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Professor of Chemistry and Biochemistry at UCSD
A key nanotechnology objective is to build molecular devices that surpass the function of single molecules. Ultimately these enhanced nanodevices would provide modern medicine with integrated therapeutic and diagnostic function within a single in vivo delivery device.
October 20th, 2008
Nano Mother Ships Designed to Detect and Treat Cancer
Co-authors: Ji-Ho Park(1), Sangeeta N. Bhatia(2), Geoffrey von Maltzahn(2), and Erkki Ruoslahti1
1 Center of Nanotechnology for Treatment, Understanding, and Monitoring of Cancer (NANO-TUMOR)
2 MIT-Harvard Center of Cancer Nanotechnology Excellence
Until recently, multi-functional hybrid nanosystems have been studied in vitro, but there have been specific obstacles in moving to animal studies. The poor stability of nanodevices led to toxicity issues and poor targeting. The natural clearing process of the animal's circulation system limited the nanodevice circulation time and subsequent effectiveness. The recent development of "nano mother ships" that detect and treat cancer cells in a specific manner utilizes unique hybrid nanodevices. Conceptually the hull is composed of modified lipids and cancer related targeting molecules which provide a stable vehicle for accurate delivery of a multifunctional payload. The payload provides one or more unique methods of imaging the tumor (e.g. quantum dots and magnetic iron oxide particles) and a toxic drug designed to destroy the tumor in vivo with minimal effect on the patient (Figure 1, Drawing on Right).
A multidisciplinary, multi-CCNE team with varying specialties came together through the support and nurturing of the NCI Alliance to address these obstacles. Led by UCSD Prof. Michael J. Sailor, the team comprises of Ji Ho Park, UCSD, Prof. Sangeeta N. Bhatia and Geoffrey von Maltzahn, MIT, and Prof. Erkki Ruoslahti of The Burnham Institute at UCSB. The NCI Alliance emphasizes collaborations focused on developing and applying nanotechnology and nanoscience solutions to the diagnosis and treatment of cancer. A purpose well represented in this team's focus on engineering multifunctional nanoparticles which exploit biological processes to guide the targeting, self-assembly, and remote function of these materials to treat tumors in mouse models of cancer. Specifically, the development of these unique long circulating "nano mother ships" of micellar hybrid nanoparticles (MHN). These MHN are composed of magnetic particles (MN) and quantum dots (QD) for dual mode imaging (magnetic resonance and fluorescence) and an anti-cancer drug doxorubicin (DOX) within a single polyethylene glycol (PEG)-phospholipid micelle. Their recent publication in Angewandte Chemie1 provides the first demonstration of a single nanodevice that utilizes multi-mode imaging and targeted drug delivery to tumor tissue both in vitro and in vivo. These unique MHN conjugated to a targeting peptide dock and merge contents into a specific cell utilizing the cells endosomal system to eventually allow the DOX to reach the nucleus. Each MHN carries multiple iron oxide nanoparticles to enhance Magnetic Resonance Imaging (MRI) brightness in locating the tumor in body and QD for near infrared (NIR) fluorescence detection to enhance tumor visualization.
Dr. Sailor and Ji Ho Park concentrated on developing and evaluating the multi-functional nanoparticles containing the magnetic iron oxide nanoparticles and quantum dots for stability and imaging efficacy in this study. Synthesis of the "nano mother ship" involved combining MN, and QD (both coated with hydrophobic chains) followed by encapsulation into micelle of PEG-modified phospholipid (60-70 nm in size, see Figure 1, inset TEM micrograph). They noted that as the ratio of MN:QD increases, the fluorescence spectra was found to decrease, though detection was observed at sub-nanomolar QD concentrations. The presence of both MN and QD in the hybrid micelles allows the detection of tumors in both fluorescence and MRI imaging systems. Thus providing dual mode imaging detection capabilities. The anti-cancer drug DOX was also incorporated during the encapsulation process to provide demonstration of targeted drug delivery.
Dr. Ruoslahti's research focuses on identifying unique tumor vasculature "zip codes" that can be used to identify homing peptides as targeting elements to deliver nanoparticles into tumors and other sites of disease. The targeting ligand F3 he identified specifically binds to endothelial cells in tumor blood vessels and was conjugated to the MHN1. This peptide has been shown to transport payloads into tumor vasculature in vivo. At MIT, Dr. Bhatia, physician and engineer and von Maltzahn research the use of micro and nanotechnologies in tissues studies. They utilized their expertise in cell and animal imaging to evaluate the targeting, detection and delivery of the "nano mother ships" for in vitro and in vivo studies. They demonstrated an increase in both NIR fluorescence and MRI contrast within cells incubated with these hybrid nanoparticles. The F3 ligand of the surface of the hybrid particles was observed to chaperone the DOX into cancer cells and utilize the endosomal pathway to facilitate the release of the drug into the nucleus. The inherent red fluorescence of the drug provided a means to visualize this delivery process (Figure 1, Left colorized cell culture image). Distinct fluorescence and MRI contrast was observed in nude mice bearing tumors, and treated with the "nano mother ships".
