Developing Nanoparticle Drug Delivery Systems for Venous Malformations

开发治疗静脉畸形的纳米颗粒药物输送系统

• 批准号: 10525714
• 负责人: Kathleen Cullion
• 金额: $ 16.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525714
• 关键词: Affect; Anatomy; Anemia; Animal Model; Animals; Area; Binding; Biodistribution; Biological; Biomedical Engineering; Blood Vessels; Blood flow; Cancer Biology; Cells; Child; Complex; Congenital Abnormality; Development Plans; Disease; Dose; Drug Delivery Systems; Drug Targeting; Endothelium; Event; Exposure to; FRAP1 gene; Formulation; Funding; Goals; Growth; Hemorrhage; Human; Immunosuppression; Incidence; Infection; Intravenous; Intravenous Drug Delivery Systems; Label; Lesion; Life; Ligands; Light; Location; Mentors; Mentorship; Modeling; Modification; Mus; Operative Surgical Procedures; Organ failure; Pain; Particle Size; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physicians; Research; Risk; Scientist; Sclerotherapy; Sirolimus; Site; Smooth Muscle; Source; Surface; Surgical Management; System; Technical Expertise; Techniques; Testing; Therapeutic Effect; Therapeutic Studies; Time; Tissues; Training; Translational Research; Treatment Efficacy; Venous Malformation; caged molecule; career; career development; drug distribution; effective therapy; fluorophore; functional disability; improved; in vivo; inhibitor; irradiation; kinase inhibitor; mouse model; nanomedicine; nanoparticle; nanoparticle drug; nanoparticulate; particle; prevent; side effect; skill acquisition; systemic toxicity; targeted treatment; thrombotic; tumor; uptake

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.

项目摘要 该提案的目的是开发针对静脉畸形（VM）的目标疗法。 VM很慢 流动血管病变与毁容，疼痛和功能障碍有关。最近，系统性 抑制雷帕霉素的哺乳动物靶标（MTOR）已证明有效治疗 患有复杂VM的孩子。但是，全身药物输送与限制治疗的副作用有关。 因此，需要最小化全身毒性的安全，有针对性的疗法。 拟议的项目将开发纳米颗粒（NP）目标药物输送系统，以实现高局部 VM中的药物浓度，同时最大程度地减少全身分布。这将通过增强来实现 渗透和保留（EPR），一种癌症生物学中良好认可的现象 与在正常的组织中相比 脉管系统。由于EPR，VMS中的被动NP积累将通过主动靶向增强 技术，例如拍照。 NP的表面将用鼓励细胞的分子涂覆 吸收。这些分子将被“笼基团”灭活，这是一种敏感的分子 到光的特定波长。用光照射后，将从NP中取出笼子分子。 因此，可以全身注射NP，并保持与组织无结合。但是，VM的辐照将 引起“分离”的发生，这将激活NP，并允许在NP结合和药物释放增强 目标站点。 为了检验这一假设，我们提出了三个特定目的：特定目的1：形成和表征 NP在VM中长时间停留时间。特定目的2：针对目标NP药物输送系统的研究 体内。特定目的3：研究NP药物输送系统在体内治疗效率上的研究。与 Cullion博士Daniel Kohane博士的指导和指导已经开发了五年的职业发展 计划提供指导的研究，技术技能发展以及实现她所需的教学培训 （1）成为纳米医学和药物提供的专家的目标，以治疗VM和（2）实现 科学独立性并成为R01资助的物理科学家，从事转化研究的职业 专注于血管异常的纳米医学和药物输送。