The Steinmetz Lab’s mission is to push to new frontiers in medicine and bio-nanotechnology through design, development and testing of materials and biologics derived from plant viruses. Our vision is the translation of promising candidates into clinical and commercial applications.
Next-generation nanotechnology depends upon the capacity to precisely alter size and shape of nanostructured features with temporal and spatial control. Nanoscale self-assembly is a technique that Nature masters with atomic precision; using this principle, we turned toward the study and application of plant viruses as an approach to generate highly structured nanoparticles with new functionalities. Viruses are playing a special role in nanotechnology and nanomedicine, because they can function as prefabricated nanoparticles naturally evolved to deliver cargos to cells and tissues. We have developed a library of plant virus-based nanoparticles and through structure-function studies we are beginning to understand how to tailor these nanomaterials appropriately for biomedical applications.
Research is organized into several interconnected research thrusts:
- Vaccines and immunotherapies.
- Drug delivery targeting human and plant health.
- Molecular imaging for diagnosis and prognosis.
- Virus-programmed materials.
Please also see our Center for Nano-ImmunoEngineering (nanoie.ucsd.edu)
Vaccines and Immunotherapy
Capitalizing on our proteinaceous plant virus-derived carriers, we are developing immunotherapeutic and prophylactic approaches. We recently demonstrated, that virus-like particles (VLPs) from plants induce a potent anti-tumor immune response when introduced into the tumor microenvironment after tumors are established [Nature Nanotechnology 2016]. The idea pursued is an “in situ vaccination” immunotherapy strategy to manipulate tumors to overcome local tumor-mediated immunosuppression and subsequently stimulate systemic anti-tumor immunity to treat metastases. The VLPs exhibited clear treatment efficacy and systemic anti-tumor immunity in melanoma, ovarian, colon, and breast tumor models in multiple anatomic locations. Ourdata indicate that anti-tumorimmune-stimulation generates immune memory to prevent tumor progression,metastasis, and most importantly recurrence. While treatment and diagnosis can improve patient outcome, the prevention of cancer development (before physicians are able to detect its onset) represents a vertical leap in the field.
We are developing tobacco mosaic virus (TMV) as a delivery system for chemotherapies, such as doxorubicin [Journal of Controlled Release 2016] and novel drug candidates, such as phenanthriplatin [ACS Nano 2016]. For example, TMV forms hollow nanotubes with a polyanionic interior surface; capitalizing on this native structure, we developed a one-step phenanthriplatin loading protocol. Phenanthriplatin release from the carrier is induced inacidic environments. This delivery system, designated PhenPt-TMV, exhibits matched efficacy in a cancer cell panel compared to free phenanthriplatin. In vivo tumor delivery and efficacy was confirmed using a mouse model of triple negative breast cancer. The biology-derived TMV delivery system provides an novel nanodrug delivery system (nanoDDS).
Applications in agriculture
The first step towards a healthier society is to reduce exposure to toxic substances. To minimize pesticide exposure, advanced methods are required to deliver pesticides more effectively to the target site and avoid its leaching into ground and drinking water. We focus on developing more effective ways to treat plant endoparasitic nematodes feeding on crop roots. Using Tobacco mild green mosaic virus (TMGMV) as a nanocarrier, we demonstrated anthelmintic drug delivery targeting nematodes. Furthermore, we demonstrated the superior soil mobility of drug-loaded TMGMV vs. free drug [ACS Nano 2017]. In our current work, experimental and computational approaches are being investigated to study the soil mobility of TMGMV and various other nanoparticles.
Improving survival and quality of life, and reducing healthcare costs depends on better non-invasive imaging techniques with better prognostic value. Magnetic resonance imaging (MRI) is an attractive modality; however, diagnosis can be difficult in areas where diseased and healthy tissues are of similar signal intensities. Contrast agents, such as peptide-targeted Gd(DOTA) have been developed, but the applications are limited, because the low relaxivity (T1 ~5 mM-1s-1) is insufficient to enable sensitive delineation of disease makers in vivo. To overcome this hurdle, the Steinmetz lab has developed molecularly-targeted nanoscale contrast agents carrying large payloads of clinically approved agent, Gd(DOTA). The contrast agent is self-assembled using the nucleoprotein components of the tobacco mosaic virus, a unique material offering a high-aspect ratio shape [Adv Healthc Mater 2015]. The protein-based contrast agents exhibits a relaxivity of T1~100,000 mM-1s-1, which is five orders of magnitude higher than current clinical agents. Using this probe targeted to vascular cell adhesion molecule, we demonstrated sensitive delineation of the molecular signatures in vivo [Nano Letters 2014, J. Mater Chem B 2015]. Our vision is the application of the probe to aid risk stratification in atherosclerosis and prostate cancer. Toward this goal, we have identified novel biomarkers and their peptide ligands to differentiate vulnerable vs. stable plaque as well as to distinguish aggressive vs. benign prostate cancer.
We are programming the assembly of biomolecular materials, immunosensors and other diagnostic tools, as well as plasmonic and photonic materials using plant virus-programmed materials.
For example, in response to the 2014 Ebola epidemic, we proposed and developed a virus-inspired design of Ebola diagnostic probes to enable sensitive detection of Ebola with higher accuracy through reduction of false negative results [Scientific Reports 2016]. In ongoing work, we are implementing the novel diagnostic probes in high-tech and low-tech assays for field use in low-resource settings, crucial for containing this deadly disease.