Copyright © 2013 American Scientific Publishers All rights reserved Printed in the United States of America Article Journal of Biomedical Nanotechnology Vol. 9, 1–11, 2013 www.aspbs.com/jbn Control of Cytolocalization and Mechanism of Cell Death by Encapsulation of a Photosensitizer Daiana K. Deda, Christiane Pavani, Eduardo Caritá, Maurício S. Baptista ∗ , Henrique E. Toma, and Koiti Araki ∗ Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes 748, Sao Paulo, SP, Brazil The most challenging and wanted development in photodynamic therapy is the control of photosensitizer (PS) cytolocal- ization and the mechanism of cell death. 5,10,15-triphenyl-20-(3-N-methylpyridinium-yl)porphyrin (3MMe) administered to HeLa cells as DMSO solution accumulates in the cytoplasmic membrane (CM) where it causes severe photodamage and cell necrosis. In contrast, when incorporated in marine atelocollagen/xantham gum polymeric nanocapsules, that PS is shuttled through CM allowing its gradual release and accumulation in mitochondria and lysosomes. Little photodamage was caused to cells in this case, but compelling evidences are presented showing that encapsulation changes the cytolo- calization and shifts the cell death mechanism from necrosis to apoptosis. In conclusion, both of those challenges can be overcome by encapsulation of typical PSs such as 3MMe by using the new concept of photodynamic treatment with minimal cell damage by targeting specifically some key organelles. We are confident that these findings are important for the development of more efficient photosensitizers tailored to induce apoptosis while minimizing undesirable side effects such as over-inflammation. KEYWORDS: Photodynamic Therapy, Polymeric Nanocapsules, Cytolocalization, Apoptosis, Necrosis. INTRODUCTION Photodynamic Therapy (PDT) is an alternative treatment for several diseases based on the light activation of photosensitizer (PS) molecules loaded onto the diseased tissues. 1–3 The first PDT drug approved by FDA has sev- eral drawbacks such as unknown molecular structure and unspecific action mechanism, low intrinsic efficiency, and prolonged photosensitivity. 4 Thus, new PSs and formula- tions with improved biocompatibility and phototherapeutic efficiency are being sought. 5–14 However, the general strat- egy continues to be based on the local generation of the largest as possible amounts of reactive species rather than trying to trigger a specific programmed cell death mecha- nism inducing the minimal photodamage as possible. The photodynamic efficiency is influenced not only by the PS concentration in the diseased tissues but also by its intracellular localization. 15 16 Production of reactive species at key organelles seems to be more effective on ∗ Authors to whom correspondence should be addressed. Emails: koiaraki@iq.usp.br, baptista@iq.usp.br Received: 20 July 2012 Revised/Accepted: 6 January 2013 inducing cell death than simply generating them all around in a non-specific way. 16–18 In general, drugs that accu- mulate in the cytoplasmic membrane tend to trigger cell necrosis, whereas those targeting intracellular organelles such as mitochondria, endoplasmic reticulum and lyso- somes tend to favor programed cell death mechanisms (apoptosis or autophagy) depending on the photosensi- tizer and light dose. 19–21 Inducing apoptosis is an ele- gant way of causing cell death avoiding over-inflammation reactions. 22–25 Ideally, PSs should be able to selectively trigger apoptosis without generating too much reactive species and without harming adjacent tissues. High photodynamic activity is generally associated with amphiphilic PSs with relatively high lipophilic- ity and therefore low solubility in biological fluids. 26 27 This limitation has been overcome by encapsulation in micro- and nano-sized biocompatible vehicles. 5 28 29 Several reports describe efficient drug carriers and release systems for circumventing in vivo drug deliv- ery issues. 30–39 We recently showed that meso-triphenyl(3- N -methylpyiridinium)porphyrin (3MMe) incorporated in marine atelocollagen/xanthan gum (MAC) polymeric nanocapsules has higher efficiency than an analogous J. Biomed. Nanotechnol. 2013, Vol. 9, No. xx 1550-7033/2013/9/001/011 doi:10.1166/jbn.2013.1614 1