PRECLINICAL ASSESSMENT OF HYPOCRELLIN-B AND HYPOCRELLIN-B-DERIVATIVESAS SENSITIZERS FOR PHOTODYNAMIC THERAPY OF CANCER - PROGRESS UPDATE

Hypocrellins are perylenequinone pigments with substantial absorption in the red spectral region and high singlet oxygen yield. They are ava ilable in pure monomeric form and may be derivatized to optimize prope rties of red light absorption, tissue biodistribution and toxicity. In vitro screening of synthetic derivatives of the naturally occurring c ompound, hypocrellin B (HB), for optimal properties of cyto-(dark) tox icity and phototoxicity resulted in selection of three compounds for p reclinical evaluation: HBEA-R1 (ethanolaminated HB), HBBA-R2 (butylami nated HB) and HBDP-R1[2-(N,N-dimethylamino)-propylamine-HB]. Extinctio n coefficients at 630 nm (epsilon(630)) are 6230, 6190 and 4800, respe ctively; and O-1(2) quantum yields, phi, 0.60, 0.32 and 0.42. Intracel lular uptake is essentially complete within 2 h (HBEA-R1, HBBA-R2) and 20 h (HBDP-R1). Greatest uptake is associated with lysosomes and Golg i. The HBEA-R1 and HBBA-R2, elicit phototoxicity in vitro primarily vi a the type II mechanism, with some type I activity under stringently h ypoxic conditions. Transcutaneous phototherapy with HBEA-R1 permanentl y ablates EMT6/Ed tumors growing in the flanks of Balb/c mice, with mi nimal cutaneous effects. The HBBA-R2 does not elicit mutagenic activit y in strains TA98 and TA100 of Salmonella typhimurium. Further develop ment of selected hypocrellin derivatives as photosensitizers for photo dynamic therapy is warranted.