approaches in targeting of drug and diagnostic delivery systems to selective cells and organs of the body as well as to specific circulating noncellular targets following parenteral administration. Here, delivery systems enlist carriers that are either simple soluble macromolecules (e.g., monoclonal antibodies, soluble synthetic polymers) or more complex particulate multicomponent structures (e.g., liposomes, nanospheres, endogenous lipid particles, and cells such as leukocytes and erythrocytes). Numerous investigators have shown that the majority of nano-sized colloids and drug carriers in the form of liposomes, nanospheres, etc. injected intravenously is retained primarily by the liver and to a certain extent by the spleen. Tissue fractionation studies have established that the retention of colloids in the liver is due primarily to their uptake by periportal and midzonal Kupffer cells. Particle uptake in the spleen is often ascribed to phagocytosis by marginal zone and red-pulp macrophages under normal conditions. Localization of nano-sized colloids in liver and spleen, though frustrating to investigators who wish to direct particles to other sites, offers a powerful method for delivery of a wide variety of therapeutic and radiopharmaceutical agents to Kupffer cells and splenic macrophages. In this respect, Bakker-Woudenberg critically review the current literature on application of liposomes as carriers of antimicrobial agents for treatment of parasitic, viral, fung-
al, and bacterial infections of tissue macrophages. Another interesting application is encapsulation of immunomodulators in drug carrier systems in order to increase the tumoricidal activity of Kupffer cells and agument host destruction of hepatic metastases. This topic is thoroughly examined by Daemen and colleagues. As mentioned above, the physiological capacity of Kupffer cells for phagocytosis of foreign and abnormal substances from the systemic circulation has been the major obstacle to efficient and selective targeting of radionulcide colloids and drug carrier systems to other sites and organs, including other organs of the reticuloendothelial system (spleen and bone marrow), which may be the necessary sites during a number of clinical and pathological conditions. Hence, new strategies must be adopted to fulfill these goals. Perhaps, we can learn wisdom from those extracellular pathogens which have deployed a clever array of surface strategies to subvert opsonization processes and to avoid phagocytosis by a particular type of phagocyte. Therefore, the concept of surface engineering and steric stabilization is introduced by Storm et al. Indeed, generation of an efficient steric barrier on the surface of a nano-sized particle can minimize the naturtal blood opsonization processes and confer a relative “invisibility” to the colloidal particles. This is reflected by a profound reduction in uptake of such particles by macrophages of the reticuloendothelial system (particularly, by the hepatic Kupffer cells) and extended blood circulation time. Because stericallystabilized carrier systems exhibit dramatically different pharmacokinetics and biodistribution, they could prove useful in delivery of radiodiagnostic imaging agents and drugs to various sites
in the body. However, in certain patho-physiological conditions macrophages may show features of activation beyond the resident stage. Can these innovations in particle engineering confer sufficient “invisibility” to nano-sized colloids and prevent their recognition by primed or activated macrophages of the reticuloendothelial system’? If one way be better than another, that you may be sure is Nature’s way [Aristotle]. Indeed, many cells in the body travel freely, originating in one site and taking up residence elsewhere with exquisite specificity. Progenitor cells, originating in bone marrow, give rise to blood cells of different lineages such as erythrocytes, leukocytes and platelets. Erythrocytes fulfill their function of oxygen transport with a life span of 110-120 days. Lymphocytes travel in the circulation and selectively recognize, bind to, and extravazate via high endothelial venules in lymph nodes, appendix and Peyer’s patches. Furthermore, certain subset of lymphocytes can infiltrate tumors. Platelets exhibit natural hemostatic properties to adhere to collagen and other vessel wall constituents revealed by injury. The circulatory pool of hemopoietic stem cells are selectively trapped by marrow sinus endothelium, permitting them to enter the hemopoietic arena. Recent advances in cell and molecular biology have enabled researches to understand some of these occurrences in molecular terms. As a result of these studies, a number of molecules have now been identified that can mediate cellular homing and targeting. Sir Philip would have not hesitated to qualify cellular homing as “shooting for the midday sun”. For, in the absence of homingmolecules, such cells can only continue to circulate or die and be buried in a bush. The implications are therefore clear. First, drugs, therapeutic agents, and radiopharmaceuticals can be targeted to various sites in the body by using cellular systems. For example, normal radiolabelled red blood cells have potentials in cardiovascular nuclear medicine, blood pool imaging, detection of vascular malformations and gastrointestinal bleeding, etc. Drugs can be electro-encapsulated within platelets and targeted to damaged blood vessels. Furthermore, the ability to introduce foreign genes into stem cells have made possible a new approach to the treatment
of bone marrow diseases and disorders. This strategy can also make possible a new approach to the treatment of non-genetic diseases (such as human immunodeficiency virus) and to complement the effect of conventional therapies. The genetic modification of tumor-infiltrating lymphocytes with retroviruses carrying the gene for either tumor necrosis factor-a or interleukin-2 may enhance their immunoreactivity towards tumour cells, hence avoiding the systemic toxicity of the cytokines. Some of these approaches are discussed in articles by Crommelin et al., Torchilin and myself in this issue of Advanced Drug Delivery
Reviews.
