Development of Endothelial Optical Exosomes for the Treatment of Port Wine Stains
Abstract
Vascular malformations are congenital vascular anomalies, present at birth, grow proportionally with age, and do not regress naturally. They usually result from developmental impairments of vasculatures including veins, arteries, capillaries, and lymphatic vessels. Vascular malformations cause a variety of severe symptoms, depending on body location and types of vasculatures involved, which makes clinical management very challenging. Research to develop novel treatments to manage vascular malformations is among the encouraged topics by the Fiscal Year 2017 Peer Reviewed Medical Research Program Discovery Award. Port Wine Stains (PWS) is one of the most common types of vascular malformations. PWS mainly occurs on the face with initial appearance as flat red macules in childhood, lesions tend to darken progressively to purple, and by middle age they often become raised as a result of the development of vascular nodules that are susceptible to spontaneous bleeding or hemorrhage. The pulsed dye laser (PDL) remains the treatment of choice for PWS; unfortunately, complete removal occurs in less than 10% patients treated. These inadequate clinical outcomes mainly result from: (1) incomplete ablation of PWS blood vessels located in the deep dermis where light from the PDL cannot reach effectively and (2) the regrowth of blood vessels from post-PDL resistant PWS hDMVECs (p-hDMVECs). In order to tackle these challenging clinical barriers, this proposal aims to develop a novel type of endothelial exosome-derived optical nanoparticles, which are referred to as functionalized endothelial optical exosomes (FEOE), to achieve better therapeutic outcomes for PWS treatment. In this proposal, we will use normal hDMVEC (n-hDMVEC)-derived exosomes as the basic nano-size constructs, followed by incorporating a chimera surface molecule in exosomes that is designed to specifically target the EphB1 receptor expressed on p-hDMVECs. These genetically modified exosomes will then be loaded with the chromophore ICG as the therapeutic agent. Subsequently, the following research objectives will be pursued: (1) whether the novel FEOE will render a specific binding to the EphB1 receptor on hDMVECs; (2) the optimal concentrations for FEOE that have maximal binding capability and specificity for the target cells; and (3) the threshold radiant energy density by using the 755 nm laser to induce photothermal destruction of FEOE targeted cells. This proposed study is highly innovative because it lays the groundwork for a novel approach to the successful treatment of PWS patients. The formulation of FEOE is novel in nanomedicine, vesicle biology, and light therapy since no such design has been ever reported. The engineered FEOE are very significant because they are designed to directly address the clinical limitations of current PWS treatment of PWS: (1) the NIR wavelength can penetrate deeper into human skin than PDL, thus targeting those blood vessels in the reticular layer of the dermis; (2) exosomes as the drug delivery vehicle can efficiently transport the therapeutic agents into the targets; and (3) the chimera molecule on FEOE will guide specific targeting of p-hDMVECs. The FEOE is also of significance as a method of creating new nanoparticles for broad new research applications for other types of vascular malformations with serious complications and limited treatment options, such as cerebral arteriovenous malformations, etc.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810096
Entities
People
- Wenbin Tan
Organizations
- Naval Information Warfare Center Pacific
- United States Army