Bharti Rashmi, Dey Goutam, Banerjee Indranil, Dey Kaushik Kumar, Parida Sheetal, Kumar B N Prashanth, Das Chandan Kanta, Pal Ipsita, Mukherjee Manabendra, Misra Mridula, Pradhan Anjan K, Emdad Luni, Das Swadesh K, Fisher Paul B, Mandal Mahitosh
School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
Division of Nuclear Medicine, Indian Institute of Chemical Biology, Kolkata 700032, West Bengal, India.
Cancer Lett. 2017 Mar 1;388:292-302. doi: 10.1016/j.canlet.2016.12.021. Epub 2016 Dec 24.
Selective targeting to the tumor niche remains a major challenge in successful cancer therapy. Somatostatin receptor 2 (SSTR2) is overexpressed in breast cancer cells thus making this receptor an attractive target for selective guidance of ligand-conjugated drug liposomes to the tumor site. In this study, a synthetic somatostatin analogue (SST) was used as SSTR2 targeting agent and Diacerein was employed as therapeutic molecule. Diacerein loaded liposomes (DNL) were prepared and they were further decorated with the synthetic and stable analogue of somatostatin (SST-DNL). Fabricated liposomes were nano-size in range and biocompatible. SST-DNL displayed significantly better anti-tumor efficacy as compared to free Diacerein (DN) and DNL in breast cancer models. Enhanced apoptosis in breast cancer cells was detected in SST-DNL treated groups as monitored by cell cycle analysis and changes in expression level of apoptotic/anti-apoptotic proteins Bcl-2, Bax, cleaved Caspase 3 and PARP. SST-DNL more effectively inhibited the oncogenic IL-6/IL-6R/STAT3/MAPK/Akt signalling pathways as compared to DN or DNL in cancer cells. In addition, SST-DNL effectively suppressed angiogenesis and cancer cell invasion. In vivo tumor growth in a MDA-MB-231 mouse xenograft model was significantly suppressed following SST-DNL treatment. In xenograft model, immunohistochemistry of Ki-67 and CD-31 indicated that SST-DNL improved the anti-proliferative and anti-angiogenic impacts of Diacerein. In vivo pharmacokinetic studies in rats showed enhanced circulation time in the DNL or SST-DNL treated groups as compared to free DN. Considering all of these findings, we conclude that SST-DNL provides a novel strategy with better efficacy for breast cancer therapy.
在成功的癌症治疗中，选择性靶向肿瘤微环境仍然是一项重大挑战。生长抑素受体2（SSTR2）在乳腺癌细胞中过度表达，因此该受体成为将配体偶联药物脂质体选择性导向肿瘤部位的一个有吸引力的靶点。在本研究中，一种合成的生长抑素类似物（SST）被用作SSTR2靶向剂，双醋瑞因被用作治疗分子。制备了负载双醋瑞因的脂质体（DNL），并用合成的稳定生长抑素类似物（SST-DNL）对其进行进一步修饰。制备的脂质体尺寸在纳米范围内且具有生物相容性。在乳腺癌模型中，与游离双醋瑞因（DN）和DNL相比，SST-DNL显示出显著更好的抗肿瘤疗效。通过细胞周期分析以及凋亡/抗凋亡蛋白Bcl-2、Bax、裂解的Caspase 3和PARP表达水平的变化监测发现，SST-DNL处理组的乳腺癌细胞凋亡增强。与癌细胞中的DN或DNL相比，SST-DNL更有效地抑制致癌的IL-6/IL-6R/STAT3/MAPK/Akt信号通路。此外，SST-DNL有效抑制血管生成和癌细胞侵袭。在MDA-MB-231小鼠异种移植模型中，SST-DNL处理后体内肿瘤生长受到显著抑制。在异种移植模型中，Ki-67和CD-31的免疫组织化学表明，SST-DNL增强了双醋瑞因的抗增殖和抗血管生成作用。大鼠体内药代动力学研究表明，与游离DN相比，DNL或SST-DNL处理组的循环时间延长。综合所有这些发现，我们得出结论，SST-DNL为乳腺癌治疗提供了一种疗效更好的新策略。
