Chiral Alkyl Groups at Position 3(1′) of Pyropheophorbide‑a Specify Uptake and Retention by Tumor Cells and Are Essential for Effective Photodynamic Therapy

To
investigate the importance of the chirality and precise structure
at position 3(1′) of pyropheophorbide-a for tumor cell specificity
and photodynamic therapy (PDT), a series of photosensitizers (PSs)
was synthesized: (a) with and without chirality at position 3(1′),
(b) alkyl ether chain with a variable number of chiral centers, (c)
hexyl ether versus thioether side chain, and (d) methyl ester versus
carboxylic acid group at position 172. The cellular uptake
and specificity were defined in human lung and head/neck cancer cells.
PSs without a chiral center and with an alkyl chain or thioether functionalities
showed limited uptake and PDT efficacy. Replacing the methyl group
at the chiral center with a propyl group or introducing an additional
chiral center improved cellular retention and tumor cell specificity.
Replacing the carboxylic acid with methyl ester at position 172 lowered cellular uptake and PDT efficacy. A direct correlation
between the PS uptake in vitro and in vivo was identified.

为探究吡罗菲罗醌-a在位置3(1')的构型及其精确结构对肿瘤细胞特异性和光动力治疗（PDT）的重要性，合成了一系列光敏剂（PSs）：（a）在位置3(1')上具有和缺乏构型，（b）具有不同手性中心数量的烷基醚链，（c）己基醚与硫醚侧链的对比，（d）在位置172上甲基酯与羧酸基团的替换。在人类肺和头颈癌细胞中，定义了这些PSs的细胞摄取和特异性。缺乏手性中心和具有烷基链或硫醚功能的PSs表现出有限的摄取和PDT效果。将手性中心上的甲基替换为丙基或引入额外的手性中心提高了细胞保留率和肿瘤细胞特异性。将位置172上的羧酸替换为甲基酯降低了细胞摄取和PDT效果。在体外PS摄取与体内摄取之间建立了直接相关性。