Peptide-based pharmacomodulation of a cancer-targeted optical imaging and photodynamic therapy agent
Peptide-based pharmacomodulation of a cancer-targeted optical imaging and photodynamic therapy agent
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DOI：
10.1021/bc0602578
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发表时间：
2007-03-01
影响因子：
4.7
通讯作者：
Zheng, Gang
中科院分区：
文献类型：
--
作者：
Stefflova, Klara;Li, Hui;Zheng, Gang
我们设计并合成了一种叶酸受体靶向，水溶性，药物调节光动力治疗（PDT）剂，选择性地检测和破坏目标癌细胞，同时保留正常组织。这是通过最小化正常器官摄取（如肝脏和脾脏）和区分具有不同叶酸受体（FR）表达水平的肿瘤来实现的。该结构物（Pyro-peptide-Folate， PPF）由三种成分组成：(1)作为显像和治疗剂的pyropheophophide a (Pyro),(2)作为提高递送效率的稳定连接和调节剂的肽序列，以及(3)作为靶向表达fr的癌细胞的归巢分子的叶酸。我们观察到，与HT 1080癌细胞（FR-）相比，KB癌细胞（FR+）中PPF的积累增强，导致pdt后KB细胞比HT 1080或正常CHO细胞更有效地杀死KB细胞。过量的游离叶酸可抑制KB细胞中PPF的积累高达70%。体内实验也证实了叶酸对KB肿瘤中PPF优先积累的影响（KB与HT 1080肿瘤的比值为2.5:1）。与此相反，在非靶向探针（焦肽，PP）的情况下，KB和HT 1080肿瘤之间没有明显差异，消除了Pyro自身对癌细胞的非特异性亲和力的潜在影响。更重要的是，我们发现结合短肽序列大大提高了探针过程的递送效率，我们认为这可能是基于肽的药物调节，与缺乏肽的探针（焦磷酸k叶酸，PKF）相比，肝脏和脾脏中的PPF积累减少了50倍。这种方法可以推广到提高其他靶向分子成像和光动力治疗剂的递送效率。
We designed and synthesized a folate receptor-targeted, water-soluble, and pharmacomodulated photodynamic therapy (PDT) agent that selectively detects and destroys the targeted cancer cells while sparing normal tissue. This was achieved by minimizing the normal organ uptake (e.g., liver and spleen) and by discriminating between tumors with different levels of folate receptor (FR) expression. This construct (Pyro-peptide-Folate, PPF) is composed of three components: (1) pyropheophorbide a (Pyro) as an imaging and therapeutic agent, (2) peptide sequence as a stable linker and modulator improving the delivery efficiency, and (3) Folate as a homing molecule targeting FR-expressing cancer cells. We observed an enhanced accumulation of PPF in KB cancer cells (FR+) compared to HT 1080 cancer cells (FR-), resulting in a more effective post-PDT killing of KB cells over HT 1080 or normal CHO cells. The accumulation of PPF in KB cells can be up to 70% inhibited by an excess of free folic acid. The effect of Folate on preferential accumulation of PPF in KB tumors (KB vs HT 1080 tumors 2.5:1) was also confirmed in vivo. In contrast to that, no significant difference between the KB and HT 1080 tumor was observed in case of the untargeted probe (Pyro-peptide, PP), eliminating the potential influence of Pyro's own nonspecific affinity to cancer cells. More importantly, we found that incorporating a short peptide sequence considerably improved the delivery efficiency of the probea process we attributed to a possible peptide-based pharmacomodulationas was demonstrated by a 50-fold reduction in PPF accumulation in liver and spleen when compared to a peptide-lacking probe (Pyro-K-Folate, PKF). This approach could potentially be generalized to improve the delivery efficiency of other targeted molecular imaging and photodynamic therapy agents.