Nanoscale drug delivery devices are a promising technology for improving drug efficacy and reducing side effects. Vesicles, which have an aqueous core bounded by a membrane, are especially useful drug delivery constructs because they can encapsulate a large aqueous-soluble payload in the vesicle core and hydrophobic payload in the membrane. The drug delivery vesicles currently in clinical use are constructed from phospholipids and synthetic polymers. However, lipids and synthetic polymers are difficult to functionalize to enable targeting and triggered release at sites of disease. The purpose of the proposed research is to engineer drug-delivery vesicles from recombinant proteins, as protein sequence can be exquisitely controlled and functional domains readily incorporated using standard molecular biology techniques. This proposal consists of three aims. The purpose of Aim 1 is to construct recombinant, unstructured, amphiphilic proteins that have distinct hydrophobic and hydrophilic domains. This will be accomplished by attaching a naturally occurring hydrophobic protein domain to an intrinsically disordered, hydrophilic protein segment.
Aim 2 will test the hypothesis that this novel class of amphiphilic proteins can assemble into vesicles useful for drug delivery. Assembly will be driven by the hydrophobic effect, wherein the hydrophobic segments associate to shield themselves from water while the hydrophilic moieties face the aqueous environment.
In Aim 3, the protein vesicles will be tailored for a specific biomedical application - triggered release of drugs at sites of inflammation. Inflammation is an important target because excessive inflammatory response is associated with numerous diseases, including cancer, atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease.
This aim will test the hypothesis that functionalizing the vesicles with a peptide that targets E-selectin, a cell adhesion molecule expressed on endothelial cells during inflammation, will cause the vesicles to adhere to activated endothelial cells in shear flow. Furthermore, specific protease cleavage sites will be incorporated into the vesicles so that proteases present at sites of inflammation will trigger vesicle rupture and drug release. Completion of the proposed work will lay the foundation for a broad new class of nanomaterials with potential for enhanced capability, tunability, and efficacy compared to existing drug delivery technologies.

Public Health Relevance

Nano-sized drug delivery devices are a promising technology for improving drug efficacy and reducing side effects. The purpose of this project is to construct drug delivery vesicles from proteins, which can be easily engineered to target sites of disease. The vesicles developed here will target inflammation, which is associated with numerous diseases, including cancer, atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
3F32GM119430-02S1
Application #
9659518
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Barski, Oleg
Project Start
2016-05-01
Project End
2018-10-31
Budget Start
2017-05-01
Budget End
2018-10-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Glantz, Spencer T; Berlew, Erin E; Jaber, Zaynab et al. (2018) Directly light-regulated binding of RGS-LOV photoreceptors to anionic membrane phospholipids. Proc Natl Acad Sci U S A 115:E7720-E7727