Sicard Guillaume, Paris Clément, Giacometti Sarah, Rodallec Anne, Ciccolini Joseph, Rocchi Palma, Fanciullino Raphaëlle
SMARTc Unit, CRCM Inserm U1068, Aix Marseille University, 13007 Marseille, France.
CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Aix Marseille University, 13007 Marseille, France.
Pharmaceutics. 2020 Nov 29;12(12):1166. doi: 10.3390/pharmaceutics12121166.
Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using antisense oligonucleotide (ASO) to silence TCTP protein is a promising therapeutic option-however, the pharmacokinetics of ASO does not always meet the requirements of proper delivery to the tumor site. In this context, developing drug delivery systems is an attractive strategy for improving the efficacy of ASO directed against TCTP. The liposome should protect and deliver ASO at the intracellular level in order to be effective. In addition, because prostate cancer cells express Her2, using an anti-Her2 targeting antibody will increase the affinity of the liposome for the cell and optimize the intratumoral penetration of the ASO, thus improving efficacy. Here, we have designed and developed pegylated liposomes and Her2-targeting immunoliposomes. Mean diameter was below 200 nm, thus ensuring proper enhanced permeation and retention (EPR) effect. Encapsulation rate for ASO was about 40%. Using human PC-3 prostate cancer cells as a canonical model, free ASO and ASO encapsulated into either liposomes or anti-Her2 immunoliposomes were tested for efficacy in vitro using 2D and 3D spheroid models. While the encapsulated forms of ASO were always more effective than free ASO, we observed differences in efficacy of encapsulated ASO. For short exposure times (i.e., 4 h) ASO liposomes (ASO-Li) were more effective than ASO-immunoliposomes (ASO-iLi). Conversely, for longer exposure times, ASO-iLi performed better than ASO-Li. This pilot study demonstrates that it is possible to encapsulate ASO into liposomes and to yield antiproliferative efficacy against PCa. Importantly, despite mild Her2 expression in this PC-3 model, using a surface mAb as targeting agent provides further efficacy, especially when exposure is longer. Overall, the development of third-generation ASO-iLi should help to take advantage of the expression of Her2 by prostate cancer cells in order to allow greater specificity of action in vivo and thus a gain in efficacy.
前列腺癌（PCa）是全球男性中第二常见的癌症，也是癌症死亡的第五大主要原因。TCTP蛋白的过表达在去势抵抗中起重要作用。在过去十年中，反义技术已成为肿瘤学中一种新兴策略。使用反义寡核苷酸（ASO）沉默TCTP蛋白是一种有前景的治疗选择——然而，ASO的药代动力学并不总是满足将其正确递送至肿瘤部位的要求。在这种情况下，开发药物递送系统是提高针对TCTP的ASO疗效的一种有吸引力的策略。脂质体应在细胞内水平保护并递送ASO以使其有效。此外，由于前列腺癌细胞表达Her2，使用抗Her2靶向抗体将增加脂质体对细胞的亲和力，并优化ASO在肿瘤内的渗透，从而提高疗效。在此，我们设计并开发了聚乙二醇化脂质体和Her2靶向免疫脂质体。平均直径低于200nm，从而确保适当的增强渗透和滞留（EPR）效应。ASO的包封率约为40%。使用人PC-3前列腺癌细胞作为典型模型，将游离ASO以及包封在脂质体或抗Her2免疫脂质体中的ASO在二维和三维球体模型中进行体外疗效测试。虽然ASO的包封形式总是比游离ASO更有效，但我们观察到包封的ASO在疗效上存在差异。对于短暴露时间（即4小时），ASO脂质体（ASO-Li）比ASO免疫脂质体（ASO-iLi）更有效。相反，对于更长的暴露时间，ASO-iLi比ASO-Li表现更好。这项初步研究表明，有可能将ASO包封到脂质体中，并产生针对PCa的抗增殖疗效。重要的是，尽管在这个PC-3模型中Her2表达较弱，但使用表面单克隆抗体作为靶向剂可提供进一步的疗效，尤其是在暴露时间更长时。总体而言，第三代ASO-iLi的开发应有助于利用前列腺癌细胞中Her2的表达，以便在体内实现更高的作用特异性，从而提高疗效。
