Tumour-localising and -photosensitising properties of a novel zinc(II) octadecylphthalocyanine

Abstract

Summary 1,4,8,11,15,18,22,, ZnODPc, incorporated into a Cremophor emulsion, was assayed for its pharmacokinetic and phototherapeutic properties in Balb/c mice bearing an intramuscularly transplanted MS-2 fibrosarcoma. The phthalocyanine was injected intravenously (i.v.) in three doses, i.e. 1.46, 0.73 and 0.37 ttmol kg-' body weight. In all cases, the octadecyl-substituted phthalocyanine showed an unusually high affinity for serum low-density lipoproteins (LDLs) and a high efficiency and selectivity of tumour targeting: the maximum accumulation in the tumour occurred at 24 h after injection, whereas no detectable amount of phthalocyanine was recovered from the muscle, i.e. the peritumoral tissue, between I h and 1 week after injection. At the same time, low amounts of phthalocyanine were recovered from skin and then only at short times after injection, with skin photosensitivity rapidly disappearing and the phthalocyanine present in the serum only. Tumour photosensitisation studies were carried out at 24 h after administration of 1.46 ,umol kg-' ZnODPc and showed that this phthalocyanine has a very high phototherapeutic efficiency; this is probably a consequence of the multiple mechanisms by which the phthalocyanine induces tumour damage, involving both direct modification of malignant cells and impairment of blood flow, as well as the alteration of a variety of subcellular components, such as mitochondria, the rough endoplasmic reticulum, the perinuclear membrane and, occasionally, cell nuclei. Tumour necrosis appears to be the consequence of both random cell death and apoptosis.

Mechanisms of porphyrinoid localization in tumors

“…The octadecyland octapentyl-phthalocyanine derivatives of 12 were found to bind to LDL (60-70%) to a higher extent than 12 (25%) and to lead to about 30% higher selectivity of tumor-targeting in mice [92,93]. The higher PDT efficacy of 8 found in apoE deficient C57BL/6 mice was correlated to the enhanced binding of this drug to VLDL and LDL (23% rather than 4%), which led to higher drug accumulation in tumor [94].…”

Like a Bolt from the Blue: Phthalocyanines in Biomedical Optics

“…Ometto et al . [ 143 ] as well as Fabris et al . [ 144 ] have tested octapentyl ( 27 ) and octadecyl ( 28 ) substituted ZnPc ( Figure 11 ).…”

“…The strong binding of both compounds to LDL is presumably responsible for this selectivity [ 145 ]. Both 27 and 28 induced a shrinkage of the tumor volume after PDT [ 143 , 144 ]. However, both derivatives accumulated to a higher extend in the liver and spleen than in the tumor even one week post-PDT, presumably because the bile-gut is the primary elimination pathway characteristic for lipidic drug delivery systems [ 143 , 146 ].…”

Derivatizable phthalocyanine with single carboxyl group: Synthesis and purification

“…In the presence of physiological oxygen, the light-absorbing photosensitizer produces reactive oxygen species (ROS) and/or free radicals in its immediate locale, rendering biological toxicity. Phthalocyanine zincs, and several other metallophthalocyines, have been successfully used as a photosensitizing agents in photodynamic therapy at both cellular and animal levels [2][3][4][5][6]. Conjugation of sensitizer with biological targeting agents, e.g., monoclonal antibodies or lipoproteins, increases the concentration of sensitizer on targeted tissue over normal tissue, providing additional level of selectivity and possibility to reduce effective sensitizer concentration, and thus phototoxicity to normal tissue [7,8].…”