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引起了极大的兴趣，但由于药物不足以传递到正确组织的正确细胞间隔，它们作为有效的人类治疗手段的充分利用一直受到阻碍。我们设计了一种水基超小纳米胶囊配方，用于靶向细胞内给药至实体肿瘤。这种递送系统利用空泡内吞作用，高效地将纳米胶囊及其货物运送到靶细胞的细胞核。这些颗粒的极小尺寸(&lt；50 nm，“s50”)通过局部应用实现了高组织渗透和经皮给药，为加压实体肿瘤提供了创造性的药物输送选择。 拥有肿瘤靶向的生物制剂递送使我们能够考虑操纵极其敏感和潜在非常有效的肿瘤根除靶点。酪蛋白激酶2(Casein Kinase 2，CK2)是一种靶标，因为它：1)在迄今研究的所有癌症中都是不受调控的；2)与不良的临床结果相关；3)对细胞增殖活性至关重要；4)调节细胞凋亡抑制以及其他已证实的化疗靶点，如拓扑异构酶2和组蛋白脱乙酰酶。在这个提案中，我们将在有希望的初步动物研究的基础上，测试s50纳米胶囊反义CK2治疗头颈部复发鳞状细胞癌(SSCHN)的临床开发的可行性，SSCHN是一种严重的疾病，五年生存率约为30%。在这些研究中，我们将优化CK2反义分子的骨架化学选择，然后用S50纳米胶囊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放在更具侵袭性的SCCHN肿瘤上；特别是那些目前正在开发的实验疗法无法治疗的肿瘤。

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.