Second, understanding the molecular basis of cellular targeting can provide an opportunity of using the same molecules or their analogues to target therapeutic agents to the desired sites. In this respect, a number of drug carriers which permit the modification of the outer surface with monoclonal antibodies and tissue specific ligands, have been proposed as means to increase the targeting potential of radiodiagnostic agents and drugs. Furthermore, grafting or covalent attachment of such homing molecules to stericallystabilized carriers have improved the targeting precision. Crommelin and associates describe recent approaches to target a number of systems to blood cells, circulating non-cellular targets (e.g., drugs), and vascular endothelium. Torchilin elegantly discusses a number of synthetic devices for use in selective imaging and therapy of cardiovascular system. The target sites includes blood pool, atherosclerotic lessions, thrombi, vessel wall, pulmonary endothelium, and myocardium. Design of synthetic carrier systems with bone marrow specificity requires a thorough understanding of bone marrow microvascular structure, receptor and antigen expression on marrow sinus endothelium, and the mode of transport of particulae matter from luminal to abluminal surfaces. These concepts are considered in a treatise by myself. Murray and Carmichael have examined and exploited tumor physiology and tumor vasculature as target for drugs. Efforts are concentrated to identify the unique properties of tumor endothelium and means for their selective destruction. Novel approaches include antibodydirected enzyme pro-drug and gene delivery
S.M. Moghirni
/ Advanced Drug Delivery Reviews 17 (199-f) l-3
(e.g., genes that can induce apoptosis in endothelium or produce tumor necrosis factor-a). Selective-targeting of carrier systems to the spleen is rather easy. The mammalian spleen is a lymphoreticular organ, possessing large capacity for removing blood cells, particles, etc. from the blood. The ability of the spleen for filtration of blood cells and blood-borne particles and the capacity for phagocytosis is largely reflected in its unique architecture and intermediate circulation. Understanding of splenic structure, blood flow, function, and performance would allow one to design simple splentotropic agents (with minimum localization to the liver). These concepts are discussed by myself in this Theme Issue. Delivery of drug carriers and diagnostic agents to the regional lymphatics have been a neglected area of research. However, among the more intriguing aspects of the progress being made in particle engineering is the possibility of using the
3
concept of steric-stabilization in order to maximize the uptake of particles into regional lymph nodes and to minimize the amount retained at the injection site. These concepts are addressed herein in the article by Hawley et al. Finally, I would like to thank all contributors for writing such interesting articles and for articulating, far more eloquently than I have here, the advances in drug delivery. If this Theme Issue of Advanced Drug Delivery Reviews excites some interest in drug delivery research and, furthermore, demonstrates that some of the problems are eminently addressable using the new techniques which are being developed, then it will have served a useful purpose. S.M. MOGHIMI Nottingham, UK May 1995
drug d&my reviews
ELSEVIER
Introduction:
Advanced
Drug
Delivery
Targeting
Reviews
17 (1995)
l-3
of drugs and delivery systems
“Who shoots at the mid-day sun, though he be sure he shall never hit the mark; yet as sure he is he shall shoot higher than who aims but at a bush ” [Sir Philip Sidney, The Arcadia 21
This monograph is a compilation of state of art reviews which highlight current trends and approaches in targeting of drug and diagnostic delivery systems to selective cells and organs of the body as well as to specific circulating noncellular targets following parenteral administration. Here, delivery systems enlist carriers that are either simple soluble macromolecules (e.g., monoclonal antibodies, soluble synthetic polymers) or more complex particulate multicomponent structures (e.g., liposomes, nanospheres, endogenous lipid particles, and cells such as leukocytes and erythrocytes). Numerous investigators have shown that the majority of nano-sized colloids and drug carriers in the form of liposomes, nanospheres, etc. injected intravenously is retained