J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 6(2):198-204, 2003 198 Corresponding Author: David Dolphin, Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z1. ddolphin@qltinc.com Correlation of photosensitizer delivery to lipoproteins and efficacy in tumor and arthritis mouse models; comparison of lipid-based and Pluronic® P123 formulations. Rubinah K Chowdhary, Isha Sharif, Namrata Chansarkar, David Dolphin Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada Leslie Ratkay, Sean Delaney QLT Inc., Vancouver, British Columbia, Canada Howard Meadows Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada Received 8 January 2003, Revised 22 April 2003, Accepted 22 April 2003 ABSTRACT. PURPOSE. The purpose of this study was the use of animal models to demonstrate the importance of drug delivery (verteporfin) to plasma lipopropteins in order to attain efficacy of photodynamic therapy (PDT) in vivo . METHODS. Photosensitzers appropriately formu- lated in various vehicles such as pluronics and lipid-based systems were compared to delivery of the drug in DMSO in two in vivo systems. The first was a tumor model using male DBA/2 mice inoculated intradermally with M1 rhab- domyosarcoma cells and in the second, arthritis in the MRL-lpr mouse strain was enhanced by two intradermal injections of complete Freunds adjunct. RESULTS. Those formulations in which the drug was in a monomeric form were better able to transfer drug to lipoproteins, which in turn led to superior PDT in vivo . CONCLU- SIONS. The ability to introduce drug in monomeric form into the circulation correlates well with efficacy of photo- sensitizer formulations in mouse arthritis and tumor mod- els. INTRODUCTION The scope of photodynamic therapy (PDT) has recently expanded well the beyond treatment of malignant tumors to conditions with hypervascularization and inflammatory involvement. This includes ocular disorders such as macu- lar degeneration, and a wide range of inflammatory and autoimmune conditions. The majority of photosensitizers of interest for PDT are hydrophobic in nature. When such drugs are injected, they tend to be transported in the bloodstream predominantly associated to lipoproteins (1). Cellular internalization of these drug-lipoprotein com- plexes via low-density (LDL) receptors, which are upregu- lated in rapidly dividing tissues undergoing rapid growth or repair, is believed to confer a degree of specificity on the preferential localization of such drugs in diseased tis- sues. Pre-association of such drugs with LDLs has been shown to result in better delivery to target tissues and improved efficacy in vivo (2). The tendency of highly hydrophobic photosensitizing drugs to undergo aggregation, in contact with aqueous systems, has a deleterious effect on the photosensitized oxidative process (3). Hence, such drugs need to be intro- duced into the bloodstream in a form that is either mono- meric, or easily dissociated in contact with plasma. For intravenous administration, therefore, hydrophobic photo- sensitizers require formulation to minimize aggregation in vivo . Verteporfin (benzoporphyrin derivative monoacid ring A, BPDMA 1; Figure 1), which has recently been approved by the FDA for the treatment of macular degen- eration, is prepared in a lipid-based formulation to mini- mize aggregation. Figure 1: Structures of BPDMA, 1, and ring B derivatives 2 and 3.