OX26-cojugated gangliosilated liposomes to improve the post-ischemic therapeutic effect of CDP-choline

Abstract

Abstract Cerebrovascular impairment still represents one of the main causes of death worldwide with a mortality rate of 5.5 million per year. Furthermore, the disability of 50% of surviving patients represents a factor with both a high social impact and high costs for long periods of time for national healthcare systems. For these reasons, the efficacious clinical treatment of patients suffering of a brain ischemic stroke is still a medical need. To this aim, a liposome nanomedicine having monosialic ganglioside type 1 (GM1) between its constituent and bearing OX26 (an anti-transferrin receptor antibody) was prepared by entrapping CDP-choline (a neurotrophic drug) (CDP-choline/OX26Lip), characterized and tested in vivo on an ischemic rat model. CDP-choline/OX26Lip were prepared by a freeze and thaw followed by extrusion through polycarbonate filters, thus achieving ~80 nm mean size and a homogeneous size distribution. It was demonstrated that CDP-choline/OX26Lip showed a suitable stability in the presence of human serum. CDP-choline/OX26Lip showed also a suitable pharmacokinetic profile, having 30.0±4.2 % of the administered dose in the blood stream 12 h after its systemic administration. The post-ischemic therapeutic effect of CDP-choline/OX26Lip is better than CDP-choline/Lip, thus showing a significant greater survival rate of re-perfused post-ischemic rats, i.e. 96% and 78% after 8 days, respectively. The treatment with CDP-choline/OX26Lip significantly decreased the peroxidation rate of almost 5-fold compared to CDP-choline/Lip, as expressed in amount of conjugated dienes,i.e. 13.9 ± 1.1 and 3.1 ± 0.8 mmol/mg proteins, respectively. The increased therapeutic effect could be attributed to the improved accumulation of the encapsulated CDP-choline delivered by the OX26-conjugated GM1-liposomes. Therefore, this nanomedicine may represent a suitable strategy for the reassessment of CDP-choline as a line option in the therapeutic treatment of post-ischemic events caused by brain stroke, thus responding to significant clinical needs.