? The development of artificial cells that have the adhesive properties of leukocytes and can carry optical imaging agents that can peer deep within tissues would be enormously useful for the non-invasive monitoring and treatment of disease, such as inflammation. Here, we propose to construct a novel artificial cell using polymer vesicles (polymersomes) as the underlying structural element. Polymersomes are vesicles in which self-assemblying block copolymers form the membrane; since the polymers can be designed synthetically to have different molecular weights and architectures, the material properties of the artificial cell can be tuned. The membrane thickness of the polymer vesicles is much larger than that of phospholipid vesicles, owing to the size of the polymers that compose the membrane, which allows space for the storage of large, hydrophobic molecules, such as imaging agents. We endeavor to use polymersomes to make an artificial leukocyte, by functionalizing the surface groups of the polymer membrane with leukocyte-like adhesive ligands, and measuring the performance of these cells in flow chambers to mimic the dynamic environment of the microvascularture. We will tune the material properties of the membrane to make the polymersomes tougher by using large molecular polymers or by crosslinking the polymers, with the goal to match the adhesive properties of leukocytes. In addition, we will employ the synthetic expertise of the Bates laboratory to synthesize a wide range of block copolymers to engineer the biodegradability, material strength and chemical reactivity of the polymersome membrane. Further, we will incorporate novel near-infrared superfluor poly-porphyrin dyes (NIRFs) synthesized in the Therien laboratory, which, depending on their size and chemical functionality, can be excited and emit in the near-infrared. Ultimately, the optical properties of these dyes will allow for deep tissue penetration of optical signals.
The aims of this proposal are: 1) to make leuko-polymersomes, by functionalizing polymersomes with the two key adhesion molecules found on leukocytes, and measure the dynamics of polymersome adhesion under flow; 2) to engineer the material properties of the membrane, through polymer synthesis, to modulate the adhesiveness of the polymersomes; and 3) to incorporate a spectrum of large, hydrophobic near-IR dyes within the membrane of functionalized polymer vesicles, and verify their incorporation does not interfere with the adhesion dynamics of the polymer vesicles in a flow chamber. ? ?
|Qi, Wei; Ghoroghchian, P Peter; Li, Guizhi et al. (2013) Aqueous self-assembly of poly(ethylene oxide)-block-poly(?-caprolactone) (PEO-b-PCL) copolymers: disparate diblock copolymer compositions give rise to nano- and meso-scale bilayered vesicles. Nanoscale 5:10908-15|
|Kamat, Neha P; Katz, Joshua S; Hammer, Daniel A (2011) Engineering Polymersome Protocells. J Phys Chem Lett 2:1612-1623|
|Maul, Timothy M; Dudgeon, Drew D; Beste, Michael T et al. (2010) Optimization of ultrasound contrast agents with computational models to improve selection of ligands and binding strength. Biotechnol Bioeng 107:854-64|
|Robbins, Gregory P; Saunders, Randi L; Haun, Jered B et al. (2010) Tunable leuko-polymersomes that adhere specifically to inflammatory markers. Langmuir 26:14089-96|
|Christian, Natalie A; Benencia, Fabian; Milone, Michael C et al. (2009) In vivo dendritic cell tracking using fluorescence lifetime imaging and near-infrared-emissive polymersomes. Mol Imaging Biol 11:167-77|
|Levine, Dalia Hope; Ghoroghchian, P Peter; Freudenberg, Jaclyn et al. (2008) Polymersomes: a new multi-functional tool for cancer diagnosis and therapy. Methods 46:25-32|
|Hammer, Daniel A; Robbins, Gregory P; Haun, Jered B et al. (2008) Leuko-polymersomes. Faraday Discuss 139:129-41;discussion 213-28, 419-2|
|Christian, Natalie A; Milone, Michael C; Ranka, Shraddha S et al. (2007) Tat-functionalized near-infrared emissive polymersomes for dendritic cell labeling. Bioconjug Chem 18:31-40|
|Ghoroghchian, P Peter; Frail, Paul R; Susumu, Kimihiro et al. (2005) Broad spectral domain fluorescence wavelength modulation of visible and near-infrared emissive polymersomes. J Am Chem Soc 127:15388-90|
|Ghoroghchian, P Peter; Frail, Paul R; Susumu, Kimihiro et al. (2005) Near-infrared-emissive polymersomes: self-assembled soft matter for in vivo optical imaging. Proc Natl Acad Sci U S A 102:2922-7|
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