Advanced materials for drug and gene delivery

The SinghLab has developed multiple nanoscale platforms for drug and gene delivery. Recent collaborations with Prof. Ulrich Bierbach in the Department of Chemistry on the Wake Forest Reynolda Campus have led to the development of two new nanomaterials for delivery of a potent class of chemotherapeutic drugs call platinum acridine. Due to their chemical structure, platinum acridine agents can bind to carbon nanotubes through strong, non-covalent interactions, but are released after uptake by cells. We have developed platinum acridine coated carbon nanotubes as a drug delivery platform and our results show efficacy for treatment of pancreatic cancer in mice. Together with Prof. Bierbach, we have developed a platinum acridine loaded, lipid coated silica nanoparticle that exhibits pH dependent drug release. We have also developed liposome-based approaches for delivery of siRNA and as coatings for recombinant adenovirus to improve tumor-specific delivery of nucleic acids for gene therapy. Using these novel technologies, our goal is to improve patient outcomes and reduce the off-target toxicity of cancer therapy.

Precision cancer medicine using nanoscale silver

We are studying the potential to use silver nanoparticles (AgNPs) as a precision redox medicine in a subset of breast, ovarian, lung, colorectal, and prostate cancers exhibiting mesenchymal features associated with poor prognosis. Our earlier published studies show that AgNPs are highly cytotoxic toward TNBC cells at doses that have little effect on nontumorigenic breast cells or cells derived from liver, kidney, and monocyte lineages. AgNPs induced more DNA and oxidative damage in TNBC cells than in other breast cells. In vitro and in vivo studies showed that AgNPs reduce TNBC growth and improve radiation therapy. These studies show that unmodified AgNPs act as a self-therapeutic agent with a combination of selective cytotoxicity and radiation dose-enhancement effects in TNBC at doses that are nontoxic to noncancerous breast and other cells. We also found that AgNPs are highly cytotoxic to some ovarian cancer cell lines, but not others. We now have discovered a biomarker that is able to identify cancers, independent of tissue of origin, that are sensitive to treatment using silver nanoparticles. Our current research aims to validate this biomarker, and ultimately translate our findings to treat patients.

Carbon Nanotube Mediated Thermal Ablative Therapy

Carbon nanotube mediated thermal therapy (CNMTT) uses lasers that emit near-infrared radiation to excite carbon nanotubes (CNTs) localized to the tumor to generate heat needed for thermal ablation. In our studies, we show that a dense coating of phospholipid-poly(ethylene glycol) on multiwalled CNTs (MWCNTS) allows for better diffusion through brain phantoms, while maintaining the ability to achieve ablative temperatures after laser exposure. We have found that thermal therapies mediated by CNTs may be more effective than treatments using only a laser at eliminating cancer initiating cells (cancer stem cells). These cells are thought to be resistant to chemo and radiation therapy and may be responsible for treatment failure and disease recurrence. We have begun testing the safety of this treatment in small animal models of a deadly brain tumor call glioblastoma.   

Novel materials and agents for cancer imaging

We are also developing carbon nanotubes to aid in image guided treatment of cancers. We have shown that CNTs are a versatile platform for the display of radionuclides for PET/SPECT imaging (64Cu; 111In), can incorporate paramagnetic materials (iron oxide) into their lumen and act as MRI contrast agents, or can display fluorophores (FITC) to enable fluorescent imaging. Moreover, CNT surfaces can be modified to display ligands that bind to molecules that are highly expressed on cancer cells (GLUT1; IL13R2a), which increases their uptake by these cells. We are now combining cancer targeting, drug delivery, and enhanced photothermal therapy  into a single CNT platform for use in treating aggressive brain tumors including glioblastoma.