Dr. Robert Ivkov Profile

Dr. Robert Ivkov

at Johns Hopkins Univ

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Publications (6)

Proceedings Article | 22 February 2013 Paper

New iron-oxide particles for magnetic nanoparticle hyperthermia: an in-vitro and in-vivo pilot study

Mohammad Hedayati, Anilchandra Attaluri, David Bordelon, R. Goh, Michael Armour, Haoming Zhou, Christine Cornejo, Michele Wabler, Yonggang Zhang, Theodore DeWeese, Robert Ivkov

Proceedings Volume 8584, 858404 (2013) https://doi.org/10.1117/12.2019834

KEYWORDS: Magnetism, Particles, Nanoparticles, Temperature metrology, Tissues, Iron, In vitro testing, Magnesium, Tumors, In vivo imaging

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Proceedings Article | 24 February 2009 Paper

Assessment of intratumor non-antibody directed iron oxide nanoparticle hyperthermia cancer therapy and antibody directed IONP uptake in murine and human cells

P. Hoopes, J. Tate, J. Ogden, R. Strawbridge, S. Fiering, A. Petryk, S. Cassim, A. Giustini, E. Demidenko, R. Ivkov, S. Barry, P. Chinn, A. Foreman

Proceedings Volume 7181, 71810P (2009) https://doi.org/10.1117/12.812056

KEYWORDS: Tumors, Nanoparticles, Iron, Particles, Oxides, Cancer, In vivo imaging, In vitro testing, Tissues, Oncology

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Hyperthermia, as an independent modality or in combination with standard cancer treatments such as chemotherapy and radiation, has been established in vitro and in vivo as an effective cancer treatment. However, despite efforts over the past 25 years, such therapies have never been optimized or widelyaccepted clinically. Although methods continue to improve, conventionally-delivered heat (RF, ultrasound, microwave etc) can not be delivered in a tumor selective manner. The development of antibody-targeted, or even nontargeted, biocompatible iron oxide nanoparticles (IONP) now allows delivery of cytotoxic heat to individual cancer cells. Using a murine mouse mammary adenocarcinoma (MTGB) and human colon carcinoma (HT29) cells, we studied the biology and treatment of IONP hyperthermia tumor treatment. Methods: Cancer cells (1 x 10⁶) with or without iron oxide nanoparticles (IONP) were studied in culture or in vivo via implanted subcutaneously in female C3H mice, Tumors were grown to a treatment size of 150 mm³ and tumors volumes were measured using standard 3-D caliper measurement techniques. Mouse tumors were heated via delivery of an alternating magnetic field, which activated the nanoparticles, using a cooled 36 mm diameter square copper tube induction coil which provided optimal heating in 1.5 cm wide region of the coil. The IONPs were dextran coated and had a hydrodynamic radius of approximately 100 nm. For the in vivo studies, intra-tumor, peritumor and rectal (core body) temperatures were continually measured throughout the treatment period. Results: Although some eddy current heating was generated in non-target tissues at the higher field strengths, our preliminary IONP hyperthermia studies show that whole mouse AMF exposure @160 KHz and 400 or 550 Oe, for a 20 minutes (heat-up and protocol heating), provides a safe and efficacious tumor treatment. Initial electron and light microscopic studies (in vitro and in vivo) showed the 100 nm used in our studies are rapidly taken up and retained by the tumor cells. Additional in vitro studies suggest antibodies can significantly enhance the cellular uptake of IONPs.

Proceedings Article | 12 February 2009 Paper

An in vivo transmission electron microscopy study of injected dextran-coated iron-oxide nanoparticle location in murine breast adenocarcinoma tumors versus time

Andrew Giustini, R. Ivkov, P. Hoopes

Proceedings Volume 7181, 71810M (2009) https://doi.org/10.1117/12.809868

KEYWORDS: Tumors, Nanoparticles, Transmission electron microscopy, Iron, Oxides, In vivo imaging, Breast, Cancer, Tissues, Particles

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Investigators are just beginning to use hyperthermia generated by alternating magnetic field (AMF) activated iron oxide nanoparticles (IONPs) as a promising avenue for targeted cancer therapy. An important step in understanding cell death mechanisms in nanoparticle AMF treatments is to determine the location of these nanoparticles in relation to cellular organelles. In this paper, we report on transmission electron microscopy (TEM) studies designed to define the position of 100 nm diameter dextran-coated iron oxide nanoparticles in murine breast adenocarcinoma (MTG-B) and human colon adenocarcinoma tumors propagated in mice. METHODS: Iron oxide nanoparticles (5 mg/g tumor) were injected into intradermal MTG-B flank tumors on female C3H/HEJ mice and into HT-29 flank tumors on female Nu/Nu mice. The IONPs were allowed to incubate for various times. The tumors were then excised and examined using TEM. RESULTS: In the MTG-B tumors, most of the nanoparticles reside in aggregates adjacent to cell plasma membranes prior to three hours post-injection. By four hours post injection, however, most of the nanoparticles have been endocytosed by the cells. At time periods after four hours post injection, few visible extracellular nanoparticles remain and intracellular nanoparticles have densely aggregated within endosomes. In the HT-29 tumor, however, endocytosis of nanoparticles has not progressed to the same extent as in the MTG-B tumors by four hours post injection. CONCLUSIONS: The time at which most of the nanoparticles transition from being extracellular to intracellular in the MTG-B system appears to be between two and four hours. The HT-29 cells, however, display different and delayed uptake pattern. These data show that there are IONP uptake differences between tumor types (cell lines) and that, based on known uptake kinetics, nanoparticle hyperthermia can be employed as an extracellular or intracellular modality. These data will be important in guiding future nanoparticle hyperthermia cancer treatments.

