Development of Degradable Diblock Copolymer, Polyphosphoester-Block-Poly(L-Lactide), and Its Conversion into Well-Defined Shell Crosslinked Nanoparticles as Delivery Carriers for Antimicrobial Agents

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Abstracts of Papers of the American Chemical Society, Vol: 247, Issue: 186

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Lim, Young H.; Heo, Gyu Seong; Kristin, Tiemann; Shah, Perth N.; Smolen, Justin A.; Cannon, Carolyn L.; Hunstad, David A.; Youngs, Wiley J.; Wooley, Karen L.
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The combination of state-of-the-art polymerization chemistries, post-polymerization chemical modifications, supramolecular assembly processes and further transformations is allowing for the design of highly well-defined polymer nanoparticles that are demonstrating unique performance toward the effective treatment of infectious diseases. A potentially fully degradable, biocompatible diblock copolymer, polyphosphoester-block-poly(L-lactide) (PPE-b-PLLA), was prepared by one-pot sequential ring-opening polymerizations (ROPs) of two cyclic monomers: alkyne-functionalized phospholane and L-lactide. Photo-induced thiol-yne “click”-type reactions with small molecule thiols bearing carboxylic acid then afforded amphiphilic diblock copolymers with carboxylate side-chain functionalities along the PPE segment of the diblock copolymer backbone. Subsequently, well-defined (1) spherical micelles with negative surface charges were prepared by direct dissolution of the anionic diblock copolymers (aPPE-b-PLLA) in aqueous solution, and (2) shell crosslinked knedel-like (SCK) nanoparticles were prepared by crosslinking of hydrophilic shell of the micelles, as confirmed by transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential. The Ag-loading capacities of the anionic micelles and SCKs from aPPE-b-PLLA were determined with three different types of Ag-containing molecules, silver acetate (AgOAc) and silver carbene complexes (SCC22 and SCC10). Similarly, Ag-release kinetics of the Ag-loaded nanoparticles, using dialysis cassettes in nanopure water, was studied. We are currently working on the study of (1) degradation capability of micelles and SCKs of PPE-b-PLLA system under hydrolytic or enzymatic degradation, (2) conjugation with target-specific proteins such as FimHA to evaluate their ability to perform as target delivery carriers, and (3) determination of their in vitro and in vivo efficacies against bacteria.