This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. critically important for therapeutic efficacy. Unfortunately, many methods for drug delivery are often highly inefficient due to non-ideal serum-stability, transport across biological barriers, and release at the target site. To address these problems, we will create bio-responsive, polymeric nano-containers for the selective delivery of therapeutic compounds to pre-determined cellular locations. We will combine the solution selfassembly of block copolymers with selective targeting and cleaving peptide linkages to permit vesicle evolution in response to critical environmental stimuli, eventually leading to site-specific release of the encapsulated payload. In the first specific aim, we will create novel peptide-containing block copolymers and characterize their self-assembly in aqueous solution. These amphiphilic copolymers will be designed to assemble into vesicular structures. Peptides designed to promote endocytotic uptake (1) and endosomal release (2) will be sequentially incorporated into the hydrophilic backbone of the block copolymer in a layered fashion. In the second specific aim, we will evaluate the protease-sensitivity and targeting efficiency of each peptide layer. The protease accessibility of each peptide sequence, as well as vesicle stability, will be assessed as a function of peptide position in the vesicle's corona. The cell-vesicle binding, vesicle internalization, and endosomolytic activity of the vesicles also will be evaluated. In the third specific aim, we will validate the ability of the peptides to direct vesicle transport to and rupture within the cytosol, and we will evaluate the cytotoxicity of both payload-free and cytotoxinincorporating vesicles. Vesicle rupture will be induced by selective placement of peptide (2) proximal to the hydrophobic block of the polymer. Our long-term vision for this project is the development of a nucleic acid delivery system for the selective targeting of tumor stromal fibroblasts and/or inflammatory cells. We envision the complete de novo design of modular vesicular nano-capsules containing a series of location specific """"""""sheddable"""""""" shells to direct payload transport in response to environmental cues at each transport barrier.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR017716-09
Application #
8360584
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2011-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
9
Fiscal Year
2011
Total Cost
$310,500
Indirect Cost
Name
University of Delaware
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Li, Linqing; Stiadle, Jeanna M; Lau, Hang K et al. (2016) Tissue engineering-based therapeutic strategies for vocal fold repair and regeneration. Biomaterials 108:91-110
Li, Linqing; Mahara, Atsushi; Tong, Zhixiang et al. (2016) Recombinant Resilin-Based Bioelastomers for Regenerative Medicine Applications. Adv Healthc Mater 5:266-75
Ou, Shu-Ching; Cui, Di; Wezowicz, Matthew et al. (2015) Free energetics of carbon nanotube association in aqueous inorganic NaI salt solutions: Temperature effects using all-atom molecular dynamics simulations. J Comput Chem 36:1196-212
Ooms, Kristopher J; Vega, Alexander J; Polenova, Tatyana et al. (2015) Double and zero quantum filtered (2)H NMR analysis of D2O in intervertebral disc tissue. J Magn Reson 258:6-11
Lau, Hang Kuen; Kiick, Kristi L (2015) Opportunities for multicomponent hybrid hydrogels in biomedical applications. Biomacromolecules 16:28-42
Li, Linqing; Luo, Tianzhi; Kiick, Kristi L (2015) Temperature-triggered phase separation of a hydrophilic resilin-like polypeptide. Macromol Rapid Commun 36:90-5
Suiter, Christopher L; Quinn, Caitlin M; Lu, Manman et al. (2015) MAS NMR of HIV-1 protein assemblies. J Magn Reson 253:10-22
Hu, Yuan; Sinha, Sudipta Kumar; Patel, Sandeep (2015) Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics. Langmuir 31:6615-31
Cui, Di; Ou, Shu-Ching; Patel, Sandeep (2015) Protein denaturants at aqueous-hydrophobic interfaces: self-consistent correlation between induced interfacial fluctuations and denaturant stability at the interface. J Phys Chem B 119:164-78
Mahadevaiah, Shruthi; Robinson, Karyn G; Kharkar, Prathamesh M et al. (2015) Decreasing matrix modulus of PEG hydrogels induces a vascular phenotype in human cord blood stem cells. Biomaterials 62:24-34

Showing the most recent 10 out of 173 publications