Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
16
4
2006
Vascular and Cellular Targeting for Photodynamic Therapy
279-306
10.1615/CritRevEukarGeneExpr.v16.i4.10
Bin
Chen
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, PA 19104
Brian W.
Pogue
Thayer School of Engineering, Dartmouth College, Hanover, NH 03755; and Wellman Centerfor Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA 02114
P. Jack
Hoopes
Thayer School of Engineering, Dartmouth College, Hanover, NH 03755; and Department of Surgery, Dartmouth Medical School, Lebanon, NH 03756
Tayyaba
Hasan
Wellman Centerfor Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA 02114
Photodynamic therapy (PDT) involves the combination of photosensitizers (PS) with light as a treatment, and has been an established medical practice for about 10 years. Current primary applications of PDT are age-related macular degeneration (AMD) and several types of cancer and precancer. Tumor vasculature and parenchyma cells are both potential targets of PDT damage. The preference of vascular versus cellular targeting is highly dependent upon the relative distribution of photosensitizers in each compartment, which is governed by the photosensitizer pharmacokinetic properties and can be effectively manipulated by the photosensitizer drug administration and light illumination interval (drug-light interval) during PDT treatment, or by the modification of photosensitizer molecular structure. PDT using shorter PS-light intervals mainly targets tumor vasculature by confining photosensitizer localization within blood vessels, whereas if the sensitizer has a reasonably long pharmacokinetic lifetime, then PDT at longer PS-light intervals can induce more tumor cellular damage, because the photosensitizer has then distributed into the tumor cellular compartment. This passive targeting mechanism is regulated by the innate photosensitizer physicochemical properties. In addition to the passive targeting approach, active targeting of various tumor endothelial and cellular markers has been studied extensively. The tumor cellular markers that have been explored for active photodynamic targeting are mainly tumor surface markers, including growth factor receptors, low-density lipoprotein (LDL) receptors, transferrin receptors, folic acid receptors, glucose transporters, integrin receptors, and insulin receptors. In addition to tumor surface proteins, nuclear receptors are targeted, as well. A limited number of studies have been performed to actively target tumor endothelial markers (ED-B domain of fibronectin, VEGF receptor-2, and neuropilin-1). Intracellular targeting is a challenge due to the difficulty in achieving sufficient penetration into the target cell, but significant progress has been made in this area. In this review, we summarize current studies of vascular and cellular targeting of PDT after more than 30 years of intensive efforts.
A Critical Comparison of the Current View of Ca Signaling with the Novel Concept of F-Actin-Based Ca Signaling
307-366
10.1615/CritRevEukarGeneExpr.v16.i4.20
Klaus
Lange
Kladower Damm 25b, D-14089 Berlin, Germany
Joachim
Gartzke
Albrechtstrasse 16, D-10117 Berlin, Germany
A detailed comparative survey on the current idea of Ca signaling and the alternative concept of F-actin-based Ca signaling is given. The two hypotheses differ in one central aspect—the mechanism of Ca storage. The current theory rests on the assumption of Ca-accumulating vesicles derived from the endoplasmic/ sarcoplasmic reticulum, which are equipped with an ATP-dependent Ca pump and IP3- or ryanodine-sensitive Ca-release channels/receptors. The alternative hypothesis proceeds from the idea of Ca storage at the high-affinity binding sites of F-actin subunits. Several prominent features of Ca signaling, which are not adequately described by the current concept, are inherent properties of the F-actin system and its dynamic state of treadmilling. F-actin is the only known biological Ca-binding system that has been proven by in vitro experiments to work within the physiological range of Ca concentrations and the only system that meets all necessary conditions to function as receptor-operated Ca store and as a coupling device between the Ca store and the store-operated Ca influx pathway. The most important properties of Ca signaling, such as store-channel coupling, quantal Ca release, spiking and oscillations, biphasic and "phasic" uptake kinetics, and Ca-induced Ca release, turn out to be systematic features of the new concept but remain unexplained by the classical vesicle storage hypothesis. A number of novel findings, specifically recent reports about direct effects of actin-specific toxins on Ca stores, have strengthened the new concept. The concept of F-actin-based Ca signaling combined with the notion of microvillar regulation of ion and substrate fluxes opens new aspects and far-reaching consequences, not only for cellular Ca signaling but also for various other cell functions, and represents an opportunity to connect several fields of cell physiology on the basis of a common mechanism.
Subject Index, Author Index - Volume 16
367-370
10.1615/CritRevEukarGeneExpr.v16.i4.30