Remote control of light-triggered virotherapy

Clinical virotherapy has been successfully approved for use in cancer treatment by the US Food and Drug Administration (FDA), however a number of improvements are still sought to more broadly develop virotherapy. A particular... [ view full abstract ]

Clinical virotherapy has been successfully approved for use in cancer treatment by the US Food and Drug Administration (FDA), however a number of improvements are still sought to more broadly develop virotherapy. A particular challenge is to administer viral therapy systemically and overcome limitations in intra-tumoral injection, especially for complex tumor within sensitive organs. To achieve this however, a technique is required that delivers the virus to tumor before the body’s natural self defense eradicates the virus prematurely. Here we show that recombinant adeno-associated virus serotype 2 (AAV2) chemically conjugated with iron oxide nanoparticles (~5 nm) have remarkable ability to be remotely guided under magnetic field (Figure 1). Transduction is achieved with micro-scale precision. Furthermore, a gene for production of the photosensitive protein KillerRed was introduced into the AAV2 genome to enable photo-dynamic therapy (PDT); or light-triggered virotherapy. In vivo experiments revealed that magnetic guidance of “ironized” AAV2-KillerRed injected by tail vein in conjunction with PDT significantly decreases the tumor growth via apoptosis (Figure 2). We have demonstrated specificity in anti-tumor effects with light-triggered virotherapy achieved with remotely guided “Ironized” virus delivery. Such a technological concept could be harnessed to improve therapeutic efficacy and accuracy with systemic delivery via the bloodstream. There are several distinguishing features of our Ironized AAV2, such as targeted delivery, light-triggered activation of virotherapy, lack of recombination and genomic integration, and strong pre-clinical safety record, that define potential advantages of this concept. Furthermore, magnetic resonance imaging (MRI) instruments can be applied to create pulsed magnetic field gradients in desired direction, and it may provide the prospect of shaping the accumulation within an internal 3D volume.This proof-of-principle demonstrates guided and highly localized micro-scale, light-triggered virotherapy.