Developing Nanoparticle Drug Delivery Systems for Venous Malformations

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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.