A cyclodextrin dimer with a photocleavable linker as a possible carrier for the photosensitizer in photodynamic tumor therapy

Abstract

A cyclodextrin dimer has been synthesized with two ␤-cyclodextrins linked by a flexible chain containing a carbon-carbon double bond. This dimer binds and solubilizes a phthalocyanine-based photosensitizer that generates singlet oxygen on irradiation. When the complex is irradiated, the singlet oxygen cleaves the carbon-carbon link, and the cyclodextrins are released, liberating the photosensitizer into the light path. Ideas about how this phenomenon could be used to make photodynamic tumor therapy into a more selective process are described. In photodynamic therapy, a dye such as a porphyrin or a phthalocyanine is used in conjunction with irradiation, e.g., by visible light. The excited-state dye converts triplet oxygen to the singlet, which is lethal to cells. Light directed into the area of a tumor can lead to the destruction of cancer cells (1, 2). One problem in this field is of course the accessibility of tumors to irradiation. Another problem has to do with the desirability of localizing the photosensitizer at the tumor site to prevent unwanted side reactions elsewhere. An approach to the latter problem has been to target the photosensitizer by using cancerspecific antibodies (3), but this use of a foreign protein may not be ideal.A different approach has been proposed by Moser et al. (4). If a quite hydrophobic photosensitizer is bound to a cyclodextrin (CD) dimer, the complex will become much more hydrophilic, and the strongly bound sensitizer may not be easily taken up by tissues, including those that are not the target tumor cells. However, if the linker in the CD dimer can be cleaved by singlet oxygen, the photosensitizer should be released from the dimer and then enter nearby cells.If this cleavage occurs in the tumor region that is being irradiated, there should be two results. First of all, cleavage of the CD dimer will deliver the photosensitizer to the affected cells, as proposed by Moser et al. (4). Perhaps more interestingly, the destruction of the dimer-sensitizer complex by light will cause more of it to diffuse into the irradiated region, concentrating the sensitizer where it is needed. In other words, the sensitizer will be concentrated into the directed light beam.We have tested this concept by using an electron-rich carboncarbon double bond as the group that is cleavable by singlet oxygen. The oxygen adds to the double bond to form a dioxetane, which fragments to form two carbonyl groups (5). Sulfur substituents at each end of the double bond increase its reactivity. Materials and MethodsCD dimer 1 was synthesized by conversion of cystamine to its N-t-butoxycarbonyl derivative, then reduction of the disulfide link with sodium in ammonia and reaction of the thiolate with cis-1,2-dichloroethylene to form 2 (Scheme 1). All compounds were characterized by NMR and MS, and this olefin 2 had the characteristic infrared signal at 627 cm Ϫ1 for a cis double bond. Acid deprotection of 2 and then acylation with iodoacetic acid anhydride afforded a bis-iodide that was converted to a bisthioacetate. ...

Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics

“…337 Here, CD provides good amphiphilic character to these compounds because the hydrophilic properties of the CD combined with the hydrophobic cavity in the center of the macrocycle allow these sugar conjugated Pc’s to be soluble in water. 338,339 These compounds were prepared via a statistical cross condensation of a 4-( β -CD)phthalonitrile with an excess of phthalonitriles or 4,5-dibutoxypthalonitrile and were characterized by MALDI-TOF-MS (Figure 56). 337 The same group also reported a methodology to synthesize asymmetrical sugar appended water-soluble Pc’s by statistical cross condensation of galactosyl-phthalonitrile with phthalonitrile.…”

S,S‐Chiral Linker Induced U Shape with a Syn‐facial Sensitizer and Photocleavable Ethene Group

“…Nonetheless, the dialkoxyethene group reacts rapidly with 1 O 2 , similar to successful 1 O 2 ‐based C=C and C=N bond types (e.g. disulfidoethenes, aminoacrylates, oximes, vinylimines and hydrazones) that also undergo cleavage as reported in the literature . Next, the mechanistic facets of the bent sensitizer conjugate were analyzed.…”

Exciting Supramolecular Architectures: Light‐Induced Processes and Synthetic Transformations in Noncovalent Assemblies

“…philes, [41] rosettes, [42] and cyclodextrins, [43] as well as to the release of masked biochemical substrates [44] or guests that compete for binding sites in supramolecular polymer architectures. [45] Light-induced conformational changes in one or more components of a supramolecular architecture can be used to significantly alter the global properties or the structure of the ensemble.…”