Antisense gene therapy with tumor-targeted nanocapsules

肿瘤靶向纳米胶囊的反义基因治疗

• 批准号: 6587455
• 负责人: GRETCHEN M UNGER
• 金额: $ 24.51万
• 依托单位: GENESEGUES, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6587455
• 关键词: antisense nucleic acid; athymic mouse; casein kinase; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; gene delivery system; gene therapy; head /neck neoplasm; nanotechnology; squamous cell carcinoma

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.

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人们的极大兴趣，但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。该递送系统利用小凹内吞作用，将纳米胶囊及其货物高效转运至靶细胞核。这些颗粒尺寸极小（< 50 nm，“s50”），可通过局部应用实现高组织渗透和透皮递送，为加压实体瘤的药物递送提供了创造性的选择。 拥有肿瘤靶向递送的生物制剂使我们能够考虑操纵极其敏感且可能非常有效的靶点来根除肿瘤。酪蛋白激酶 2 (CK2) 就是这样一个靶标，因为它： i) 在迄今为止研究的所有癌症中始终不受监管； ii) 与不良临床结果相关； iii) 对于细胞增殖活性至关重要； iv) 调节细胞凋亡抑制以及其他经过验证的化疗靶标，例如拓扑异构酶 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 纳米胶囊反义 CK2 治疗剂用于治疗复发性头颈鳞状细胞癌 (SSCHN) 临床开发的可行性，这是一种五年生存率约为 30% 的严峻疾病。在这些研究中，我们将优化CK2反义分子主链化学的选择，然后用s50纳米封装分子进行体外研究和体内动物研究。我们这些研究的重点将是更具侵袭性的 SCCHN 肿瘤；特别是那些预计无法通过目前正在开发的实验疗法治疗的肿瘤。

项目成果

Tenfibgen-DMAT Nanocapsule Delivers CK2 Inhibitor DMAT to Prostate Cancer Xenograft Tumors Causing Inhibition of Cell Proliferation.

• DOI: 10.4255/mcpharmacol.14.02
• 发表时间: 2014
• 期刊: Molecular and cellular pharmacology
• 作者: J. Trembley;G. Unger;O. Gomez;J. Abedin;V. Korman;R. Vogel;G. Niehans;B. Kren;K. Ahmed

Tenfibgen ligand nanoencapsulation delivers bi-functional anti-CK2 RNAi oligomer to key sites for prostate cancer targeting using human xenograft tumors in mice.

• DOI: 10.1371/journal.pone.0109970
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Trembley JH;Unger GM;Korman VL;Abedin MJ;Nacusi LP;Vogel RI;Slaton JW;Kren BT;Ahmed K
• 通讯作者: Ahmed K

Mechanism and efficacy of sub-50-nm tenfibgen nanocapsules for cancer cell-directed delivery of anti-CK2 RNAi to primary and metastatic squamous cell carcinoma.

亚 50 nm tenfibgen 纳米胶囊用于癌细胞定向递送抗 CK2 RNAi 至原发性和转移性鳞状细胞癌的机制和功效。

• DOI: 10.1158/1535-7163.mct-14-0166
• 发表时间: 2014
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Unger,GretchenM;Kren,BetsyT;Korman,VicciL;Kimbrough,TylerG;Vogel,RachelI;Ondrey,FrankG;Trembley,JaneenH;Ahmed,Khalil
• 通讯作者: Ahmed,Khalil

CK2 modulation of NF-kappaB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub-50-nm nanocapsules.

• DOI: 10.1158/1078-0432.ccr-09-3200
• 发表时间: 2010-04-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Brown MS;Diallo OT;Hu M;Ehsanian R;Yang X;Arun P;Lu H;Korman V;Unger G;Ahmed K;Van Waes C;Chen Z
• 通讯作者: Chen Z

Preclinical evaluation of cyclin dependent kinase 11 and casein kinase 2 survival kinases as RNA interference targets for triple negative breast cancer therapy.

• DOI: 10.1186/s13058-015-0524-0
• 发表时间: 2015
• 期刊: Breast cancer research : BCR
• 作者: Kren BT;Unger GM;Abedin MJ;Vogel RI;Henzler CM;Ahmed K;Trembley JH
• 通讯作者: Trembley JH