Chemical Functionalization of PEG-b-PPS Nanocarriers for Applications in Targeted and Sustained DeliveryPublic
Nanomaterials are broadly defined as materials that exhibit at least one dimension that is less than 1,000 nm. Encompassed within nanomaterials are a class of constructs known as nanocarriers, which are applied as delivery vehicles for both encapsulated and covalently bound payloads. Poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) is an amphiphilic block copolymer (BCP) that has been utilized for the self-assembly of a variety of nanocarriers. Since it was first described in 2001, studies concerning the chemical functionalization of PEG-b-PPS BCPs for the alteration of nanocarrier surface characteristics have been limited. The objective of this work was to 1) expand the pool of functionalized PEG-b-PPS BCPs for the preparation of nanocarriers with diverse surface characteristics and 2) to explore the potential benefits afforded by these surface functionalities in both passive targeting and sustained nanocarrier delivery. This study explores the synthesis of a variety of functionalized-derivatives of PEG-b-PPS and utilizes several of these BCPs for the preparation of nanocarriers. The role of PEG-b-PPS nanocarrier surface chemistry is explored in the context of protein adsorption and cell interactions. Finally, a proof-of-concept study depicting how nanocarrier surface chemistry can be exploited for sustained delivery is described. An array of techniques was utilized in these investigations. Morphological and size characterization of the nanocarriers was performed prior to in vitro assessments of nanocarrier immunogenicity and cytotoxicity. Nanocarrier-cell associations in vitro were quantified via flow cytometry and explored through differences observed in the amount and composition of protein adsorbed to the nanocarrier surface. Finally, constructs for sustained nanocarrier delivery were prepared and investigated in vivo. Nanocarrier release was observed through intravital fluorescence imaging and cellular uptake was assessed through flow cytometric analysis. I have developed and executed several previously unexplored synthetic pathways for the preparation of functionalized PEG-b-PPS. I have found that surface modification of PEG-b-PPS nanocarriers can impact their immunogenicity and cellular interactions, the latter highlighting the potential of using surface chemistry to tailor nanocarrier uptake. Furthermore, surface chemistry was shown to alter both the quantity and composition of adsorbed proteins. Lastly, I demonstrated that functionalized PEG-b-PPS nanocarriers could be the basis of a sustained nanocarrier delivery system. Therefore, I conclude that the surface functionality of PEG-b-PPS nanocarriers is a useful design characteristic for nanocarrier performance. Selection and successful incorporation of an appropriate chemistry can permit further construct optimization and investigation into previously unattainable applications.
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