Programmed dual targeted lipopolymeric delivery systems for cancer gene therapy

用于癌症基因治疗的编程双靶向脂聚合物递送系统

• 批准号: 226359844
• 负责人: Professor Dr. Ernst Wagner
• 金额: --
• 依托单位: National Engineering Research Center for Biomaterials
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226359844?language=en
• 关键词: Programmed; dual; targeted; lipopolymeric; delivery

Gene therapeutic strategies require efficient and safe vector systems. Synthetic delivery systems have been developed to circumvent drawbacks of viral vectors. Based on our most encouraging results of our existing collaboration (since 2008), we will develop lipopolyplex carriers which are inspired by targeting characteristics of natural viruses and take advantage from both polymeric and liposomal carriers, in DNA compaction and endosomal escape, respectively. For tumor targeted delivery, full length proteins or antibodies were used binding cell surface receptors that are overexpressed in tumor cells or tumor vessels. In order to overcome the complexities of proteins, the current design will focus on synthetic short peptide or chemical ligands. Efficient cellular uptake of many natural viruses is based on the utilization of more than one receptor type on target cells. Inspired by viruses, in our previous joint efforts (Nie J. Controlled Release 2011) we developed a gene delivery strategy targeting two different receptors (transferrin receptor and alpha v beta 5 integrin) on prostate cancer cells with dual peptide-ligand containing PEG-PEI polyplexes. We now extend the studies to new combinations of ligands and carriers with better intracellular delivery characteristics. In our collaboration, programmed lipopolyplexes with deshieldable PEGylation were designed (Nie Biomaterials 2011). This intracellularly more effective platform will now be merged with the dual-ligand targeted strategy. Lipopolyplexes will be generated by physical association of polyplexes with targeting peptide-PEG-cholesterol containing liposomes (with or without cleavable PEG linkers). Alternatively, chemical conjugated lipopolymers will be the basis for targeted lipopolyplexes. Established (RGD, B6) and new (such as GE11, folate, TAT) ligands will be evaluated in the lipopolyplexes. The study will explore mechanisms of dual targeting ligand combinations in different cancer types (beyond prostate cancer, such as neuroblastom, hepatocellular carcinoma), especially the effect on cell association and intracellular uptake kinetics, and overall transfection activity. Stable or pH/reductive-deshieldable PEGylation will be compared.

基因治疗策略需要有效和安全的载体系统。已经开发了合成递送系统以规避病毒载体的缺点。基于我们现有合作（自2008年以来）最令人鼓舞的结果，我们将开发脂多聚物载体，其灵感来自天然病毒的靶向特性，并分别在DNA压缩和内体逃逸中利用聚合物和脂质体载体。对于肿瘤靶向递送，使用全长蛋白质或抗体结合在肿瘤细胞或肿瘤血管中过表达的细胞表面受体。为了克服蛋白质的复杂性，目前的设计将集中在合成短肽或化学配体。许多天然病毒的有效细胞摄取是基于靶细胞上一种以上受体类型的利用。受病毒的启发，在我们先前的共同努力中（Nie J. Controlled Release 2011），我们开发了一种基因递送策略，其用含有PEG-PEI多聚复合物的双肽-配体靶向前列腺癌细胞上的两种不同受体（转铁蛋白受体和α v β 5整联蛋白）。 我们现在将研究扩展到具有更好细胞内递送特性的配体和载体的新组合。在我们的合作中，设计了具有可去屏蔽聚乙二醇化的程序化脂质复合物（Nie Biomaterials 2011）。这种细胞内更有效的平台现在将与双配体靶向策略合并。通过聚合复合物与含有靶向肽-PEG-胆固醇的脂质体（具有或不具有可裂解的PEG接头）的物理缔合来产生脂质聚合复合物。或者，化学缀合的脂聚合物将是靶向脂聚合复合物的基础。将在脂质聚合复合物中评价已建立的（RGD，B6）和新的（如GE 11，叶酸，达特）配体。该研究将探索双靶向配体组合在不同癌症类型（除前列腺癌外，如成神经细胞瘤、肝细胞癌）中的机制，特别是对细胞缔合和细胞内摄取动力学以及总体转染活性的影响。将比较稳定或pH/还原性可去屏蔽的PEG化。

项目成果

Combinatorial Optimization of Sequence-Defined Oligo(ethanamino)amides for Folate Receptor-Targeted pDNA and siRNA Delivery.

用于叶酸受体靶向 pDNA 和 siRNA 递送的序列定义寡聚（乙氨基）酰胺的组合优化

• DOI: 10.1021/acs.bioconjchem.5b00649
• 发表时间: 2016
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: Dongsheng He;Katharina Müller;Ana Krhac Levacic;Petra Kos;Ulrich Lächelt;Ernst Wagner
• 通讯作者: Ernst Wagner

Combination of sequence‐defined oligoaminoamides with transferrin‐polycation conjugates for receptor‐targeted gene delivery

• DOI: 10.1002/jgm.2838
• 发表时间: 2015-08
• 期刊: The Journal of Gene Medicine
• 作者: Wei Zhang;W. Rödl;Dongsheng He;M. Döblinger;Ulrich Lächelt;E. Wagner

Native chemical ligation for conversion of sequence-defined oligomers into targeted pDNA and siRNA carriers.

• DOI: 10.1016/j.jconrel.2014.02.015
• 发表时间: 2014-04
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: C. Zhang;P. Kos;Katharina Müller;Waldemar Schrimpf;Christina Troiber;Ulrich Lächelt;C. Scholz;D. Lamb;E. Wagner