Pyropheophorbide-a (Pyro) is a highly promising photosensitizer for tumor photodynamic therapy (PDT), although its very limited tumor-accumulation ability seriously restricts its clinical applications. A higher accumulation of photosensitizers is very important for the treatment of deeply seated and larger tumors. The conjugation of Pyro with tumor-homing peptide ligands could be a very useful strategy to optimize the physical properties of Pyro. Herein, we reported our studies on the conjugation of Pyro with a cyclic cRGDfK (cRGD) peptide, an integrin binding sequence, to develop highly tumor-specific photosensitizers for PDT application. To further reduce the nonspecific uptake and, thus, reduce the background distribution of the conjugates in normal tissues, we opted to add a highly hydrophilic polyethylene glycol (PEG) chain and an extra strongly hydrophilic carboxylic acid group as the linker to avoid the direct connection of the strongly hydrophobic Pyro macrocycle and cRGD ligand. We reported here the synthesis and characterization of these conjugates, and the influence of the hydrophilic modification on the biological function of the conjugates was carefully studied. The tumor-accumulation ability and photodynamic-induced cell-killing ability of these conjugates were evaluated through both in vitro cell-based experiment and in vivo distribution and tumor therapy experiments with tumor-bearing mice. Thus, the synthesized conjugate significantly improved the tumor enrichment and tumor selectivity of Pyro, as well as abolished the xenograft tumors in the murine model through a one-time PDT treatment.

中文翻译：

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cRGD肽缀合的焦脱镁叶绿酸-a光敏剂，用于光动力疗法中的肿瘤靶向。

焦脱镁叶绿酸-a（Pyro）是用于肿瘤光动力疗法（PDT）的高度有前途的光敏剂，尽管其非常有限的肿瘤蓄积能力严重限制了其临床应用。光敏剂的更高积累对于治疗深度较大的肿瘤非常重要。Pyro与肿瘤归巢肽配体的结合可能是优化Pyro物理性质的非常有用的策略。本文中，我们报道了有关吡咯与环状cRGDfK（cRGD）肽（整联蛋白结合序列）结合的研究，以开发用于PDT的高度肿瘤特异性光敏剂。为了进一步减少非特异性摄取，从而减少正常组织中结合物的背景分布，我们选择添加高亲水性聚乙二醇（PEG）链和超强亲水性羧酸基团作为连接基，以避免强疏水性Pyro大环与cRGD配体的直接连接。我们在这里报道了这些缀合物的合成和表征，并仔细研究了亲水修饰对缀合物生物学功能的影响。这些结合物的肿瘤蓄积能力和光动力诱导的细胞杀伤能力通过荷瘤小鼠的体外基于细胞的实验以及体内分布和肿瘤治疗实验进行评估。因此，合成的结合物显着改善了Pyro的肿瘤富集度和肿瘤选择性，