LbL Nanotechnologies for Synergistic Therapy of Advanced Ovarian Carcinoma

描述(申请人提供)：卵巢癌手术和治疗的进步已将该疾病的5年存活率从20世纪70年代末的36%提高到2007年的44%。尽管分子靶向疗法对其他疾病部位的肿瘤表现出了显著的疗效，但这些疗法对卵巢癌的疗效较差，部分原因是效力/毒性和适应性抵抗不佳。迫切需要安全、有效、有效、持久的卵巢癌治疗方法。联合疗法可以克服这些挑战；然而，最佳的协同药物相互作用需要严格控制细胞共定位和递送顺序/时机。使用传统配方和给药方法很难满足这些限制；然而，自组装逐层(LBL)聚合物纳米颗粒技术非常适合，提供药物共定位和对给药顺序/时间的精确控制。越来越多的证据表明，癌基因ErbB3信号在卵巢癌中的患病率和治疗意义正在迅速出现。这种跨膜受体在超过一半的肿瘤来源的细胞系中被结构性激活，代表着卵巢癌的单一治疗靶点，但可能更重要的是，它是对其他治疗方法产生适应性抵抗的显著途径。我们推测，使用聚合物纳米技术进行ErbB3靶向联合治疗卵巢癌可能是最安全和有效的，这些聚合物纳米技术旨在通过最佳识别的组合、顺序和时机实现细胞内释放。通过将(A)分析基因表达、蛋白质表达/信号、毒性和治疗潜力的高通量方法与(B)高度先进的卵巢癌细胞和动物模型相结合，我们将识别合成致命药物组合，并利用新开发的siRNA掺入LBL聚合物纳米技术来概述协同组合调度和传递到患者来源的原发肿瘤异种移植模型。这些研究整合了一个由生物学家、工程师、化学家和临床医生组成的高度多学科的团队，并寻求开发和加速应用纳米技术，以日益安全、有效和持久地联合治疗卵巢癌。该提案将解决晚期卵巢癌临床治疗中尚未得到满足的5个需求：(I)概括合成致命药物组合的最佳递送序列/时机的纳米技术的开发；(Ii)致癌ErbB3信号的协同阻断；(Iii)ErbB3在输卵管疾病发病机制中的表达/信号的研究；(Iv)实现稳健/持久的RNAi；以及(V)阐明ErbB3靶标联合治疗的耐药途径/干预措施。我们预计这些发现将直接与治疗复发性和高度恶性卵巢恶性肿瘤的纳米治疗技术的临床转化相关。

DESCRIPTION (provided by applicant): Advances in surgery and therapy for ovarian cancer have improved 5-year survival rates for the disease from 36% in the late 1970s to 44% in 2007. Although molecularly-targeted therapies have demonstrated remarkable efficacy against tumors in other disease sites, these therapies have been less effective against ovarian cancers, in part, due to sub-optimal potency/toxicity and adaptive resistance. Safe, effective, potent, and durable treatments for ovarian carcinoma are urgently needed. Combination therapies can overcome these challenges; however, optimally synergistic drug interactions require tight control of both cellular co-localization and delivery sequence/timing. These constraints can be challenging to meet using traditional formulations and delivery methods; however self-assembled layer-by-layer (LbL) polymer nanoparticle technologies are wellsuited, affording drug co-localization and precise control of delivery sequence/timing. Increasing evidence of the prevalence and therapeutic-significance of oncogenic ErbB3 signaling in ovarian carcinoma is rapidly emerging. This transmembrane receptor, constitutively activated in more than half of all tumor-derived cell lines, represents a singular therapeutic target for ovarian cancer, but perhaps more importantly, a prominent pathway for adaptive resistance to other therapies. We hypothesize that ErbB3-targeting combination therapies for ovarian cancer can be most safe and impactful when delivered using polymer nanotechnologies engineered to achieve intracellular release with optimally-identified combination, sequence, and timing. By integrating (a) high-throughput methods for analyzing gene expression, protein expression/signaling, toxicity, and therapeutic potential with (b) highly advanced cellular and animal models of ovarian carcinoma, we will identify synthetically lethal drug combinations and leverage newly-developed siRNA-incorporating LbL polymer nanotechnologies to recapitulate synergistic combination scheduling and delivery to patient-derived primary tumor xenograft models. These studies integrate a highly multidisciplinary team of biologists, engineers, chemists, and clinicians and seek to develop and accelerate the application of nanotechnologies for increasingly safe, effective, and durable combination therapies for ovarian cancer. The proposal will address 5 unmet needs in clinical therapy for advanced ovarian carcinoma: (i) the development of nanotechnologies that recapitulate optimal delivery sequence/timing of synthetically lethal drug combinations, (ii) the synergistic blockade of oncogenic ErbB3 signaling, (iii) the investigation of ErbB3 expression/signaling in the pathogenesis of fallopian-derived disease, (iv) the realization of robust/durable RNAi, and (v) the elucidation of resistance pathways/interventions for ErbB3-targteted combination therapies. We anticipate these findings to be directly relevant to the clinical translation of therapeutic nanotechnologies for recurrent and high-grade ovarian malignancies.