| NSF Org: |
DMR Division Of Materials Research |
| Recipient: |
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| Initial Amendment Date: | June 26, 2013 |
| Latest Amendment Date: | June 27, 2013 |
| Award Number: | 1343991 |
| Award Instrument: | Continuing Grant |
| Program Manager: |
Joseph A. Akkara
DMR Division Of Materials Research MPS Directorate for Mathematical and Physical Sciences |
| Start Date: | August 11, 2012 |
| End Date: | July 31, 2015 (Estimated) |
| Total Intended Award Amount: | $313,639.00 |
| Total Awarded Amount to Date: | $313,639.00 |
| Funds Obligated to Date: |
FY 2012 = $150,000.00 FY 2013 = $150,000.00 |
| History of Investigator: |
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| Recipient Sponsored Research Office: |
10889 WILSHIRE BLVD STE 700 LOS ANGELES CA US 90024-4200 (310)794-0102 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
Los Angeles CA US 90095-2000 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): | BIOMATERIALS PROGRAM |
| Primary Program Source: |
01001213DB NSF RESEARCH & RELATED ACTIVIT 01001314DB NSF RESEARCH & RELATED ACTIVIT |
| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.049 |
ABSTRACT
This award by the Biomaterials program in the Division of Materials Research to Northwestern University is to study the interactions of nanodiamond (ND)-gadolinium III (Gd(III)) conjugates, and to further optimize the relaxivity and integration with polyethylenimine (PEI) for enhanced imaging and medical treatments. The development of novel imaging and therapeutic modalities with significantly enhanced performance over current standards remains an important focus at the intersection of biomaterials and nanoengineering. Nanodiamonds serve as promising biomaterial platforms as they unite a spectrum of unique chemical/physical properties, enabling significantly improved capabilities in imaging and therapy. Recent studies have shown that ND-gadolinium (III) complexes can produce a 12-fold enhancement in per-Gd relaxivity, yielding among the highest values that have been reported. Furthermore, gene therapy challenges are often based on the inability to develop platforms that integrate both safety and efficacy. We have shown that complexes comprised of NDs and the polyethylenimine polymer yield a 70-fold enhancement in DNA transfection efficacy. Furthermore, both the ND-Gd(III) and ND-PEI hybrid complexes are biocompatible. This project will modulate the linker length between ND surfaces and Gd(III) to optimize relaxivity. The ND-Gd(III) complexes will then be combined with PEI and a targeting agent to generate order of magnitude increases in both imaging and therapy into a single platform. Optimized by fundamental science and engineering investigations, this nanodiamond platform will combine unprecedented improvements to contrast and therapeutic efficacy in targeted drug delivery and imaging. These advancements will further serve as the foundation for developing new educational modules and hands-on research experiences for K-12 students. The planned preparation of ND block and magnetic resonance imaging kits to educate students is expected to provide the interesting nature of ND facets/electrostatics and how these materials could mediate drug binding/release and imaging. In addition to their research training in science and engineering, the graduate students supported by this proposal will also serve as mentors for undergraduate researchers as well as K-12 students and high school teachers from partnering institutions who are taking part in the learning modules prepared. The integration of scientific discoveries and educational resources from this project will thus serve as a foundation for the education and training of the scientific and engineering leaders of tomorrow.
Current challenges in understanding, diagnosing, and treating cancer are based on the needs of improved imaging and therapy. To address these challenges, the investigators are developing a nanodiamond-based platform that is capable of mediating greater than 10-fold increases in imaging and drug treatment efficiency, which are significant improvements over current standards. The integration of fundamental studies with applied engineering will be used to synthesize integrated nanodiamond complexes to target, image, and treat a selected breast cancer model, with the ultimate goal of optimizing diagnostic capabilities and therapeutic efficiency while remaining biocompatible and safe. It is envisioned that this novel technology will provide unprecedented advances in imaging/diagnostics and cancer therapy, among other areas. The discoveries realized from this study will also inspire new methodologies for educating and training the next generation of science and engineering leaders. To merge scientific discovery with educational impact, the investigators are planning to develop innovative experimental modules using imaging kits and nanodiamond blocks that could be used to educate students from K-12. Furthermore, these kits will be used as a hands-on tool for magnetic resonance imaging instruction. Graduate students supported by this study will serve as educational module leaders to instruct partnering K-12 teachers on the emerging applications of nanodiamonds, as well as the use of these kits. Furthermore, these graduate students will mentor undergraduate students in designated research projects, and these activities are expected to provide an optimal framework for scientific impact and educationally developing the next generation of scientific leadership.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
INTRODUCTION
The primary research objective of this work has been the fundamental development of a nanodiamond-based molecular delivery and magnetic resonance imaging to target breast cancer cells. Nanodiamonds are promising molecular delivery vehicles as they combine many important properties for therapy carriers into a single platform. These include unique surface chemical properties that enable the potent binding of a broad array of drug compounds, as well as the ability to mediate remarkable enhancements to the efficiency of imaging agents, particularly gadolinium, which is used for magnetic resonance imaging and the detection of cancer. As a foundation for this work, the fundamental synthesis and characterization of the nanodiamond-gadolinium agents resulted in a per-gadolinium increase in relaxivity, or imaging contrast efficiency, of 12-fold. This is among the highest ever reported values compared to all nanoparticle as well as clinically-used gadolinium-based imaging agents. Importantly, it should be noted that nanodiamonds are byproducts of conventional mining or refining processes. Therefore, it is an already-produced and relatively inexpensive material. Using straightforward and scalable cleaning procedures, the nanodiamonds can be rendered applicable towards biological applications, representing a form of ‘sustainable nanotechnology.’ As such, the accessibility of the nanodiamond material may enable a large population to access its unique molecular delivery efficiency capabilities.
INTELLECTUAL MERITS
Major findings from this project have shown that the nanodiamond-gadolinium contrast efficiency can be adjusted and further optimized, resulting in the potential for much larger increases in per-gadolinium relaxivity. This is an important finding as it may enable a substantial decrease in the amount of gadolinium needed to achieve the same or better level of imaging contrast for effective cancer diagnostics. This would potentially enable more recipients to benefit from the use of magnetic resonance imaging to track treatment progress due to the reductions in toxicity from markedly decreased dosages of gadolinium with unimpaired function.
Additional findings from this project have shown that nanodiamonds can enable increased gadolinium uptake into cancer cells, as well as no apparent toxicity of the nanodiamond-gadolinium agents in the form of unimpaired cell growth. Nanodiamond particles that were targeted to an aggressive form of breast cancer resulted in marked improvement in the inhibition of cancer cell growth to the point where the cancers were no longer detectable. In addition, comprehensive safety studies using indicators derived from the blood were conducted, demonstrating that the nanodiamonds are well tolerated during the molecular delivery and imaging processes.
An important component of this project was the ability to optimize the way that nanoparticle-therapeutic compounds are designed. This would enable substantial improvements to treatment efficacy and safety, as the systematic development of the right nanoparticle-therapy ratios can have a profound impact on how cancer cells respond to therapy. With collaborators, project team members validated a powerful technology that can rationally design the delivery of multiple drug compounds using nanodiamonds. This resulted in nanodiamond-chemotherapy drug combination efficacy that far exceeded that observed with unmodified drug combinations, single drug compounds, and randomly selected nanodiamond-chemotherapy combinations. This approach can be broadly applied to other nanoparticles or unmodified therapies to impact the broad field of cancer cell inhibition.
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