Estey E P, Brown K, Diwu Z, Liu J, Lown J W, Miller G G, Moore R B, Tulip J, McPhee M S
Department of Surgery, Cross Cancer Institute, Edmonton, AB, Canada.
Cancer Chemother Pharmacol. 1996;37(4):343-50. doi: 10.1007/s002800050395.
Hypocrellin compounds were selected as potential photosensitizers for photodynamic therapy (PDT) owing to their high quantum yields of singlet oxygen (1O2), and facility for site-directed chemical modification to enhance phototoxicity, pharmacokinetics, solubility, and light absorption in the red spectral region, among other properties. Parent hypocrellins A and B share an absorption peak at 658 nm. These molecules may therefore be considered useful progenitors of derivatives which absorb more strongly in the red, considering that the ideal sensitizer should absorb in the 650-800 nm range, beyond the absorption range of hemoglobin and melanin, and where light penetration in tissues is maximized through reduced scattering. A series of pure, monomeric hypocrellin derivatives was tested for properties of dark cytotoxicity and photosensitizing potential by clonogenic assay in monolayer cultures of EMT6/Ed murine tumor cells. Their respective toxicities are reported on a molar basis. The in vitro screening assay has, to date, resulted in the selection of four hypocrellin derivatives for further development as photosensitizers for PDT. Cellular uptake for photosensitizing doses of selected compounds was determined by fluorimetry. Dose escalation studies in rodents indicate that potentially photosensitizing doses promote no demonstrable systemic toxicity.
由于竹红菌素化合物具有较高的单线态氧（1O2）量子产率，并且能够进行位点定向化学修饰以增强光毒性、药代动力学、溶解度以及在红色光谱区域的光吸收等特性，因此被选为光动力疗法（PDT）的潜在光敏剂。母体竹红菌素A和B在658 nm处有一个吸收峰。鉴于理想的敏化剂应在650 - 800 nm范围内吸收，该范围超出了血红蛋白和黑色素的吸收范围，且在此范围内组织对光的穿透因散射减少而最大化，所以这些分子可被视为在红色区域吸收更强的衍生物的有用前体。通过对EMT6/Ed小鼠肿瘤细胞单层培养进行克隆形成试验，对一系列纯的单体竹红菌素衍生物进行了暗细胞毒性和光敏潜力特性测试。它们各自的毒性以摩尔为基础进行报告。迄今为止，体外筛选试验已选出四种竹红菌素衍生物作为PDT光敏剂进行进一步开发。通过荧光法测定了选定化合物光敏剂量的细胞摄取情况。在啮齿动物中进行的剂量递增研究表明，潜在的光敏剂量不会产生明显的全身毒性。
