Developing Nanoparticle Drug Delivery Systems for Venous Malformations

项目摘要 该提案的目的是开发静脉畸形（VM）的靶向治疗。虚拟机很慢- 与毁容、疼痛和功能损害相关的血流血管病变。最近，系统 用西罗莫司抑制雷帕霉素的哺乳动物靶标（mTOR）已被证明有效用于治疗 患有复杂VM的儿童。然而，全身药物递送与限制治疗的副作用相关。 因此，需要安全的靶向治疗，最大限度地减少全身毒性。 拟议的项目将开发纳米颗粒（NP）靶向给药系统，以实现高局部 VM中的药物浓度，同时使全身分布最小化。这将通过加强 渗透和滞留（EPR）是癌症生物学中公认的现象， 与正常组织中的摄取相比，血管系统允许优先摄取纳米颗粒。 脉管系统由于EPR，VM内的被动NP积累将通过主动靶向增强 技术，如图像定位。纳米粒子的表面将被包裹上一层分子， 摄取。这些分子将被一个“笼状基团”灭活，这是一种可逆结合的分子， 一种特定波长的光在用光照射时，将从NP中除去笼状分子。 因此，NP可以全身注射并保持与组织未结合。然而，VM的照射将 导致“解开”发生，这将激活NP，并允许增强的NP结合和药物释放， 目标地点。 为了验证这一假设，我们提出了三个具体目标：具体目标1：制定和表征 在VM中具有延长的停留时间的NP。具体目标2：靶向NP给药系统的研究 in vivo.具体目标3：研究NP药物递送系统在体内的治疗功效。与 在丹尼尔·科汉博士的指导和指导下，库利昂博士制定了一个为期五年的职业发展计划， 计划提供指导研究，技术技能发展，并实现她所需的教学培训 目标（1）成为纳米医学和药物输送治疗VM的专家，（2）实现 科学独立，成为R 01资助的医生，科学家，从事转化研究 专注于纳米医学和血管异常的药物输送。

Project Summary The objective of this proposal is to develop targeted therapies for venous malformations (VMs). VMs are slow- flow vascular lesions associated with disfigurement, pain, and functional impairment. Recently, systemic inhibition of the mammalian target of rapamycin (mTOR) with sirolimus has proven efficacious for treating children with complex VMs. However, systemic drug delivery is associated with side effects that limit treatment. Therefore, safe, targeted therapies that minimize systemic toxicity are required. The proposed project will develop nanoparticulate (NP) targeted drug delivery systems to achieve high local drug concentration in VMs while minimizing systemic distribution. This will be achieved by virtue of enhanced permeation and retention (EPR), a well-recognized phenomenon in cancer biology whereby leaky tumor vasculature allows for preferential uptake of nanoparticles compared to uptake in tissues with normal vasculature. Passive NP accumulation within VMs, due to EPR, will be enhanced with active targeting techniques, such as photo-targeting. The surfaces of NPs will be coated with molecules that encourage cell uptake. These molecules will be inactivated with a “caging group,” a reversibly bound molecule that is sensitive to a specific wavelength of light. Upon irradiation with light, the caging molecule will be removed from the NP. Therefore, NPs can be systemically injected and remain unbound to tissues. However, irradiation of the VM will cause “uncaging” to occur, which will activate the NPs, and allow for enhanced NP binding and drug release at the target site. To test this hypothesis, we propose three specific aims: Specific Aim 1: Formulation and characterization of NPs with prolonged dwell times in VMs. Specific Aim 2: Study of targeted NP drug delivery systems in vivo. Specific Aim 3: Study of NP drug delivery systems on therapeutic efficacy in vivo. With the guidance and mentorship of Dr. Daniel Kohane, Dr. Cullion has developed a five- year career development plan to provide the mentored research, technical skill development, and didactic training needed to achieve her goals of (1) becoming an expert in nanomedicine and drug delivery for the treatment of VMs and (2) achieving scientific independence and becoming an R01 funded physician-scientist with a career in translational research focused on nanomedicine and drug delivery for vascular anomalies.