Coyin Oh & Joanna Yeh
Title of Proposed Project
20.109(F12) Pre-Proposal: Engineering viral magnetic nanoparticles for magnetic hyperthermic cancer therapy
Magnetic hyperthermia is an attractive cancer therapy due to its specificity and low toxicity to surrounding healthy tissue. Currently, this treatment struggles with low heat generation due to low local concentration of magnetic nanoparticles around the tumor site. The proposed study would investigate complexes composed of various phages and magnetic nanoparticles (MNPs) to increase the local concentration and hence the efficacy of magnetic hyperthermia.
The field of magnetic hyperthermia has attracted a lot of attention in the past thirty years as an alternative cancer therapy method. Magnetic hyperthermia proposes the placement of magnetic nanoparticles (MNP) in tumor cells under an alternating magnetic field. Nanoparticles often have unique physical and chemical properties that can be varied based on size and shape. MNPs are no different; these nanoparticles are superparamagnetic, gaining magnetic properties in the presence of a magnetic field. As the direction of the magnetic field alternates, MNPs undergo magnetic hysteresis losses that are dissipated to local surroundings as thermal energy. Targeted sites usually are heated to temperatures between 42 and 45 C to cause cell damage or death. A mean challenge with magnetic hyperthermia is the localization of MNPs to targeted tumor cells. It is possible for MNPs to circulate through the bloodstream and not reach the intended targeted sites. In addition, they at times are internalized and absorbed by the endoplasmic reticulum system of the cells. This low efficiency of MNP transport calls for a higher applied dosage of MNPs. How can we concentrate MNPs within tumor cells to produce sufficient heat for complete cell apoptosis?
- A.J. Giustini, A.A. Petryk, S.M. Cassim, J.A. Tate, I. Baker, P.J. Hoopes. Magnetic nanoparticle hyperthermia in cancer treatment. Nano LIFE 2010; 01: 17.
- D. Ghosh, Y. Lee, S. Thomas, A. G. Kohli, D. S. Yun, A. M. Belcher, K. A. Kelly. M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer. Nat. Nanotechnol. 2012; 7 (10): 677–82.
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Our proposed project aims to employ viral magnetic nanoparticles to increase the efficacy of magnetic hyperthermia. Viral MNP complexes consist of MNPs attached to viruses that have minimal harmful effects to humans. While the medical applications of viral MNPs has been studied for over a decade now, their functions have been mostly limited to in vivo MRI imaging and targeted gene delivery. Using viral MNPs, we are essentially providing a scaffold for the binding of MNP and a vehicle for the concentrated transport of MNPs to target sites. This way, we are reducing the number of MNPs that are "wasted" from getting internalized or circulated in the bloodstream without arriving at the appropriate target sites. Our approach can potentially increase the concentration of MNPs in targeted tumor cells, thereby achieving the level of heat necessary for effective cell apoptosis yet at the same time, lowering the minimum MNP dosage required for the treatment.
We hypothesize that our engineered viral MNPs can increase the current efficacy of magnetic hypothermia. <ref>The current best efficacy of magnetic hyperthermia is approximately 60%, measured in terms of mass of iron accumulated in tumor cells per total mass of MNP injected into the body. This was achieved with the aid of 10Gy radiation.</ref> This will be measured in terms of tumor cell death per mass of MNPs used. Our general preliminary approach involves five stages:
Stage 1: Virus Hunt
- We need to investigate how the selected virus (likely one of the following: TMV, M13, CCMV, CPMV, BMV or TPMV) interacts with mammalian cells in vivo.
Stage 2: Screening for MNP binding site on virus
- We will start by using Fe3O4 as our MNP of interest. With this, a protein coat screen of the selected virus for a protein coat that can bind with our MNP is necessary.
Stage 3: Screening for tumor-specific sequence binding site on virus
- We need to do a protein coat or RNA screen of the virus for a region that can bind with a tumor-specific peptide sequence. If necessary, we might need to screen tumors for unique short sequences on their cell surfaces.
Stage 4: Virus engineering
- We can now engineer wild-type viruses using specific protein coats or RNA regions isolated in Stage 2 and 3 to produce the viral MNP of interest.
Stage 5: in vivo testing
- Perform an in vivo experiment by injecting the engineered viral MNPs into the circulatory system of mice that have developed tumors. By subjecting these mice to an alternating magnetic field under standard hyperthermia conditions and measuring the change in tumor size, we will be able to quantify the efficacy of using viral MNPs in magnetic hypothermia.
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