Lipid nanocapsule-loaded polymer-free hydrogels: a new generation of implants to control drug sustained releases.
Marion Pitorre, Karolina Frankova, Jérôme Béjaud, Le Thuy Trang Pham, Jean- Pierre Benoit and Guillaume Bastiat
Micro et Nanomédecines Translationnelles (MINT, INSERM U1066 / CNRS 6021), Université d’Angers, France
Contact: [email protected]
New drug delivery systems are designed as nanoparticle-loaded hydrogels. These attractive pharmaceutical systems combine the gel advantages: local administration and/or a drug sustained release, and nanoparticle properties: stealthiness, targeting and decreased toxicity. Nevertheless, even using biodegradable polymer to design the gel matrix, implants can always be found at the injection site long time after administration. This research focuses on the development of lipid nanocapsule (LNCs)-based hydrogels without the use of polymer, and the drug release profiles from the hydrogel (using fluorescent probes as drug models) and their modulation correlated to hydrogel characteristics.
Lauroyl-modified gemcitabine (Gem-C12) or palmitoyl-modified cytidine (Cyt-C16), added during the LNC formulation process (phase-inversion formulation process), allows spontaneous gelling of LNC formulations. These two molecules exhibit amphiphilic properties. Positioned at oil/water interface, they act as crosslinking agents between LNCs. LNCs are associated in a three-dimensional network due to H-bond interaction between Gem or Cyt moieties at LNC surfaces leading to formation of polymer-free hydrogels. The viscoelastic properties of the hydrogels depend on the LNC concentration, Gem-C12 or Cyt-C16 loading, but are not affected by LNC size distribution.
In the hydrogel, Nile Red (lipophilic drug model) is encapsulated in LNCs and fluorescein (hydrophilic one) is loaded in medium around the LNC network. Both releases of LNCs and drugs in aqueous buffer are controlled by the mechanical properties of the hydrogels. Slower release profiles for the LNCs, so for the lipophilic drug model, are correlated with higher mechanical properties, while similar release profiles are obtained for the lipophilic drug model, independent from the hydrogel mechanical properties. Whatever the hydrogel characteristics, total LNC release is achieved and hydrogels are totally solubilized leading to LNC suspensions.
New generation of nanoparticle-loaded hydrogels: LNC-based, polymer-free hydrogels is promising as implants for health application. Once the LNC release is completed, no gel matrix remains at the injection site, minimizing the additional toxicity due to the persistence of polymeric implant. Drug sustained release profiles can be controlled by the mechanical properties of the hydrogels and will be tailor- made, depending on the therapeutic strategies.
