Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
Department of Medical Imaging, Taipei Tzu-Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; School of Medicine, Tzu-Chi University, Hualien, Taiwan.
Biomaterials. 2016 Aug;99:1-15. doi: 10.1016/j.biomaterials.2016.05.015. Epub 2016 May 12.
While there has been extensive development of anti-cancer drugs for treatment of prostate cancer, the therapeutic efficacy of such drugs remains inadequate in many cases. Here, we performed in vitro biopanning of the PC3 human prostate carcinoma cell line to select prostate cancer-specific peptides by phage display. We successfully identified specific peptides targeting prostate cancer cells, and their specificity was confirmed by cellular ELISA and flow cytometry. Moreover, we found that the phage clones also recognize other prostate cancer cell lines and surgical specimens from prostate cancer patients. The tumor targeting ability of these phages was validated in a xenograft model, in which high accumulation of targeting phage was observed. To investigate whether selected peptides are able to target tumors and enhance drug delivery into cancer cells, we synthesized peptide-PEGylated lipids and post-inserted them into preformed liposomal doxorubicin and vinorelbine. The results of our cellular uptake and MTT assays indicate that peptide-conjugated liposomes exhibit enhanced drug intracellular delivery and cytotoxicity. The conjugation of targeting peptide to imaging agents, such as quantum dots (QDs) and superparamagnetic iron oxide nanoparticles (SPIONs), results in more precise delivery of these agents to tumor sites. Furthermore, administration of liposomal doxorubicin and vinorelbine conjugated with targeting peptides was found to markedly increase the inhibition of human prostate tumor growth in mouse xenograft and orthotopic models. These results indicate that targeting peptide, SP204, has significant potential for targeted therapy and molecular imaging in prostate cancer.
尽管已经开发出了大量用于治疗前列腺癌的抗癌药物，但在许多情况下，这些药物的治疗效果仍然不够理想。在这里，我们通过噬菌体展示技术对人前列腺癌细胞系 PC3 进行了体外生物淘选，以筛选出针对前列腺癌的特异性肽。我们成功地鉴定出了靶向前列腺癌细胞的特异性肽，其特异性通过细胞 ELISA 和流式细胞术得到了证实。此外，我们发现这些噬菌体克隆还可以识别其他前列腺癌细胞系和前列腺癌患者的手术标本。噬菌体在异种移植模型中的肿瘤靶向能力得到了验证，在该模型中观察到了靶向噬菌体的高聚集。为了研究所选肽是否能够靶向肿瘤并增强药物递送至癌细胞，我们合成了肽-PEG 化脂质，并将其插入预先形成的脂质体阿霉素和长春瑞滨中。我们的细胞摄取和 MTT 测定结果表明，肽偶联脂质体表现出增强的药物细胞内递送和细胞毒性。将靶向肽与成像剂（如量子点（QDs）和超顺磁性氧化铁纳米颗粒（SPIONs））缀合，可使这些剂更精确地递送至肿瘤部位。此外，发现与靶向肽缀合的脂质体阿霉素和长春瑞滨的给药显著增加了荷瘤小鼠异种移植和原位模型中对人前列腺肿瘤生长的抑制作用。这些结果表明，靶向肽 SP204 具有在前列腺癌中进行靶向治疗和分子成像的巨大潜力。
