Polymer-free hydrogel made of lipid nanocapsules, as a local drug delivery platform

Abstract

Nanoparticle-loaded hydrogels are attractive pharmaceutical drug delivery systems that combine the advantages of both hydrogel (local administration and/or sustained drug release) and nanoparticle (stealthiness, targeting and decreased toxicity). The design of nanoparticle-loaded hydrogels is largely conventional, consisting of the dispersion of nanoparticles in a natural or synthetic polymer matrix to form a gel network. Novel nanoparticle-loaded hydrogels architecture could provide advantages in terms of innovation and application. We focused on the development of lipid nanocapsule (LNC)-based hydrogels without the use of a polymer matrix as a platform for drug delivery. Cytidine was modified by grafting palmitoyl chains (CytC16) and the new entity was added during the LNC phase-inversion formulation process allowing spontaneous gelation. Positioned at the oil/water interface, CytC16 acts as a crosslinking agent between LNCs. Association of the LNCs in a three-dimensional network led to the formation of polymer-free hydrogels. The viscoelastic properties of the LNC-based hydrogels depended on the LNC concentration and CytC16 loading but were not affected by the LNC size distribution. The LNC and drug-release profiles were controlled by the mechanical properties of the LNC-based hydrogels (slower release profiles correlated with higher viscoelasticity). Finally, the subcutaneous administration of LNC-based hydrogels led to classic inflammatory reactions of the foreign body-reaction type due to the endogenous character of CytC16, shown by cellular viability assays. New-generation nanoparticle-loaded hydrogels (LNC-based polymer-free hydrogels) show promise as implants for pharmaceutical applications. Once LNC release is completed, no gel matrix remains at the injection site, minimizing the additional toxicity due to the persistence of polymeric implants. Sustained drug-release profiles can be controlled by the mechanical properties of the hydrogels and could be tailor-made, depending on the therapeutic strategy chosen.

Keywords: Hydrogel; Lipid nanocapsule; Modified cytidine; Nanomedicine; Subcutaneous injection; Sustained release.