(584ao) Safety and Biodistribution of Carbohydrate-Functionalized Polyanhydride Nanoparticles

An emerging area of research in vaccine development is the design of adjuvant formulations that can be targeted to specific receptors and activate specific cell populations. Biodegradable polymers have shown promising characteristics as adjuvants and/or delivery vehicles by enhancing antigen presentation and processing compared with soluble protein. The properties of these materials can be tailored to enhance their interactions with specific receptors on a variety of cells. In particular, polyanhydride nanoparticles exhibit these desirable characteristics both as adjuvants, including immune response enhancement, modulate inflammation, activation of antigen presenting cells, and induction of high titer and highly avid antibodies; and as delivery vehicles in which they sustain antigen release, and stabilize protein antigens. Pattern recognition receptors such as C-type lectin receptors (CLRs) are key components of innate immunity, and also important for the modulation of adaptive immune responses. In these studies, the effect of carbohydrate functionalization on the safety and biodistribution of polyanhydride nanoparticles was analyzed. 

Upon in vivo administration, nanoparticle distribution depends on size, chemistry, interactions with a variety of cells, and route of administration. In this context, toxicity studies are a necessary first step to assess the safety of the carbohydrate-functionalized particles prior to future efficacy studies. Analysis of the distribution of targeted polyanhydride nanoparticles is necessary to rationally select and design particles targeted to specific cells and/or locations in order to induce-effective immune responses.

In this work, the effect of carbohydrate functionalization on the toxicity and biodistribution of polyanhydride nanoparticles following intranasal administration of mice was investigated. Dye-loaded polyanhydride nanoparticles based on 1,6-bis-(p-carboxyphenoxy)hexane (CPH), and 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) were synthesized using anti-solvent nanoencapsulation. Surface functionalization with di-mannose, galactose, or glycolic acid (as a “linker” control) was performed using an amine-carboxylic acid coupling reaction. These studies have important implications for the in vivo performance of carbohydrate-functionalized nanoparticle-based systems for vaccine delivery.