Exploiting nano-in-micro-technologies to couple PLGA-hydroxyl-FK866 nanoparticles to a hydrogel network for local drug release†

Abstract

Technological advancements in the formulation and delivery strategies of potent chemotherapeutic agents have been exploited to direct a site-specific drug delivery for the local treatment of tumours. Of these, new generations of nanoparticles are engineered to control the release of therapeutic agents, but they still possess off-target and overall systemic delivery. Injectable hydrogels have unique physico-chemical properties enabling their use as carriers to ensure site-specific targeting. Based on such observations, nanoparticle-loaded hydrogels represent an optimal candidate to both make use of controlled release chemotherapeutic agents (nanoparticles) and local delivery agents (hydrogels) using minimally invasive procedures to reach the target site. Here, we explore the interaction of drug-polymer conjugated nanoparticles with an alginate-based hydrogel network to confine and release a highly cytotoxic compound (hydroxyl-FK866). Specifically, chitosan coating was used to covalently link poly(lactic-co-glycolic acid) nanoparticles to oxidised alginate: confinement and interaction of nanoparticles within alginate-based hydrogels were evaluated using atomic force microscopy measurements, confirming the nanoparticle/hydrogel interaction. Deployment of composite injectable hydrogels in 3D printing was finally investigated. Rheological characterisation and printability tests were performed to assess the printability of alginate-based drug delivery systems to match site-specific geometrical requirements. Then, alginate hydrogels loaded with nanoparticles were ionically crosslinked to match the properties of soft tissues (e.g. breast tissue). The efficacy of 3D printed hydrogels loaded with a known dose of hydroxyl-FK866 was tested using human breast cancer MDA-MB-231 cells. Results confirmed the expected cytotoxicity, showing approx. 52% toxicity of the hydrogel loaded, after 48 hours of incubation, whereas lower viability (approx. 36%) was measured in cells treated with free nanoparticles (control).