Water-soluble aluminium phthalocyanine–polymer conjugates for PDT: photodynamic activities and pharmacokinetics in tumour-bearing mice

Abstract

Among the second-generation photosensitizers (PS) developed for the treatment of neoplastic diseases by photodynamic therapy (PDT) (Kessel, 1996;Ochsner, 1997), metallo-phthalocyanines (MePc) have been proposed (Spikes, 1986;van Lier, 1990;Rosenthal, 1991) as an alternative to Photofrin (PII), the only PS currently approved for clinical use. Their stronger absorption in the red part of the spectrum (molar extinction coefficient, 2.5 × 10 5 M -1 cm -1 at 675 nm), where the depth of light penetration in tissues is twice that obtained at 630 nm with PII (Svaasand, 1984), together with their chemical homogeneity and their lower potential to induce cutaneous photosensitivity (Roberts et al, 1989;Tralau et al, 1989) are major advantages over PII.Unsubstituted MePc are not soluble in physiological solvents and their in vivo administration relies upon their incorporation into carriers, such as the liposomal formulation of ZnPc (Isele et al, 1995), or their chemical conversion into water-soluble dyes by the attachment of selected substituents onto the benzene rings of the macrocycle. An inverse relationship was related between the degree of substitution by sulphonato groups of MePc and their hydrophobicity and photodynamic activities, both at the cellular level and in tumour-bearing mice (Brasseur et al, 1987(Brasseur et al, , 1988Paquette et al, 1988;Berg et al, 1989;Chan et al, 1990Chan et al, , 1991Margaron et al, 1996a). The potential of the water-soluble aluminium sulphophthalocyanine (AlPcS) to generate activated oxygen species (Sharman et al, 1999) and to induce a photodynamic response in vivo has been widely evaluated, and a mixture of AlPcS bearing 2-4 sulphonato groups per Pc (Photosense) is used extensively and successfully in clinical PDT in Russia (Zharkova et al, 1994). Furthermore, the di-sulphonated derivative has been shown to induce tumour regression mainly via direct tumour cell kill rather than damage to the tumour vasculature, as observed for PII (Chan et al, 1996;Margaron et al, 1996b). The unsubstituted AlClPc has, however, attracted less attention even though it has been shown that this compound formulated as a Cremophor emulsion was preferentially retained by a gliosarcoma and was able to induce tumour necrosis in this model (Dereski et al, 1994). More recently, we demonstrated that the Cremophorformulated AlClPc was more effective in inducing tumour regression in EMT-6 tumour-bearing mice than the mono-through tetrasulphonated derivatives, while exerting relatively minor effects against normal tissues (Chan et al, 1997). The low dosage required together with the absence of systemic toxicity, even at much higher doses, renders the AlClPc Cremophor emulsion one of the most potent photosensitizer preparations currently available in terms of therapeutic window. However, Cremophor oil is known to induce unwanted side-effects in patients (Dye and Watkins, Summary The potential use of unsubstituted aluminium phthalocyanine (AlClPc) as a sensitizer for photodynamic therapy (PDT) of cancer has not been f...

Engineering of relevant photodynamic processes through structural modifications of metallotetrapyrrolic photosensitizers

“…Another strategy to increase the hydrophilicity of PSs, and hence their bioavailability, is coordination of the polymer moieties, including polyethylene glycol (pegylation), polyvinyl alcohol or N-(2-hydroxypropyl)methacrylamide [217][218][219]. Complexes of PS with polymers are characterized by a prolonged intravascular half-life, improved tumor selectivity and enhanced PDT efficacy [220].…”

Nanodrug applications in photodynamic therapy

“…Examples of encapsulation of hydrophobic photosensitizers into nanomaterials are polymeric nanoparticles [88], e.g., a hydrophobic photosensitizer meso-tetra(phydroxyphenyl)porphyrin (m-THPP) encapsulated into polymeric nanoparticle poly(D,Llactide-co-glycolide) [89,90], dendrimer phthalocyanine (DPc)-encapsulated polymeric micelles (DPc/m) [32], polymeric protoporphyrin IX micelles [55], and organically modified silica-based nanoparticles [91] entrapping the photosensitizing anti-cancer drug 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide [59] have been used.…”

Tat/HA2 Peptides Conjugated AuNR@pNIPAAm as a Photosensitizer Carrier for Near Infrared Triggered Photodynamic Therapy

“…However, AlPcS 4 is not readily taken up by cells due to the negative charges of sulfonation groups on AlPcS 4 molecule. 43 A previous study indeed supported the notion that free AlPcS 4 lacks the ability to efficient uptake by cells. 44 This may be a major limiting factor hampering its clinical application.…”