primarily by the liver and to a certain extent by the spleen. Tissue fractionation studies have established that the retention of colloids in the liver is due primarily to their uptake by periportal and midzonal Kupffer cells. Particle uptake in the spleen is often ascribed to phagocytosis by marginal zone and red-pulp macrophages under normal conditions. Localization of nano-sized colloids in liver and spleen, though frustrating to investigators who wish to direct particles to other sites, offers a powerful method for delivery of a wide variety of therapeutic and radiopharmaceutical agents to Kupffer cells and splenic macrophages. In this respect, Bakker-Woudenberg critically review the current literature on application of liposomes as carriers of antimicrobial agents for treatment of parasitic, viral, fung-
al, and bacterial infections of tissue macrophages. Another interesting application is encapsulation of immunomodulators in drug carrier systems in order to increase the tumoricidal activity of Kupffer cells and agument host destruction of hepatic metastases. This topic is thoroughly examined by Daemen and colleagues. As mentioned above, the physiological capacity of Kupffer cells for phagocytosis of foreign and abnormal substances from the systemic circulation has been the major obstacle to efficient and selective targeting of radionulcide colloids and drug carrier systems to other sites and organs, including other organs of the reticuloendothelial system (spleen and bone marrow), which may be the necessary sites during a number of clinical and pathological conditions. Hence, new strategies must be adopted to fulfill these goals. Perhaps, we can learn wisdom from those extracellular pathogens which have deployed a clever array of surface strategies to subvert opsonization processes and to avoid phagocytosis by a particular type of phagocyte. Therefore, the concept of surface engineering and steric stabilization is introduced by Storm et al. Indeed, generation of an efficient steric barrier on the surface of a nano-sized particle can minimize the naturtal blood opsonization processes and confer a relative “invisibility” to the colloidal particles. This is reflected by a profound reduction in uptake of such particles by macrophages of the reticuloendothelial system (particularly, by the hepatic Kupffer cells) and extended blood circulation time. Because stericallystabilized carrier systems exhibit dramatically different pharmacokinetics and biodistribution, they could prove useful in delivery of radiodiagnostic imaging agents and drugs to various sites
in the body. However, in certain patho-physiological conditions macrophages may show features of activation beyond the resident stage. Can these innovations in particle engineering confer sufficient “invisibility” to nano-sized colloids and prevent their recognition by primed or activated macrophages of the reticuloendothelial system’? If one way be better than another, that you may be sure is Nature’s way [Aristotle]. Indeed, many cells in the body travel freely, originating in one site and taking up residence elsewhere with exquisite specificity. Progenitor cells, originating in bone marrow, give rise to blood cells of different lineages such as erythrocytes, leukocytes and platelets. Erythrocytes fulfill their function of oxygen transport with a life span of 110-120 days. Lymphocytes travel in the circulation and selectively recognize, bind to, and extravazate via high endothelial venules in lymph nodes, appendix and Peyer’s patches. Furthermore, certain subset of lymphocytes can infiltrate tumors. Platelets exhibit natural hemostatic properties to adhere to collagen and other vessel wall constituents revealed by injury. The circulatory pool of hemopoietic stem cells are selectively trapped by marrow sinus endothelium, permitting them to enter the hemopoietic arena. Recent advances in cell and molecular biology have enabled researches to understand some of these occurrences in molecular terms. As a result of these studies, a number of molecules have now been identified that can mediate cellular homing and targeting. Sir Philip would have not hesitated to qualify cellular homing as “shooting for the midday sun”. For, in the absence of homingmolecules, such cells can only continue to circulate or die and be buried in a bush. The implications are therefore clear. First, drugs, therapeutic agents, and radiopharmaceuticals can be targeted to various sites in the body by using cellular systems. For example, normal radiolabelled red blood cells have potentials in cardiovascular nuclear medicine, blood pool imaging, detection of vascular malformations and gastrointestinal bleeding, etc. Drugs can be electro-encapsulated within platelets and targeted to damaged blood vessels. Furthermore, the ability to introduce foreign genes into stem cells have made possible a new approach to the treatment
