Developing Nanoparticle Drug Delivery Systems for Venous Malformations

项目摘要 这项提议的目标是开发针对静脉畸形(VMs)的靶向治疗方法。VMS速度很慢- 与毁容、疼痛和功能障碍相关的血流血管病变。最近，系统性的 用西罗莫司抑制哺乳动物靶点雷帕霉素(MTOR)已被证明是有效的治疗 患有复杂VM的儿童。然而，全身给药与限制治疗的副作用有关。 因此，需要安全、有针对性的治疗方法，将全身毒性降至最低。 拟议的项目将开发纳米颗粒(NP)靶向药物传递系统，以实现高局部 在最大限度地减少全身分布的情况下，药物在VM中的浓度。这将通过增强的 渗透和滞留(EPR)，这是癌症生物学中公认的一种现象，通过这种现象可以使肿瘤渗漏 与正常组织相比，血管系统允许优先摄取纳米颗粒 脉管系统。由于EPR，虚拟机内的被动NP积累将通过主动目标得到增强 技术，如照相目标。NPs的表面将覆盖有促进细胞生长的分子 领悟。这些分子将被“笼基”灭活，笼基是一种可逆结合的敏感分子。 到特定波长的光。在光照射下，笼子分子将从NP中移除。 因此，NPs可以系统地注射，并保持与组织的不结合。然而，对VM的照射将 导致“去化”发生，这将激活NP，并允许增强NP结合和药物释放。 目标站点。 为了验证这一假设，我们提出了三个具体目标：具体目标1：表述和表征 在VM中驻留时间较长的NP。具体目标2：靶向NP给药系统的研究 在活体内。具体目的3：研究纳米粒给药系统对体内治疗效果的影响。与 在Daniel Kohane博士的指导和指导下，Cullion博士发展了五年的职业发展 计划提供实现其目标所需的指导研究、技术技能发展和教学培训 目标：(1)成为治疗VM的纳米医学和药物输送方面的专家；(2)实现 科学独立，成为R01资助的内科科学家，从事翻译研究 专注于治疗血管畸形的纳米药物和药物输送。

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.