Therapeutic inhibition of peritoneal carcinomatosis by nanoparticle/siRNA-mediated knockdown of specific integrins and selectins

通过纳米颗粒/siRNA介导的特定整合素和选择素敲低来治疗性抑制腹膜癌

• 批准号: 411866030
• 负责人: Professor Dr. Achim Aigner
• 金额: --
• 依托单位: Rudolf-Boehm-Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/411866030?language=en
• 关键词: Therapeutic; inhibition; peritoneal; carcinomatosis; nanoparticle

Peritoneal carcinomatosis (PC) is a common form of pancreatic and gastric carcinoma progression, which substantially contributes to the rather poor prognosis. New therapeutic strategies, including the selective inhibition of PC, are thus desperately needed. In this regard, tumor cells as well as endothelial/mesothelial/non-malignant stroma cells can be explored as therapeutic target. Integrins are heterodimeric cell adhesion molecules consisting of α- and β-subunits. Certain integrins are upregulated in tumors and putatively play a pivotal role in PC. Previous results from the Wicklein group indicate that the integrins α2, α3, α5, α6, αV, β1 and β4 are most promising for being explored. Likewise, in xenografts E- and P-selectin were demonstrated to increase hematogenous metastasis and PC formation. This project aims at the exploration of novel therapeutic intervention strategies in preclinical mouse models and the functional analyses of selected selectins/integrins in vitro and in vivo. For specific single or combined target gene inhibition, we will employ RNA interference (RNAi)-mediated gene knockdown based on the delivery of RNA molecules (small interfering RNAs, siRNAs). siRNAs will be formulated in nanoparticles and applied intraperitoneally. A major challenge is the development of nanoparticle formulations with high stability and activity in the peritoneum. From the Aigner group, polymeric nanoparticles comprising low molecular weight polyethylenimines (PEI) and chemical modifications thereof are available. In this project, these nanoparticles will be further developed and explored for the first time for PC inhibition. Beyond knockdown of integrins, this will also involve targeting upstream regulators (PCDHB9, FBXO50), and using the integrin-inhibiting miR-31 for miRNA replacement therapy. For prolonged treatment duration, hydrogels as sustained NP release systems will be established as well and optimized with regard to desired release kinetics. Objectives thus include (i) the identification and analysis of optimal target genes (integrins, selectins, integrin upstream genes and combinations thereof) for RNAi-based inhibition of PC, (ii) exploring tumor cells (integrins) as well as endothelial/mesothelial/non-malignant stroma cells (selectins, integrins) as targets, (iii) the development and in vitro / in vivo analysis of optimized, polymeric nanoparticles and sustained release systems for peritoneal delivery of therapeutic siRNAs/miRNAs, and (iv) preclinical therapy studies in mouse models, using optimal nanoparticle systems and siRNAs. This will cover pre-treatment (prior to tumor cell exposure, aiming at the abolishment of the onset of PC), post-treatment (after tumor cell exposure, for treating established intraperitoneal carcinomas) and prolonged treatment protocols, aiming at both.

腹膜癌病（PC）是胰腺癌和胃癌进展的常见形式，其实质上导致相当差的预后。因此，迫切需要新的治疗策略，包括选择性抑制PC。在这方面，肿瘤细胞以及内皮/间皮/非恶性基质细胞可以作为治疗靶点进行探索。整合素是由α-和β-亚基组成的异源二聚体细胞粘附分子。某些整联蛋白在肿瘤中上调，并且puplatin在PC中起关键作用。来自Wicklein小组的先前结果表明整合素α2、α3、α5、α6、αV、β1和β4最有希望被探索。同样，在异种移植物中，E-和P-选择素被证明增加血行转移和PC形成。该项目旨在探索临床前小鼠模型中的新型治疗干预策略，并在体外和体内对选定的选择素/整合素进行功能分析。对于特定的单一或组合靶基因抑制，我们将采用基于RNA分子（小干扰RNA，siRNA）递送的RNA干扰（RNAi）介导的基因敲除。siRNA将配制成纳米颗粒并腹膜内施用。一个主要的挑战是开发在腹膜中具有高稳定性和活性的纳米颗粒制剂。从艾格纳组，可获得包含低分子量聚乙烯亚胺（PEI）及其化学改性的聚合物纳米颗粒。在这个项目中，这些纳米颗粒将被进一步开发和探索，首次用于PC抑制。除了敲低整合素，这还将涉及靶向上游调节因子（PCDHB 9，FBXO 50），并使用整合素抑制miR-31进行miRNA替代疗法。对于延长的治疗持续时间，也将建立水凝胶作为NP持续释放系统，并就所需的释放动力学进行优化。 因此，目标包括（i）鉴定和分析最佳靶基因（ii）探索肿瘤细胞（整合素、选择素、整合素上游基因及其组合），（整合素）以及内皮/间皮/非恶性基质细胞（iii）优化的，用于腹膜递送治疗性siRNA/miRNA的聚合物纳米颗粒和持续释放系统，和（iv）使用最佳纳米颗粒系统和siRNA在小鼠模型中的临床前治疗研究。这将涵盖治疗前（肿瘤细胞暴露前，旨在消除PC发作）、治疗后（肿瘤细胞暴露后，用于治疗已建立的腹膜内癌）和延长治疗方案，旨在两者。