Formulation and characterization of new Polymeric/Lipidic Hybrid systems for cidofovir delivery

Cidofovir is an antiviral drug with a remarkable antitumour activity in several animal models, associated or not with viral infections [1]. More recently, cidofovir has also been shown to be an effective treatment against Primary Effusion Lymphoma (PEL), a B cell non–Hodgkin lymphoma involving the serous cavities, invariably associated with Human HerpesVirus-8 (HHV8) and often with Epstein–Barr Virus (EBV) infection. A hindrance to the clinical applications of cidofovir is the high systemic toxicity, mainly the nephrotoxicity. Cidofovir encapsulation into specific micro- or nanocarriers, able to extend the release of the drug, may represent an effective strategy both to minimize the off-target organ exposure as well as to simultaneously increase the concentration of drug within the site of action. Unfortunately, the physical-chemical characteristics of the drug (low molecular weight, high solubility at different pH, unfavourable partition coefficient) limit the encapsulation into delivery systems [2,3]. Recently, we proposed the use of cationic liposomes to stably encapsulate cidofovir; unfortunately, the in vivo applicability of such cidofovir carriers is limited by the presence of cationic lipids, inducing a dose-related toxicity [4]. To overcome this problem, in this work we aimed to investigate a novel hybrid system, consisting in a specific combination of biocompatible materials, capable to build a crossbred between polymeric particles and liposomes. This innovative cidofovir-delivering systems (called PLHs, polymeric/lipidic hybrid systems) made of phosphatidilcholine (PC), cholesterol (CHOL) and polylactic acid (PLA) have been characterized (size, zeta potential, morphology, structure and thermal behaviour) in comparison to multilamellar liposomes and polymeric particles. Microscopical studies (atomic force and confocal microscopy), in agreement with the other characterizations, suggested that a rearrangement of the components has taken place to form a new matricial porous structure different both from liposomes and polymeric particles, with a wide dispersion of polymer in the lipidic bulk. This new crossbeald delivery systems was able to increased the encapsulation of cidofovir (encapsulation efficiency twice higher than liposomes and about 10 times higher than polymeric particles) and resulted atossic against PEL tumor cells (BCBL-1 cell line) revealing also a capability to better traslocate the drug into the cells causing and increased apoptosis respect to the free drug.