Induction of Drug Photosensitization in Man After Parenteral Exposure to Hematoporphyrin

103

Summary Zn(II)-phthalocyanine (Zn-Pc) incorporated into unilamellar liposomes of dipalmitoylphosphatidylcholine has been injected intraperitoneally (0.5mgkg-1) to BALB/c mice bearing a transplanted MS-2 fibrosarcoma. The drug is specifically transported by serum lipoproteins and cleared from the serum via the bile-gut pathway in a biphasic process: -60% of Zn-Pc is eliminated with a serum half-life of -9 hours, while the remaining aliquot is eliminated at a very slow rate. Several normal tissues take up the drug within 3 hours after administration but release it almost completely after 24-48 hours. On the other hand, the tumour shows a maximum concentration of Zn-Pc (-0.6.ugg-1 of tissue) after 18-24 hours; at this time, the ratio between the Zn-Pc levels in the tumour and the muscle (which represents the surrounding normal tissue) is -7.5. The results are discussed in terms of a possible use of Zn-Pc as a photosensitizer in the photodynamic therapy of tumours.

Section: Resultssupporting

confidence: 77%

Pharmacokinetic studies with zinc(II)-phthalocyanine in tumour-bearing mice

Reddi

Castro²,

Biolo³

et al. 1987

103

“…Our pharmacokinetic studies show that a fraction of the Zn-Pc is cleared from the serum at a slow rate; this circumstance may be responsible for some cutaneous photosensitivity (Zalar et al, 1977). However, our pharmacokinetic studies showed that only negligible amounts of Zn-Pc (around 0.1 tg g-' tissue) are accumulated in the skin between 3 h and 1 week after administration.…”

Section: Resultsmentioning

confidence: 66%

Liposome- or LDL-administered Zn (II)-phthalocyanine as a photodynamic agent for tumours. I. Pharmacokinetic properties and phototherapeutic efficiency

Reddi

Zhou²,

Biolo³

et al. 1990

144

Summary The pharmacokinetics of Zn-phthalocyanine (Zn-Pc) in mice bearing a transplanted MS-2 fibrosarcoma has been studied using dipalmitoyl-phosphatidylcholine (DPPC) liposomes and low density lipoproteins (LDL) as drug delivery systems. LDL induce a higher Zn-Pc uptake by the tumour and improve the selectivity of tumour targeting as compared to DPPC liposomes. Experimental photodynamic therapy (PDT) of the MS-2 fibrosarcoma has been performed using liposome-delivered Zn-Pc and the efficiency of tumour necrosis has been measured following four different irradiation protocols. We found that Zn-Pc doses as low as 0.07-0.35 mg kg-' are sufficient for inducing an efficient tumour response that is linearly dependent on the injected dose. The amount of Zn-Pc in the tumour decreases very slowly as a function of time, hence PDT gives satisfactory results even if performed at relatively long time intervals after administration.

“…Sensitiser photodegradation may be exploited to improve selectivity as demonstrated by Barr et al (1990), who used low dose sensitisation with AlSPc in the colonic tumour model, although with this method the extent of tumour necrosis was considerably reduced. A further problem experienced with the best known clinical photosensitiser haematoporphyrin derivative (HpD) is the extended skin photosensitivity which may persist for months (Zalar et al, 1977).…”

mentioning

confidence: 99%

Fluorescence distribution and photodynamic effect of ALA-induced PP IX in the DMH rat colonic tumour model

Bedwell

MacRobert²,

Phillips³

et al. 1992

251

114

Summary Aminolaevulinic acid (ALA) is the first committed step in haem synthesis. In the presence of excess ALA the natural regulatory feedback system is disrupted allowing accumulation of protoporphyrin IX (PP IX) the last intermediate product before haem, and an effective sensitiser. This method of endogenous photosensitisation of cells has been exploited for photodynamic therapy (PDT). We have studied the fluorescence distribution and biological effect of induced PP IX in normal and tumour tissue in the rat colon. Fluorescence in normal colonic tissue was at a peak of 4 h with a rapid fall off by 6 h. The fluorescence had returned to background levels by 24 h. All normal tissue layers followed the same fluorescence profile but the mucosa showed fluorescent levels six times higher than the submucosa, with muscle barely above background values. At 6 h the ratio of fluorescence levels between normal mucosa and viable tumour was approximately 1:6. At this time laser treatment showed necrosis of normal mucosa and tumour with sparing of normal muscle. There was good correlation between the fluorescence distribution and the biological effect of ALA-induced photosensitisation on exposure to red light. ALA may be superior to conventional sensitisers for tumours that produce haem as the PP IX is synthesised in malignant cells while the other sensitisers mainly localise to the vascular stroma of tumours. There is also a greater concentration difference between the PP IX levels in tumours and in normal mucosa and normal muscle than with the other photosensitisers raising the possibility of more selective necrosis in tumours.