Targeting approaches to visualize the viral latent membrane protein (LMP1) on tumour surface for cancer therapy

Epstein-Barr virus (EBV), a member of the gammaherpsevirus, is etiologically implicated in several lymphoid and epithelial malignancies, substantially contributing to the development of a diversity of lymphomas and, especially, carcinomas. Although current treatments for EBV-associated carcinoma, such as radiotherapy and chemotherapy have long been adopted, the former is inadequate either to kill advanced, metastatic tumours or to prevent their recurrence, while the latter is still under development. The latent membrane protein (LMP1) is an oncoprotein known to be responsible for regulating EBV and human gene expression and even maintenance of EBV episome. Such presence of EBV and LMP1 in the tumor cells of EBV-associated cancers can therefore, provide an overarching basis for specific therapy. Compared with other EBV-associated cancer regulators inside nucleus, the membrane subcellular localization is easier and more effectively accomplished by targeting anti- cancer/imaging agents than in nucleus. Therefore, a lower-dosed concentration and more selective anti-EBV related cancer therapy through LMP1 can be expected.

More recently, there have been several studies on the LMP1 inhibition using peptides or small molecules. However, the function of these inhibitors cannot be monitored in real- time. As justified by our recent publications on responsive luminescent lanthanide materials towards various biological tasks in solution/in vitro/in vivo, our research team has thorough expertise in lanthanide coordination chemistry, spectroscopy, peptide chemistry, and in vitro biological applications. Therefore, we aim to develop luminescent LMP1-specific lanthanide bio-probes with high selectivity towards LMP1 and capability of selectively inhibiting LMP1 on the membrane surface and in-vitro real-time monitoring as anti- EBV-related carcinoma agents.

To further support our work, we have performed a range of proof-of-concept experiments to consolidate our proposal: (1) several LMP1-specific ytterbium complexes with tailor-made synthetic peptides have been prepared which can be excited in the visible, and near-infrared region, for LMP1 imaging; (2) molecular dynamic simulation shows our proposed complexes can fit in the LMP1; and (3) they are all water-soluble, and membrane specific for LMP1 in vitro imaging and inhibition of EBV specific cancer cells.

This proposal paves the way for the development of new-generation lanthanide complexes conjugated with LMP1-specific peptides as dual probes with imaging and anti-tumour properties. Making a success of this research can bring to society a more powerful tool (especially with a combination of multi-photon and time-resolved technology) to unveil the mystery and understand the very roles of LMP1 in EBV- associated carcinoma, ultimately furthering cancer therapy and research.