Cellular Internalization Mechanisms of Polyanhydride Particles: Implications for Rational Design of Drug Delivery Vehicles

Polyanhydride nanoparticles have emerged as a versatile delivery platform, due to their ability to encapsulate diverse drugs, immunogens, antibodies, and proteins. However, mechanistic studies on the effects of particle chemistry interactions with immune cells have yet to be described. Understanding the mechanism by which these particles are internalized by immune cells will enable rational selection of delivery vehicles for specific applications. In the present study, the internalization, mechanism(s) of uptake by monocytes, and intracellular fate of polyanhydride nanoparticles were evaluated using copolymers based on 1,6- bis(p-carboxyphenoxy) hexane (CPH), sebacic acid (SA), and 1,8-bis(p-carboxyphenoxy)3,6- dioxaoctane (CPTEG). The results showed that 20: 80 CPH: SA and 20: 80 CPTEG: CPH nanoparticles were internalized to a greater extent by monocytes as compared to the 50: 50 CPH: SA and 50: 50 CPTEH: CPH nanoparticles. Further, cytochalasin-D treatment of cells inhibited uptake of all the particles, regardless of chemistry, indicating that actin-mediated uptake is the primary mechanism of cellular entry for these particles. The insights gained from these studies were used to identify lead nanoparticle formulations to enhance treatment of intracellular bacterial infections. The use of doxycycline-loaded nanoparticles exhibited enhanced therapeutic efficacy compared to soluble drug in treating monocyte monolayers infected with the virulent intracellular pathogen Brucella abortus. Altogether, these studies demonstrate how rational design and selection of nanoscale delivery platforms can be used for a wide spectrum of biomedical applications.