Cancer represents the leading cause of death in European countries (EU-27). Given the heterogeneity and multifaceted complexity of cancer, it stands to reason that requires both multimodal therapies along with the development of anticancer agents with enhanced efficacy and safety profiles. Combination therapy, consisting of the administration of two or more drugs, is the bedrock of
many cancer treatment regimens. On the other hand, multitarget ligands integrating various biological activities into a single chemical entity is a cornerstone of a modern medicinal chemistry to overcome drawbacks associated with the co-administration of two or more agents. At the same time, nanoparticles have been efficiently developed to improve drugs efficacy, passage through biological barrierrs and selectivity of intracellular delivery.
Heme oxygenase 1 (HO-1) is an endoplasmic reticulum-anchored enzyme responsible for heme catabolism. High levels of this inducible enzyme have been linked to tumor aggressiveness and poor clinical outcome supporting the use of HO-1 inhibitors in anticancer adjuvant chemotherapy.
The challenge of our project is to establish a new multidisciplinary approach involving the integration of two different strategies based on hybrids (i.e., double hybrid or Hybrid2) to improve the anticancer efficacy of the widely used drug 5-fluorouracil (5-FU) by targeting the HO-1. Specifically, 5-FU/HO-1 hybrids will be developed for improving 5-FU activity, pharmacokinetics, and mitigating its toxicity, while hybrid nanoconstructs composed of gold nanoparticles covered by cyclodextrins will be assembled with new active small molecules to allow an effective delivery to the tumor. Hence, a first approach relying on drug design, synthesis, analytical, and biochemical methodologies will be implemented to discover innovative anticancer agents (Milestones 1, 2). Concurrently, a second approach will exploit smart nanotechnologies for potential theranostic applications through supramolecular assembly by means of spectroscopic, analytical, and biochemical methods (Milestone 3). An efficient interplay between research units working together in synergism will facilitate the integration of specific tasks, thus establishing a new technology platform for original therapeutic modalities. Finally, the last approach, encompassing molecular and cellular biology procedures, will be used to test the preclinical efficacy of our pretty unique “double hybrid” constructs on mammosphere or prostatospheres 3D cell models. These innovative cellular models will help to mimick the in vivo tumor environment considering the growing ethical concerns over the use of animals’
models (Milestone 4).