Antisense gene therapy with tumor-targeted nanocapsules

描述（由申请人提供）： 自1978年首次展示以来，反义寡核苷酸作为治疗分子已经产生了巨大的兴趣，但是由于药物递送到正确组织的正确细胞区室的不足，阻碍了它们作为有效的人类疗法的充分利用。我们设计了一种水基超小纳米胶囊制剂，用于将生物制剂靶向细胞内递送至实体瘤。该递送系统利用小窝内吞作用将纳米胶囊及其货物高效转运至靶细胞的细胞核。这些颗粒的极小尺寸（< 50 nm，“s50”）使得能够通过局部应用实现高组织渗透和经皮递送，为药物递送至加压实体瘤提供了创造性的选择。 生物制剂的肿瘤靶向递送使我们能够考虑操纵极其敏感且可能非常有效的肿瘤根除靶点。酶酪蛋白激酶2（CK 2）是这样的靶标，因为它：i）在迄今为止研究的所有癌症中始终不受调节; ii）与不良临床结果相关; iii）对于细胞增殖活性是必需的;以及iv）调节凋亡抑制以及其他经验证的化疗靶标，如拓扑异构酶2和组蛋白脱乙酰酶。在这项提案中，基于有希望的初步动物研究，我们将测试s50纳米帽反义CK 2治疗剂用于治疗头颈部复发性鳞状细胞癌（SSCHN）的临床开发的可行性，SSCHN是一种严峻的疾病，五年生存率约为30%。在这些研究中，我们将优化CK 2反义分子的骨架化学选择，然后用s50纳米胶囊化分子进行体外研究和体内动物研究。我们在这些研究中的重点将是更具侵袭性的SCCHN肿瘤;特别是那些目前正在开发的实验性疗法预计无法治疗的肿瘤。

DESCRIPTION (provided by applicant): Antisense oligonucleotides have generated enormous interest as therapeutic molecules since their initial demonstration in 1978, but their full utilization as effective human therapies has been hampered by inadequate drug delivery to the correct cellular compartment of the correct tissue. We have designed a water-based, ultra-small nanocapsule formulation for targeted intracellular delivery of biologics to solid tumors. This delivery system takes advantage of caveolar endocytosis for highly efficient transit of nanocapsules and their cargo to the target cell's nucleus. The extremely small size of these particles (< 50 nm, "s50") enables high tissue penetration and transdermal delivery via topical application offering creative options for drug delivery to pressurized solid tumors. Possession of a tumor-targeted delivery for biologics enables us to consider manipulation of extremely sensitive and potentially very effective targets for tumor eradication. The enzyme Casein Kinase 2 (CK2) is such a target as it: i) is consistently unregulated in all cancers studied to date; ii) correlates with poor clinical outcome; iii) is essential for cellular proliferation activity; and, iv) regulates apoptosis suppression as well as other validated chemotherapeutic targets, such as Topoisomerase 2 and histone deacetylase. In this proposal, building on promising initial animal studies, we will test feasibility of the s50 nanocapsule antisense CK2 therapeutic for clinical development in the treatment of recurrent squamous cell carcinoma of the head and neck (SSCHN), a grim disease with an approximate 30% five-year survival rate. In these studies, we will optimize the choice of backbone chemistry for the CK2 antisense molecule, then conduct in vitro studies and in vivo animal studies with the s50 nanoencapsulated molecule. Our focus in these studies will be on more aggressive SCCHN tumors; in particular, those tumors not expected to be treatable by experimental therapies currently in development.