Targeted liposomal drug delivery for the treatment of pain and opioid addiction

Opioids are the most efficacious analgesics for the treatment of pain. However, repeated and prolonged use of opioids leads to tolerance and addition, which drastically limits their efficacies and applications. Mu opioid receptors (MORs) and a number of intracellular targets (eg, CaMKII) have been identified to be involved in opioid tolerance and addiction. Developing therapeutic agents targeting these novel sites will require targeted drug delivery systems.;In this study, we successfully prepared a dermorphin-conjugated sterically stabilized liposome (dermorphin-SSL) system for peptides and siRNAs delivery to achieve cell-specific targeting of intracellular CaMKII for the treatment of pain and opioid addiction. Dermorphin-SSL was prepared by thin-film rehydration and post-insertion method, which showed high affinity and selectivity for MOR based on the receptor binding results. Cell uptake studies demonstrated that dermorphin-SSL was able to target MOR-expressing cells both in vitro and in vivo, and the uptake was mediated by MOR. AIPII peptide incorporated in dermorphin-SSL was able to attenuate morphine tolerance and dependence in mice by inhibiting CaMKII activity, while free AIPII showed no effects. Moreover, CaMKIIalpha siRNA encapsulated in dermorphin-SSL was found to attenuate morphine tolerance and dependence in mice by specifically knocking down CaMKIIalpha expression without inducing non-specific interferon response, while negative control siRNA did not have any effects.;In summary, we successfully prepared an MOR-targeted dermorphin-SSL system which can be applied to the delivery of peptides and siRNAs to MOR-expressing cells for the treatment opioid tolerance and dependence. Dermorphin-SSL may be a promising drug carrier to deliver large molecules (peptides and siRNAs) for potential pain and addiction therapies.