With any in vivo study, toxicity must be a consideration. The potentially toxic nature of QD (cadmium), was not observed in this encapsulated form. Additionally the efficacy of the DOX was increased. The cytotoxicity of the delivered DOX in the hybrid nanoparticles was significantly greater than equivalent levels of free or untargeted DOX containing hybrid particles. The circulation of the PEG coated MHN remained significantly longer in the blood circulation than previous formulations.
These long circulating MHN provided stable "nano mother ships" for target specific delivery to cells in vitro and in vivo. This form of dual mode imaging may one day allow diagnosticians the advantage of full body tumor localization (MRI) and optical imaging at higher resolution using NIR. Followed by secondary payload delivery of a therapeutic drug into specific cells. The enhanced efficacy may lead to smaller doses of drug, and reduced side effects of toxic cancer drugs by limiting the exposure to normal tissues.
The recent discovery that aggregates of polymer coated iron oxide nanoparticles, coined "nanoworms", can effectively evade the body's natural elimination process further reflects on the potential impact of these nanodevices for both diagnostics (enhanced and tumor specific detection) and therapeutics (target specific delivery effective killing drugs).2 In addition to MRI and fluorescence imaging consider the possibility of future hybrid nanodevices which may allow a combination of photo-thermal therapy, and/or Raman imaging. This unique NCI Alliance provides a powerful example of what can be accomplished from a cross CCNE collaboration, the development and successful demonstration of a nanodevice with potential impact on cancer diagnostics and therapeutics.
1. J.-H. Park, G. von Maltzahn, E. Ruoslahti, S. N. Bhatia, M. J. Sailor, Angewandte Chemie, Early View published on-line August 11, 2008.
2. J.-H. Park, G. von Maltzahn, L. Zhang, M. P. Schwartz, E. Ruoslahti, S. N. Bhatia, M. J. Sailor, Adv. Mater. 2008, 20, 1630.
3. "Biomimetic amplification of nanoparticle homing to tumors" Dmitri Simberg, Tasmia Duza, Ji Ho Park, Markus Essler, Jan Pilch, Lianglin Zhang, Austin M. Derfus, Meng Yang, Robert M. Hoffman, Sangeeta Bhatia, Michael Sailor and Erkki Ruoslahti, Proc. Natl. Acad. Sci. USA. 104 (2007) 932-936.
4. "Nanoparticle Self-Assembly Gated by Logical Proteolytic Triggers" Geoffrey von Maltzahn, Todd J Harris, Ji-Ho Park, Alexander J Schmidt, Michael J. Sailor, Sangeeta N. Bhatia, J. Am. Chem. Soc. 129 (2007) 6064-6065.
5. "Nanoparticle Self-Assembly Directed by Antagonistic Kinase and Phosphatase Activities" Geoffrey von Maltzahn*, Dal-Hee Min*, Yingxin Zhang, Ji-Ho Park, Todd J. Harris, Michael Sailor, and Sangeeta N. Bhatia, Adv. Mater. 19 (2007) 3579-3582 (*These authors contributed equally.)
6. "Magnetic Iron Oxide Nanoworms for Tumor Targeting and Imaging" Ji-Ho Park, Geoffrey von Maltzahn, Lianglin Zhang, Michael P. Schwartz, Sangeeta N. Bhatia, Erkki Ruoslahti, and Michael J. Sailor, Adv. Mater. (Cover Article) 20 (2008) 1630-1635.
7. "Protease-Triggered Unveiling of Bioactive Nanoparticles" Todd J. Harris, Geoffrey von Maltzahn, Matthew E. Lord, Ji-Ho Park, Amit Agrawal, Dal-Hee Min, Michael J. Sailor, and Sangeeta N. Bhatia, Small. 4 (2008) 1307-1312.
8. "In vivo Tumor Cell Targeting with "Click" Nanoparticles" Geoffrey von Maltzahn*, Yin Ren*, Ji-Ho Park, Dal-Hee Min, Venkata Ramana Kotamrju, Jayanthi Jayakumar, Valentina Fogal, Michael J. Sailor, Erkki Ruoslahti, and Sangeeta N. Bhatia, Bioconjugated Chem. 19 (2008) 1570-1578. (*These authors contributed equally.)
9. "Micellar Hybrid Nanoparticles for Simultaneous Magneto-Fluorescent Imaging and Drug Delivery" Ji-Ho Park, Geoffrey von Maltzahn, Erkki Ruoslahti, Sangeeta N. Bhatia, and Michael J. Sailor, Angew. Chem. Int. Ed. 47 (2008) 7284-7288.