Engineering nanomaterials for cancer theranostics

Abstract

This thesis aims to engineer novel nanomaterial to target receptors on the surface of cancer to diagnose and deliver cytotoxic drugs or siRNA selectively. Receptor-targeting peptides have been relatively unexplored to deliver nanomaterial to cancer. The paucity is due to the challenge associated with the synthesis in assembling the components on a nanomaterial. We developed a universal methodology to overcome the synthetic difficulty and generated a library of peptide-targeted nanomaterial. These materials are targeted towards the following receptors: PD-L1, GRPR, and cMET, which are overexpressed in cancers. In addition, we investigated the diagnostics efficacy of nanomaterials targeted towards PD-L1, and the results showed the unique advantage of these classes of particles to quantify the receptors. Finally, we evaluated the in vitro and in vivo (in GRPR) efficacy of the targeted nanomaterials attached with the Doxorubicin drug in ovarian and hepatocellular cancers. The in vitro results established the superiority of the targeted material over the conventional chemotherapeutics. However, the in vivo evaluation of GRPR targeted nanomaterials showed only moderate efficacy compared with the chemo drug. Importantly, all the animals administered with targeted nanomaterial were healthy and alive at the end of the study; in contrast, all mice administered with doxorubicin succumbed to death. During this study, we gathered that targeted delivery of chemotherapeutics alone might be insufficient to overcome drug resistance and genetic inhibition is imperative. Therefore, we developed another nanomaterial to deliver two siRNAs to co-inhibit drug-resistant proteins and performed preliminary cancer cells. Further studies are warranted to establish this as a therapeutic modality. The experience allowed us to embark on an audacious project wherein we used non-cancer drugs to treat the tumor. Based on the solid scientific rationale, we combined COPD drug and tyrosine kinase inhibitor to treat lung cancer, and the results show benefit. The significance of this study is that the engineered nanomaterial possesses the potential to deliver the drug to cancer, reduce toxicity, and overcome drug resistance; further studies using clinically relevant patient-derived xenograft mouse models help translate the materials to clinics for patient benefits.