MIREA - Russian Technological University, Moscow, Russian Federation.
RUDN University, Moscow, Russian Federation.
Anticancer Agents Med Chem. 2020;20(1):49-58. doi: 10.2174/1871520619666190801102617.
Conventional antitumor Photosensitizers (PS) are normally low toxic in the dark whereas light activation triggers massive cell death (photodynamic therapy, PDT).
To expand the therapeutic potential of PS to dual potency cytocidal agents, taking advantage of the use of bacteriopurpurin for a deeper tissue penetration of light, and suitability of the tetrapyrrolic macrocycle for chemical modifications at its periphery.
Conjugation of a pro-oxidant thiolate Au (I) moiety to the bacteriopurpurin core and evaluation of cytotoxicity in cell culture and in vivo.
New water-soluble derivatives showed micromolar cytotoxicity for cultured human tumor cell lines in the dark, including the subline with an altered drug response due to p53 inactivation. Cellular PDT with the selected conjugate, thiolate Au (I)-dipropoxybacteriopurpurinimide (compound 6) with two triphenylphosphine Au fragments, triggered rapid (within minutes) cell death. Damage to the plasma membrane (necrosis) was a hallmark of cell death by compound 6 both in the dark and upon light activation. Furthermore, one single i.v. injection of compound 6 caused retardation of transplanted syngeneic tumors at the tolerable dose. Illumination of tumors that accumulated compound 6 significantly synergized with the effect of 6 in the dark.
Complexes of virtually non-toxic, photoactivatable bacteriopurpurin with the gold-containing organic moiety are considered the dual potency antitumor agents, tentatively applicable for intractable tumors.
传统的抗肿瘤光敏剂（PS）在黑暗中通常毒性较低，而光激活会引发大量细胞死亡（光动力疗法，PDT）。
利用细菌卟啉在更深组织中的光穿透能力，以及四吡咯大环在其外围进行化学修饰的适用性，将 PS 的治疗潜力扩展为双重细胞毒性药物。
将一个促氧化剂硫醇 Au（I）部分连接到细菌卟啉核心，并在细胞培养和体内评估其细胞毒性。
新的水溶性衍生物在黑暗中对培养的人类肿瘤细胞系具有微摩尔级的细胞毒性，包括由于 p53 失活而导致药物反应改变的亚系。所选化合物 6（硫醇 Au（I）-二丙氧基细菌卟啉亚胺）与两个三苯基膦 Au 片段的细胞 PDT 会在数分钟内引发快速的细胞死亡。细胞膜损伤（坏死）是化合物 6 引起的细胞死亡的标志，无论是在黑暗中还是在光激活时。此外，单次静脉注射化合物 6 在可耐受剂量下可延缓同种异体移植肿瘤的生长。积聚化合物 6 的肿瘤的光照显著增强了其在黑暗中的作用。
具有含金有机部分的几乎无毒、可光激活的细菌卟啉复合物被认为是双重抗肿瘤药物，可用于治疗难治性肿瘤。
