(203d) Polyelectrolyte Multilayer Films As Templates for Surface Modification to Design Liposomes Mediated Local and Sustained Therapeutic Delivery

The engineering of drug delivery platforms facilitating spatial and temporal release of a therapeutic is one of the key challenges in biomedical research that can ultimately lead to society-wide improvement in disease management. In recent years, substrate mediated delivery of cargo has shown great promise in applications including drug and gene eluding films/scaffolds, coatings for stents and other implantable devices, and controlling stem cell differentiation. Specifically, the drug delivery kinetics is particularly relevant when it is necessary to achieve effective dose and spatiotemporal release kinetics of the therapeutic agent at the intended site of injury. Delivery via immobilization of the therapeutic cargo by modifying the surfaces demonstrates higher translatable success compared to delivery using the free â??bolusâ? form by overcoming unfavorable burst kinetics, toxic offsite effects, and efficacy reduction due to systemic dilution. However, the lack in the development of a substrate mediated delivery platform that can exploit the advantages of nanocarriers to address bolus based therapeutic limitations has greatly hindered application. Here, we report the engineering of novel nanostructured substrate mediated therapeutic delivery system comprising of covalently functionalized liposomes (LNPs) with a surface decoration of hyaluronic Acid (HALNPs) embedded into an engineered Polyelectrolyte Multilayer (PEM) platform (HALNP-PEM) via ionic stabilization (Nature Scientific Reports, 2016). PEM provides an ideal surface modification tool that enables tuning the substrates to facilitate the immobilization of biomolecules including liposomes. The PEM base platform was constructed from poly-L-Lysine (PLL) and poly(sodium styrene sulfonate) (SPS) followed by adsorption of anionic HALNPs. An adsorption affinity assay and saturation curve defined the preferential HALNP deposition density for precise therapeutic dosing. A capping layer on top of the deposited HALNP monolayer was found to promote complete nanoparticle immobilization, support cell adhesion, and provide multi-dimensional nanoparticle confinement for predictable linear release profiles of both the nanocarrier and encapsulated cargo. Doxorubicin (DOX) was chosen as a model hydrophilic cargo and used to verify the structural integrity of the particles following deposition as well as to probe the therapeutic index of the HALNP-PEM platform. Furthermore, a direct comparison between bolus HALNP and the HALNP-PEM exemplified the effect of liposome confinement on intracellular uptake kinetics in patient derived metastatic breast cancer cells and confirmed sustained therapeutic release from the PEM platform. Lastly, we employed micropatterning to pattern both fluorescently conjugated HALNPs and DOX encapsulated in HALNPs into our PEM platform and found cell mediated uptake of HALNPs leading to micro-scale spatial control and sustained therapeutic release for over 60 hrs.