Ravi Singh Laboratory
Nanotechnology and cancer
To take advantage of the unique capabilities offered by nanotechnology to enhance cancer diagnosis and therapy, experts in multiple disciplines including chemistry, physics, mathematics, biology and medicine, must work together as a cohesive group. In general, physicists, chemists, and materials scientists enjoy a far deeper understanding than biomedical scientists of the unique optical, structural and electronic properties of nanomaterials that have driven research in this field. Yet, even as engineering of nanoscale, biomedical diagnostic and therapeutic agents evolves into its own cross-disciplinary field, few nanomaterials have been used for clinical applications. The bottleneck in the clinical development of novel therapeutics using any nanomaterials is caused by the current lack of relevant structural/physicochemical characterizations linked to fundamental knowledge of biological function relationships at the pre-clinical level that would help to bridge cell culture-to mouse-to human studies.
My research program integrates specific clinical applications into the development of nanotechnology-based, multifunctional entities that can diagnose cancer, deliver therapeutic agents, and monitor cancer treatment (so called "theranostic" agents). The research will facilitate the translation of nanoparticle-based therapeutics from the lab to the clinic. Two major areas of research are currently being explored in my laboratory:
Therapeutic and diagnostic applications of carbon nanotubes for cancer:
We are working to develop a new agent based on multiwalled carbon nanotubes (MWCNT) for the diagnosis and monitoring of advanced breast cancer. Carbon nanotubes will be engineered to display small molecules on their surface to target them to tumors through selective binding to specific surface marker. The nanotubes will be labeled with positron emitters, enabling the nanotubes to serve as a sensitive imaging tool for positron emission tomography (PET) or magnetic resonance imaging (MRI). Carbon nanotubes offer many advantages for targeted molecular imaging techniques: foremost is their ability to deliver large numbers of imaging agents per each targeted molecular recognition event, which can improve the sensitivity of imaging; secondly, they can deliver several different types of agents to perform multimodality imaging; thirdly, they can be used for therapeutic applications including chemotherapeutic drug or gene delivery, and as mediators for photothermal cancer therapy. Furthermore, they are efficient transducers of near infrared radiation into heat for use in thermal ablation or optical imaging than SWCNT, increasing the possibilities for applications in a single particle.
This research program aims to: 1) selectively target tumors with carbon nanotubes following intravenous injection; 2) trace the distribution and clearance of carbon nanotubes using non-invasive imaging modalities including PET and MRI; 3) optimize the spatial and temporal distribution of heat used for thermal ablation in order to localize heating to the tumor target and reduce collateral damage to normal cells and tissues; 4) develop targeted thermal ablation therapies based upon CNTs for the treatment of cancers that are highly resistant to current therapies; 5) minimize the toxicity of engineered nanomaterials through the application of rationale design principles.
Designer adenoviruses for nanomedicine and nanodiagnostics
The interdisciplinary nature of viral nanotechnology, a field lying at the interface of virology, biomedicine, chemistry, and materials science, facilitates the bridging of ideas and techniques between these disciplines. Current developments in medicine include the engineering of VNPs as diagnostics, vaccines, imaging modalities and targeted therapeutic devices. The goal of this line of research is to develop viral nanoparticles (VNPs) as biologic scaffolds for the display of metal nanoparticle arrays for use in cancer imaging and therapy. From a materials science point of view, VNPs are interesting: 1) they are of nanoscale dimensions, polyvalent and monodisperse; 2) they are robust and are stable in many solvents and buffers, which is essential for chemical modification; 3) they can be produced in milligram quantities in the laboratory or purchased commercially for a reasonable cost.
Adenovirus (Ad), a DNA virus commonly used for gene therapy applications, could be considered the ideal vehicle for a number of emerging biomedical applications which rely on highly localized targeting including non-invasive cancer therapy and imaging: 1) they represent near ideal nanoparticles due to their regular geometries, well characterized surface properties, nanoscale dimensions, and their structure being known to near atomic resolution; 2) extensive research has been conducted regarding their biocompatibility and tumor targeting capacity; 3) they can serve as biocompatible scaffolds to which a wide variety of inorganic and biological structures may be attached. There are no other nanoparticle platforms that achieve the same degree of control over size, homogeneity, and versatility as molecular shuttles. A detailed understanding of its capsid structure and surface chemistry makes Ad an excellent starting point. The ability to link multiple functionalities to the Ad capsid theoretically allows for incorporation of several therapeutic and diagnostic modalities within a single vector, though such a vector based on Ad has not yet been developed.
This research will lead to: 1) development of a platform technology for the interchangeable display of multiple diagnostic and therapeutic nanoparticle functionalities; 2) optimization of the placement of nanomaterials in precise positions within a VNP-carrier scaffold to enhance the optical properties of such tethered nanoparticle arrays; 3) in vitro testing of both toxicity and function of these nanoparticle arrays in normal human and cancer cell lines. As additional chemistries and VNP platforms become available, the possibilities for the design of new nanomaterial arrays will continue to expand exponentially, impacting areas ranging from electronics to tissue engineering in addition to new developments in "smart" targeted devices for tissue-specific imaging and therapy.