Latrunculin A Nanoparticle Therapeutics: Development and Applications


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Nanoparticles are nanometer scale (1-1000 nm) structures capable of encapsulating a diverse range of cargoes. Encapsulation of a cargo can drastically alter its pharmacokinetics, cytotoxicity, and biodistribution while allowing for informed and rational design of the nanoparticle itself. Poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) is an amphiphilic diblock co-polymer able to self-assemble into a diverse array of morphologies with different properties. The purpose of this work is to show the rational design of a Latrunculin A loaded PEG-b-PPS micelle as well as two different applications for the platform. Latrunculin A (Lat A), an actin depolymerizing agent, has been used as a cell softening agent for the treatment of glaucoma and as a tool to alter the endocytosis of macrophages and dendritic cells. However, Lat A is hydrophobic and cytotoxic at high concentrations, two problems which can be abrogated through encapsulation in nanoparticles. This work covers the screening, selection, and characterization of Lat A as a desirable small molecule inhibitor of endocytosis as well as two applications; use of a targeted Lat A micelle for the treatment of glaucoma, and the development of a novel macropinocytosis inhibitory nanoparticle designed to suppress non-specific clearance of second ‘effector’ nanoparticle. We demonstrated that latrunculin A is able to be stably and consistently loaded into PEG-b-PPS micelles without any changes to micelle morphology or LatA functionality. Furthermore, we have found that LatA-MC are able to alter the cell stiffness of Schlemm’s canal endothelial cells and reduce intraocular pressure when administered in mice. We have also developed a Flt4/VEGFR3 targeted LatA-MC which is able to further reduce intraocular pressure in vivo. This targeted LatA-MC represents a proof of concept for a nanoparticle treatment of glaucoma. We have also developed a novel macropinocytosis inhibitory nanoparticle (MiNP) using LatA-MC. We have found that MiNP are able to alter the biodistribution of a secondary effector-MC when both are injected either intravenously (IV) or subcutaneously (SC). This effect is reversible and allows for SC injections to achieve serum levels comparable to IV injections. Furthermore, when used in a B16F10 cancer model, MiNP were able significantly increase the amount of tumor treatment nanoparticles present in the tumor. We conclude therefore, that PEG-b-PPS micelles are an effective drug delivery platform for LatA. I have demonstrated proof of concept for targeted LatA-MC as a novel therapeutic platform for glaucoma as well as shown the biodistribution altering properties of LatA containing MiNP.

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