– Proposal full title: Nature-inspired theranostic nanodevices for tumor imaging, early diagnosis and targeted drug-release
- The overriding goal of this research program is to mimic Nature in the design of novel nucleic acid based nanodevices that detect cancer, provide detection-driven therapy, and monitor treatment efficacy.
- I will design, engineer and optimize highly specific biomolecular nanodevices that undergo binding-induced conformational changes upon target binding and, in doing so, signal the presence of the cancer marker (Aim I) or release a therapeutic cargo (Aim II). Moreover, by coupling these events in a single platform I will develop a theranostic nanodevice capable of smart drug release and treatment monitoring.
- I propose to use different switching mechanisms and to target a wide range of tumor markers (one of which is shown in the figure below). I will test the targeted drug-release efficiency with different therapeutics including aptamers, siRNA and DNA binders.
- Finally, I will exploit and mimic several naturally occurring mechanisms (e.g. allostery, cooperativity etc.) to optimize the signalling output and drug release efficiency of the nanodevices (Aim III)
During my PhD studies (in Italy) I developed a strong expertise on the development of point-of-care devices for clinical analysis. For my post-doctoral studies (in US) I moved towards the design and synthesis of DNA-based sensors inspired by complex biological mechanisms (synthetic biology approach). By taking advantage of the simplicity and versatility of DNA chemistry, I was able to understand the thermodynamics basis of my sensors, and apply this know-how to engineer nanoprobes for various applications (see my CV). Embracing a similar research philosophy for my lab and coupling my previous PhD experience in clinical analysis, I propose in this project to study the fundamentals of nature-inspired mechanisms and use this knowledge to design self-regulated theranostic nanodevices capable of providing diagnostic information and delivering targeted therapy. In the following section I will explain how I conceive these nature-inspired nanodevices, the overall concept behind this proposal and the progress beyond the state of the art that this project could bring.
NATURE INSPIRED NANODEVICES
Nature uses nanometer-scale, protein and nucleic-acid-based “switches” to sense chemical inputs and transduce molecular binding events into specific, high-gain signal outputs. Examples of these switches are calmodulin proteins, cytokine receptors and riboswitches. These biomolecular switches shift between two or more conformations in response to the binding of a specific target (see figure on the right). This leads to very specific and sensitive output signals that regulate important biological functions. But why has nature evolved these complex structure-switching nanodevices?
Why nature uses such switches?
- Robust (selective): Structure switching is generally only induced by a specific target/receptor interaction and thus remains insensitive to the presence of other molecules present in highly complex environments.
- Rapid and reversible: the switching mechanism is controlled by its thermodynamic equilibrium: it is rapid and reversible, which makes it suitable for real-time monitoring.
- Versatile and easily tunable: the conformational equilibrium of biomolecular switches depends on the target concentration and on the switch’s thermodynamics. This provides a means by which the sensitivity and dynamic range of the receptor can be rationally optimized by simply tuning the switching equilibrium constant (Ks).
Inspired by the mechanisms employed by nature to detect the inputs from thousands of distinct molecules in a complex physiological environment, I propose here to exploit the “designability” of nucleic acids to develop molecular nanodevices that undergo binding-induced conformational changes (switches) upon target binding and, in doing so, can 1) Signal the presence of a tumor marker or 2) Release a therapeutic agent. The diagnostic nanodevices will be applied for the optical imaging of tumor cells and for the electrochemical point-of-care detection of tumor markers. In line with this “nature-inspired” synthetic biology view of the project I also propose to mimic naturally occurring mechanisms such as allosteric control and catalytic amplification to tune and edit the dose-response curve of these nanodevices, improve their analytical sensitivity and achieve a better drug-release efficiency.
IMPACT AND ADDED VALUE
The current and ongoing need for better diagnostic tools and more efficient drug delivery renders the proposed research extremely timely. Current state-of-the-art approaches for tumor marker detection and drug delivery present several disadvantages that nanoswitch-based technology promise to overcome providing important added values (see table). The proposed project could thus significantly impact the safety and efficacy of therapies and medical procedures providing in turn many scientific, technological and socio-economic benefits.
The advantages of switch-based devices are numerous. Unlike traditional molecular detection methods switch-based probes require neither processing steps nor exogenous reagents. Likewise, because structure switching is largely immune to the non-specific binding of contaminants, switch-based devices will perform well in complex, multi-component samples. The drug-delivery nanodevices should be adaptable to potentially any tumor marker and could release a wide range of cancer drugs. Also, because the nanodevices activate/release their drug cargo only in the presence of the tumor marker, the side effects against healthy cells will be greatly minimized. Finally, nucleic acid, among other advantages is highly designable and very stable, rendering it an excellent “material” for use in the development of nanodevices.
NEWS: see here the article appeared on the national Newspaper “La Stampa”