OHSU

Research

Overview: Functionalized Nanomaterials for use in Biomedical Devices and Medicine

Our research program employs functionalized nanomaterials in biomedical devices and medicine. Our laboratory is a part of the Department of Biomedical Engineering, Oregon Health Science University (OHSU) School of Medicine. Our interest involves the development of animal models of cancer, kidney disease, and metals-related diseases, as well as applying engineered nanomaterials to diagnose, prevent, or treat such diseases. The nanomaterials of focus are porous inorganic metal oxides with surfaces that are chemically modified for specific medical needs.

NANOPARTICLE ENGINEERING FOR TARGETED DELIVERY OF CANCER THERAPIES

We have developed nanoconstructs for targeted delivery of siRNA, drugs and imaging agents for the treatment and diagnosis of cancer, particularly those over-express HER2, known to be resistant or acquire resistant to current HER2 targeted therapies. Layer-by-layer modification was performed on mesoporous silica nanoparticles. High protein silencing efficacy using siRNA loaded on our nanoconstructs has been demonstrated both in vitro cell culture and in mice bearing breast cancer tumor xenograft. Once the HER2 had been silenced, tumor growth reduction in the mice was apparent. We are applying these engineered nanoparticles for therapeutic delivery of siRNA for other cancers and fibrosis diseases.
Mesoporous Silica Nanoprticle Construct

RNA Interference

RNA Interference (RNAi). Recent advances in genetic sequencing are beginning to shed light on functionally redundant genes which drive cancer development. RNA interference circumvents the druggability issue associated with many disease-driven genes by acting at the mRNA level. Thus, successful RNAi therapy has the potential to revolutionize cancer therapy by mediating the silencing of any gene deemed essential for cancer progression. However, the lack of safe and effective methods to deliver siRNA remains the primary technical hurdle for this revolutionary treatment modality.   
science
Unlike cationic lipid based nanoparticles that are well known for rapid liver and spleen deposition, our nanoparticles (Figure 1) are optimized by the particle size (based on the survey of 130 clinically relevant nanoparticles done at the Nanotechnology Characterization Laboratory of NCI), charge (by tuning the net charge of silica, cationic polymer, and siRNA altogether), and solubility (enhanced with PEG) to avoid the recognition by the body’s immune system and subsequently prolong blood circulation time following intravenously injection (IV), leading to tumor accumulation based on the leaky vasculature and poor drainage of the tumors (Figure 2(A)). The HER2-antibody conjugated on the nanoparticles will target HER2 receptors on the cells and enter the cells via endocytosis (Figure 2(B)).

The selected cationic polymer has buffering ability and thus compromises the endosomal membrane due to influx of protons and water molecules, thereby allowing the siRNA to escape (Figure 2(B)) to the cytoplasm where siRNA can be processed and function to silence the target gene (Figure 2(C)). It’s important that the nanoparticles allow siRNA to escape the endosome in a timely manner before it is degraded in the lysosome.

Confocal Images showing colocalization of the nanoconstructs (A) and loaded siRNA (B) in BT-474 cells.
Confocal Images showing colocalization of the nanoconstructs (A) and loaded siRNA (B) in BT-474 cells.
Silencing of HER2 in BT474 breast cancer cells
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Luciferase silencing effects by the nanoconstructs loaded with either scrambled siRNA (mouse #1,2) or luciferase siRNA (mouse #3,4) in the xenograft mouse model.
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All test materials were given IV; siRNA dose of 1.25 mg/kg, Herceptin dose of 5 mg/kg, and Paclitaxel dose of 3.125 mg/kg, all given once weekly for 5 weeks.
tumor curve

Development of Nephrogenic Systemic Fibrosis (NSF) and Chronic Kidney Disease (CKD) animal models

The next thrust area is dedicated to developing Nephrogenic Systemic Fibrosis (NSF) and chronic kidney disease (CKD) animal models to study the mechanism of how gadolinium (Gd)-based contrast agents trigger the NSF disease in patients with severe renal impairment. Understanding the triggering mechanism will allow us to make recommendation on safe use of Gd contrast agents and the development of safer contrast agents in the future. We have also applied functionalized nanomaterials for blood cleaning of Gd based contrast agents in hemoperfusion devices.

Other research efforts

Other research efforts include the development of orally delivered drugs based on organically modified mesoporous silica for preventing and treating heavy metal poisoning, first aid drugs for preventing gut absorption of radionuclides (in the event of dirty bomb and nuclear explosion), and phosphate binding drug for treating hyperphosphatemia in CKD patients. In collaboration with PNNL, these nanomaterials have been chemically modified for selective capture of specific metal targets on the Periodic Table (see below). They have been applied for selective preconcentration of toxic metal ions at on-site portable metal analyzers for biomonitoring of heavy metal exposure.

Sponsors: NIGMS, NIAID, NIOSH, NIEHS, DOE, ONAMI, Knight Cancer Institute.

Tailoring organic groups on Nanoporous Silica for selective capture of various metal ions