Targeted Docetaxel-Nanocolloid for the Treatment of Ovarian Cancer

描述(由申请人提供)：项目概要本提案是为响应美国国家卫生研究院小企业创新研究(SBIR)计划对纳米技术支持的癌症诊断和治疗药物(SBIR[U43/U44])[计划公告编号：PA-10-286]的征求建议书而提出的第一阶段建议。Nemucore医疗创新公司的这项第一阶段SBIR提案的目标是全面确定新型整合素v3和v5靶向多西紫杉醇(DTX)的受控释放、靶向、细胞毒性、药代动力学和疗效曲线，该纳米胶体采用名为NMI-700的专利逐层制造工艺创建，用于治疗表达整合素的卵巢癌。NMI的长期目标是将NMI-700与配套诊断结合起来，利用AutoGenics的Infiniti“平台筛选表达整合素的卵巢肿瘤，以便将患者分成从这一独特治疗中受益最大的队列。标准化疗药物的部分挑战是药物的保留和分布，这可以通过使用NMI的长期循环纳米胶体技术来解决，该技术是为包裹难溶药物而开发的，如DTX。整合素靶向对于卵巢癌是非常适用的，因为大多数卵巢癌与其他成人组织相比表达不同的整合素。因此，NMI-700的设计包含了许多关键属性，这些属性通过缓解溶解性问题来应对DTX的物理限制，并根据临床观察，限制全身暴露，通过靶向和控制释放隔离的DTX来减少药物毒性、清除性和灭活。对于新诊断的卵巢癌患者，其中大多数人迅速进展到耐药状态，NMI的纳米医学提供了一种治疗顽固性疾病患者急需的解决方案，这种疾病通常是无法治愈的，目标是 进一步治疗由治愈转变为姑息治疗。预计临床前研究将推进到随后的临床试验，在这些试验中，患者将被分成使用配套的Infiniti“诊断”的潜在应答者。到授权期结束时，NMI应该拥有进入下一阶段临床前开发所需的大量数据，并进一步推动这种独特的整合素靶向/DTX纳米药物进入临床。NMI预计，NMI-700产品的开发将提供以下好处：？为迫切需要临床解决方案的患者群体的肿瘤提供一种新的高度细胞毒治疗方法。推进纳米医学的发展，这是对个性化医学承诺的关键补充。？将一种溶解难溶药物的新制造方法商业化。

DESCRIPTION (provided by applicant): PROJECT SUMMARY This proposal is a Phase 1 proposal in response to The National Institute of Health Small Business Innovation Research (SBIR) Program call for proposals for the Cancer Diagnostics and Therapeutic Agents Enabled By Nanotechnology (SBIR [U43/U44]) [Program Announcement Number: PA-10-286]. Nemucore Medical Innovation, Inc.'s (NMI) goal for this Phase 1 SBIR proposal is to fully determine the controlled release, targeting, cytotoxicity, pharmacokinetics, and efficacy profile for a novel integrins v3 and v5 targeted docetaxel (DTX) encased in a nanocolloid created with a proprietary layer-by-layer manufacturing process, designated NMI-700, for treatment of integrin expressing ovarian cancers. NMI's long- term goal is to couple NMI-700 with a companion diagnostic utilizing AutoGenomic's INFINITI" platform to screen for integrin expressing ovarian tumors in order to stratify patients into a cohort who would most benefit from this unique treatment. Part of the challenge with standard chemotherapeutic agents is the retention and distribution of the agent, which can be solved with the use of the NMI's long circulating nanocolloid technology developed for encapsulating poorly soluble drugs, such as DTX. Integrin targeting is highly applicable for ovarian cancer because most of ovarian cancers differentially express integrins compared to other adult tissues. Therefore design of NMI-700 incorporates a number of key attributes, which respond to physical limitations of DTX by mitigating solubility issues and to clinical observations that limiting systemic exposure that reduces drug toxicity, clearance, and inactivation through targeting and controlled release of sequestered DTX. For newly diagnosed ovarian cancer patients, a majority of whom rapidly progress to a chemoresistant state, NMI's nanomedicine offers a solution that is urgently needed for treating patients with refractory disease, which is generally incurable, and the goal of further treatment changes from one of cure to one of palliation. It is anticipated that the pre-clinical studies will advance to subsequent clinical trials where patients will be segregated into potential responders using the companion INFINITI" diagnostic. By the end of the grant period NMI should have much of the data needed to proceed to the next stage of preclinical development and to further the advancement of this unique integrin-targeted/DTX nanomedicine into the clinic. NMI anticipates that development of NMI-700 product will provide the following benefits: ¿ Provide a new highly cytotoxic treatment for tumors of a patient population in desperate need for a clinical solution. ¿ Advance the development of nanomedicine, a key compliment to the promise of personalized medicine. ¿ Commercialize a new method of manufacture for solubilizing poorly soluble drugs.