Novel Heterotopic Colloids of Anionic Porphyrins Entangled in Cationic Amphiphilic Cyclodextrins: Spectroscopic Investigation and Intracellular Delivery Antonino Mazzaglia,* [a] Nicola Angelini, [b] Raphael Darcy, [c] Ruth Donohue, [c] Domenico Lombardo, [b] Norberto Micali, [b] Maria Teresa Sciortino, [d] Valentina Villari, [b] and Luigi Monsú Scolaro* [a] Introduction Over the past decade cyclodextrin (CD) colloids with lyo- tropic and thermotropic properties have been widely report- ed. In particular, macrocyclic amphiphiles of hydrophobical- ly modified CDs can form a variety of supramolecular as- semblies, including monolayers, [1] micelles, [2] and nanoparti- cles of pharmaceutical importance. [3] Amphiphilic CDs have been admixed with phospholipid monolayers [4] and lipo- somes. [5] Recently, some of us prepared micellar aggregates [6] and vesicles [6a,7] entirely composed of amphiphilic cyclodex- trins. Their structural properties in water are due to the bal- ance between hydrophobic tails, such as thioalkyl chains, and the hydrophilic components, such as ethylene glycol oligomers. The presence of ethylene glycol chains, in partic- ular, increases the colloidal stability of the nanoparticles while potentially decreasing their adverse immune response as ™stealth∫ liposomes. [8] The presence of a complex hydro- philic head group, on the other hand, constitutes an impor- tant difference to most of the investigated double-tailed lipids, such as phospholipids. In this respect the correspond- ing supramolecular aggregates are very sensitive to the geo- metrical properties of the individual molecule, such as sur- [a] Dr. A. Mazzaglia, Prof. L. M. Scolaro Istituto per lo Studio dei Materiali Nanostrutturati ISMN-CNR, Unit‡ di Messina Dipartimento di Chimica Inorganica, Chimica Analitica e Chimica Fisica Universit‡ di Messina and INFM, Unit‡ di Messina Salita Sperone 31, 98166 Messina (Italy) Fax: (+ 39) 090-393-756 E-mail: mazzaglia@chem.unime.it E-mail: monsu@chem.unime.it [b] Dr. N. Angelini, Dr. D. Lombardo, Dr. N. Micali, Dr. V. Villari Istituto per i Processi Chimico Fisici IPCF-CNR, Sezione di Messina (Italy) [c] Dr R. Darcy, Dr. R. Donohue Centre for Synthesis and Chemical Biology Department of Chemistry National University of Ireland, University College Dublin (Ireland) [d] Dr. M. T. Sciortino Dipartimento di Scienze Microbiologiche, Genetiche e Molecolari, Universit‡ di Messina (Italy) Supporting information for this article is available on the WWW under http://www.chemeurj.org/ or from the author. Abstract: The entanglement process between water-soluble 5,10,15,20-tetra- kis(4-sulfonatophenyl)-21H,23H-por- phine and the amphiphilic cyclodextrin (CD) heptakis(2-w-amino-O-oligo- (ethylene oxide)-6-hexylthio)-b-CD and the occurrence of various species at dif- ferent porphyrin:CD ratios were stud- ied by a combination of UV/Vis ab- sorption, fluorescence anisotropy, time- resolved fluorescence, resonance light scattering, and circular dichroism. The effect of the entanglement process on the mean vesicle diameter was investi- gated over a wide concentration range by quasielastic light-scattering techni- ques. The experimental results indicate that the presence of porphyrins in this colloidal system promotes some struc- tural rearrangements, essentially driven by charge interaction, which are re- sponsible for a sensitive change of vesi- cle dimensions. In the range of por- phyrin:CD molar ratios between 1:10 and 1:50, the porphyrin is solubilized in monomeric form (t 1 = 11.5 ns) and pho- tosensitizes the production of singlet oxygen ( 1 O 2 ). At the same molar ratio the ability of this amphiphilic cyclodex- trin to transport porphyrins into tumor cells indicates specificity at the nuclear- compartment level. These findings may be of potential interest for the of devel- opment agents for photodynamic thera- py of tumors. Keywords: cyclodextrins ¥ drug delivery ¥ fluorescence spectroscopy ¥ nanostructures porphyrinoids ¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/chem.200304861 Chem. Eur. J. 2003, 9, 5762 ± 5769 5762 FULL PAPER