(L5295) Traceless Delivery of 4-Hydroxytamoxifen for Controllable Gene Expression in Astrocytes

Nipuni Gunawardhana (Stony Brook University)| Scott Laughlin (Stony Brook University)

Astrocytes are the most abundant type of non-neuronal cells in the brain. In addition to maintaining blood-brain barrier integrity and providing nutrients to the surrounding cells, they play an active role in brain function by the uptake and release of neurotransmitters through the tripartite synapse. Astrocytes play a crucial role in the maintenance of the health and function of the central nervous system and thus astrocytic dysfunction has been implicated in many neurological diseases like Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), glioblastoma and depression. Hence, the delivery of small molecule drugs specifically to astrocytes in coordination with gene therapy is a potential therapeutic tool to activate the expression of therapeutic genes to re-establish healthy astrocytic functions. Recently, a targeting moiety was developed in our group that transports small molecule cargo to astrocytes. Here we adapt the astrocyte targeting moiety to deliver the drug tamoxifen, which is widely used for controlling gene expression in rodents. Since tamoxifen does not have a potential site of modification to attach the tag while retaining the activity of the molecule, we explored a traceless delivery strategy. The active metabolite 4-hydroxytamoxifen will be caged with a linker attached to the targeting moiety, where the release of the active drug will occur in the presence of light when delivered to astrocytes. The traceless targeted delivery strategy will help us to evaluate the ability of the targeting moiety to deliver drugs to astrocytes and to explore the release of different drug candidates in the native form inside astrocytes. Additionally, it will open the door to study the controlled gene expression of specific genes in astrocytes using the tamoxifen inducible Cre-ER/loxP system. In the future, the molecules we describe have potential use in gene therapy applications for exploring therapeutic aspects of astrocytes in various neurological diseases.