Novel carriers for efficient drug delivery
Recent discovery of gene silencing by RNA interference (siRNA) led to the development of a new class of oligonucleotide-based therapeutics. These genetic elements specifically inactivate genes and are being investigated for treatment of cancer, diabetes, viral infections and inflammation. This novel drug development has been hampered by the issue of systemic delivery. siRNA oligonucleotides suffer from a poor pharmacological profile in vivo. Attempts to use conventional liposomes for delivery has resulted in non-specific immune stimulation, toxicity issues and limited distribution. EU-financed ‘Targeted amphoteric carriers in immunotherapy’ (TACIT) project was formed by two academic and two commercial partners to address the urgent need for an effective delivery system. The aim was to develop novel clinically relevant carriers for delivery to the immune system and test them in inflammatory diseases models. The TACIT researchers designed and synthesised new lipids with rational variations of the head group and lipid anchor chemistry. Amphoteric liposome carriers for systemic delivery of oligonucleotides were developed using the new lipids and a methodology that predicts the stability and efficacy of liposomes. The liposomes were tested for siRNA delivery in vitro, and effective formulations were identified. New liposomal carriers were further tested in vivo for their tropism (attraction) to specific immune cell populations, such as macrophages and dendritic cells and potency for target knock-down and safety. For topical administration of siRNA straight to the lung, the scientists developed several formulations. In addition, TACIT evaluated novel peptide carriers for the in vivo delivery of siRNA molecules. These vehicles efficiently delivered cargo siRNA to macrophages in cell culture and in vivo in the model of allergic asthma in mice. Researchers used their expertise to target a central signaling pathway in macrophage activation (Akt kinase) in culture and in vivo in a model of aspiration-induced lung injury in mice. Overall, new lipid-based and non-lipid carriers were developed and can be effective for systemic or topical delivery of siRNA to immune cells and inflamed tissues. TACIT is likely to have a broad impact on the development of personalised therapeutics.
Keywords
siRNA, lipids, liposomes, drug delivery, amphoteric liposomes, inflammation, macrophages
