Institute of Medicinal Biotechnology , Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , 100050 , P.R. China.
Bioconjug Chem. 2018 Sep 19;29(9):3104-3112. doi: 10.1021/acs.bioconjchem.8b00456. Epub 2018 Aug 23.
Depending on increasing extracellular protein utilization and altering metabolic programs, cancer cells could proliferate and survive without restricion by ingesting human serum albumin (HSA) to serve as nutritional amino acids. Here, we hypothesize that the consumption of albumin by cancer cells could be utilized as an efficient approach to targeted drug delivery. Lidamycin (LDM), an antitumor antibiotic with extremely potent cytotoxicity to cultured cancer cells, consists of an apoprotein (LDP) and an active enediyne chromophore (AE). In the present study, a novel albumin-lidamycin conjugate was prepared by DNA recombination and molecular reconstitution. Results show that the IC values of albumin-lidamycin conjugate (HSA-LDP-AE) for a variety of tested cancer cells were at subnanomolar levels. At tolerated doses, the albumin-lidamycin conjugate significantly inhibited the growth of lung carcinoma PG-BE1 xenografts by 97.8%. The therapeutic efficacy of the albumin-lidamycin conjugate was much stronger than that of free lidamycin. Meanwhile, the images of albumin-lidamycin conjugate showed obvious and lasting tumor localization and fluorescence enrichment and there was no detectable signal in nontumor locations. Taken together, albumin-lidamycin conjugate, a new format of lidamycin, could be a promising antitumor therapeutic agent and albumin-integration might be a feasible approach to targeted antitumor drug delivery.
根据增加细胞外蛋白质的利用和改变代谢程序，癌细胞可以在不受限制的情况下增殖和存活，通过摄取人血清白蛋白（HSA）作为营养氨基酸。在这里，我们假设癌细胞对白蛋白的消耗可以被用作靶向药物递送的有效方法。
力达霉素（LDM）是一种抗肿瘤抗生素，对培养的癌细胞具有极强的细胞毒性，由脱辅基蛋白（LDP）和活性烯二炔类发色团（AE）组成。在本研究中，通过 DNA 重组和分子重建制备了一种新型的白蛋白-力达霉素缀合物。结果表明，白蛋白-力达霉素缀合物（HSA-LDP-AE）对多种测试的癌细胞的 IC 值均处于纳摩尔级以下。在耐受剂量下，白蛋白-力达霉素缀合物显著抑制肺腺癌 PG-BE1 异种移植物的生长，抑制率为 97.8%。白蛋白-力达霉素缀合物的治疗效果明显强于游离力达霉素。同时，白蛋白-力达霉素缀合物的图像显示出明显且持久的肿瘤定位和荧光富集，在非肿瘤部位没有检测到信号。
综上所述，白蛋白-力达霉素缀合物，作为力达霉素的一种新形式，可能是一种有前途的抗肿瘤治疗剂，而白蛋白整合可能是一种可行的靶向抗肿瘤药物递送方法。
