Cellular and Molecular Imaging Laboratory
Cellular and Molecular Imaging
My laboratory is focused on state-of-the-art technology in imaging, nanomedicine and drug delivery systems to enable the development of multifunctional nano-construction with MRI, targeting and therapy. The main objective of my research program is to develop nanomedicine monitoring with molecular imaging and cellular drug delivery for brain tumor therapy with minimal drug-induced toxic effects.
Delivery of nanomedicine across blood brain tumor barrier (BBTB)
The delivery of anti-cancer drugs to brain tumors such as glioblastoma mutiforme (GBM) represents a challenge because the blood-brain barrier (BBB) effectively limits the delivery of many agents, and the high tumor interstitial fluid pressure presents an additional delivery barrier. However, nanotechnology has demonstrated the potential to transfer drugs across the BBB and into brain tumors. We have developed a nano-sized dual mode imaging agent that uses a generation 5 (G5) polyamidoamine (PAMAM) dendrimer to carry clinically relevant Gd-DOTA and a fluorescent dye. Systemic delivery of the designed nanomedicine in Figure 1 [(GdDOTA)54-G5-DL680] resulted in the agent homing into its glioma tumor site selectively. In vivo MRI detected the agent in a glioma tumor, but not in contralateral tissue (Figure 2A and 3); the specificity of the agent was validated by whole body NIR-optical imaging and ex vivo fluorescence imaging (Figure 2B-C). The in vivo MRI showed the macroscopic location of the tumor while fluorescence imaging showed the biodistribution of the agent, demonstrating that the dual-mode imaging agent has utility for practical applications.
Figure 1. Schematic view of nanoparticle. MRI contrast agent, Gd- (DOTA) is conjugated with a G5 PAMAM dendrimer. Fluorescent dye, DyLight (DL680) is also conjugated with the same nanostructure.
Figure 2. The coronal in vivo MRI image shows the location of U-251 glioma tumor (A). The agent was Gd-G5-DL680 and injected at a dose of 0.03 mmol Gd/kg. In vivo optical image obtained under simultaneous white light and filtered (540-690 nm) excitation detected with the emission filter set at 750 nm demonstrating fluorescence in the glioma (B). Ex vivo fluorescence imaging of rat brain clearly shows the selective accumulation of the Gd-G5-DL680 within the tumor (C). Tumor is indicated as dotted white circle.
Nanotechnology is already benefiting in delivering drugs and imaging agents across the BBTB and into brain tumors. We have engineered a nano-sized polymeric combretastatin A4 (CA4) conjugate which demonstrates high water solubility and bioavailability. Preliminary intravenous (i.v.) delivery of nanocombretastatin (G3-CA4) in an orthotopic glioma model demonstrated necrosis at the core of the tumor leaving a rim of viable tissue (Figure 3). By applying the designed nanoprodrug strategy and tumor-specific prodrug activation mechanism, we observed the true success of inducing necrosis at the core of the tumor in an orthotopic U-251 glioma animal model (Figure 3).
Figure 3. (A) Post-contrast T1-weighted MR images 24h after administration of G3-CA4. Tumors are indicated as dotted red circles. Solid yellow arrow indicates G3-CA4 induced necrosis. (B) Hematoxylin-eosin stain proves massive intratumoral necrosis leaving viable tumor cells at the rim. Representative images of tumor blood vessels (red visualized with vWF-TRITC staining) at panels C and D at the rim. (E) In contrast, the core of the tumor did not show any active blood vessel. Red for vWF-TRITC and blue for nuclear dapi.
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