of bone marrow diseases and disorders. This strategy can also make possible a new approach to the treatment of non-genetic diseases (such as human immunodeficiency virus) and to complement the effect of conventional therapies. The genetic modification of tumor-infiltrating lymphocytes with retroviruses carrying the gene for either tumor necrosis factor-a or interleukin-2 may enhance their immunoreactivity towards tumour cells, hence avoiding the systemic toxicity of the cytokines. Some of these approaches are discussed in articles by Crommelin et al., Torchilin and myself in this issue of Advanced Drug Delivery
Reviews.
Second, understanding the molecular basis of cellular targeting can provide an opportunity of using the same molecules or their analogues to target therapeutic agents to the desired sites. In this respect, a number of drug carriers which permit the modification of the outer surface with monoclonal antibodies and tissue specific ligands, have been proposed as means to increase the targeting potential of radiodiagnostic agents and drugs. Furthermore, grafting or covalent attachment of such homing molecules to stericallystabilized carriers have improved the targeting precision. Crommelin and associates describe recent approaches to target a number of systems to blood cells, circulating non-cellular targets (e.g., drugs), and vascular endothelium. Torchilin elegantly discusses a number of synthetic devices for use in selective imaging and therapy of cardiovascular system. The target sites includes blood pool, atherosclerotic lessions, thrombi, vessel wall, pulmonary endothelium, and myocardium. Design of synthetic carrier systems with bone marrow specificity requires a thorough understanding of bone marrow microvascular structure, receptor and antigen expression on marrow sinus endothelium, and the mode of transport of particulae matter from luminal to abluminal surfaces. These concepts are considered in a treatise by myself. Murray and Carmichael have examined and exploited tumor physiology and tumor vasculature as target for drugs. Efforts are concentrated to identify the unique properties of tumor endothelium and means for their selective destruction. Novel approaches include antibodydirected enzyme pro-drug and gene delivery
S.M. Moghirni
/ Advanced Drug Delivery Reviews 17 (199-f) l-3
(e.g., genes that can induce apoptosis in endothelium or produce tumor necrosis factor-a). Selective-targeting of carrier systems to the spleen is rather easy. The mammalian spleen is a lymphoreticular organ, possessing large capacity for removing blood cells, particles, etc. from the blood. The ability of the spleen for filtration of blood cells and blood-borne particles and the capacity for phagocytosis is largely reflected in its unique architecture and intermediate circulation. Understanding of splenic structure, blood flow, function, and performance would allow one to design simple splentotropic agents (with minimum localization to the liver). These concepts are discussed by myself in this Theme Issue. Delivery of drug carriers and diagnostic agents to the regional lymphatics have been a neglected area of research. However, among the more intriguing aspects of the progress being made in particle engineering is the possibility of using the
3
concept of steric-stabilization in order to maximize the uptake of particles into regional lymph nodes and to minimize the amount retained at the injection site. These concepts are addressed herein in the article by Hawley et al. Finally, I would like to thank all contributors for writing such interesting articles and for articulating, far more eloquently than I have here, the advances in drug delivery. If this Theme Issue of Advanced Drug Delivery Reviews excites some interest in drug delivery research and, furthermore, demonstrates that some of the problems are eminently addressable using the new techniques which are being developed, then it will have served a useful purpose. S.M. MOGHIMI Nottingham, UK May 1995