Proceedings Article | 12 February 2009 Paper

Comparison of iron oxide nanoparticle and waterbath hyperthermia cytotoxicity

J. Ogden, J. Tate, R. Strawbridge, R. Ivkov, P. Hoopes

Proceedings Volume 7181, 71810K (2009) https://doi.org/10.1117/12.809818

KEYWORDS: Particles, Magnetism, Transmission electron microscopy, Cancer, Iron, Oxides, Nanoparticles, Cell death, Tissues, Temperature metrology

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Proceedings Article | 22 February 2007 Paper

Development of antibody directed nanoparticles for cancer therapy

R. Ivkov, S. DeNardo, L. Meirs, A. Natarajan, G. DeNardo, C. Gruettner, A. Foreman

Proceedings Volume 6440, 64400I (2007) https://doi.org/10.1117/12.710712

KEYWORDS: Tumors, Cancer, Nanoparticles, Tissues, Magnetism, Iron, Particles, Oxides, Magnesium, Blood

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The pharmacokinetics, tumor uptake, and biologic effects of inductively heating 111In-chimeric L6 (ChL6) monoclonal antibody (mAb)-linked iron oxide nanoparticle (bioprobes) by externally applied alternating magnetic fields (AMF) were studied in athymic mice bearing human breast cancer HBT 3477 xenografts. In addition, response was correlated with calculated total deposited heat dose. Methods: Using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl, 111In-7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid-ChL6 was conjugated to the carboxylated polyethylene glycol on dextran-coated iron oxide 20-nm particles, one to two mAbs per nanoparticle. After magnetic purification and sterile filtration, pharmacokinetics, histopathology, and AMF/bioprobe therapy were done using 111In-ChL6 bioprobe doses (20 mcg/2.2 mg ChL6/ bioprobe), i.v. with 50 mcg ChL6 in athymic mice bearing HBT 3477; a 153 kHz AMF was given 72 hours postinjection for therapy with amplitudes of 1,300, 1,000, or 700 Oe. Weights, blood counts, and tumor size were monitored and compared with control mice receiving nothing, or AMF, or bioprobes alone. Results: 111In-ChL6 bioprobe binding in vitro to HBT 3477 cells was 50% to 70% of that of 111In-ChL6. At 48 hours, tumor, lung, kidney, and marrow uptakes of the 111In-ChL6 bioprobes were not different from that observed in prior studies of 111In-ChL6. Significant therapeutic responses from AMF/bioprobe therapy were shown compared with no treatment. In addition, greatest therapeutic benefit was observed for the 700 Oe treatment cohort. Toxicity was only seen in the 1,300 Oe AMF cohort, with 4 of 12 immediate deaths associated with skin erythema and petechiae. Conclusion: This study shows that mAb-conjugated nanoparticles (bioprobes), when given i.v., escape into the extravascular space and bind to cancer cell membrane antigen.Thus, bioprobes can be used in concert with externally applied AMF to deliver thermoablative cancer therapy. Therapeutic benefit was observed with increasing calculated heat dose deposited in tumors.

Proceedings Article | 13 February 2007 Paper

Intratumoral iron oxide nanoparticle hyperthermia and radiation cancer treatment

P. J. Hoopes, R. Strawbridge, U. Gibson, Q. Zeng, Z. Pierce, M. Savellano, J. Tate, J. Ogden, I. Baker, R. Ivkov, A. Foreman

Proceedings Volume 6440, 64400K (2007) https://doi.org/10.1117/12.706302

KEYWORDS: Tumors, Nanoparticles, Iron, Oxides, Particles, Cancer, Oncology, Tissues, Temperature metrology, Breast cancer

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The potential synergism and benefit of combined hyperthermia and radiation for cancer treatment is well established, but has yet to be optimized clinically. Specifically, the delivery of heat via external arrays /applicators or interstitial antennas has not demonstrated the spatial precision or specificity necessary to achieve appropriate a highly positive therapeutic ratio. Recently, antibody directed and possibly even non-antibody directed iron oxide nanoparticle hyperthermia has shown significant promise as a tumor treatment modality. Our studies are designed to determine the effects (safety and efficacy) of iron oxide nanoparticle hyperthermia and external beam radiation in a murine breast cancer model. Methods: MTG-B murine breast cancer cells (1 x 106) were implanted subcutaneous in 7 week-old female C3H/HeJ mice and grown to a treatment size of 150 mm3 +/- 50 mm3. Tumors were then injected locally with iron oxide nanoparticles and heated via an alternating magnetic field (AMF) generator operated at approximately 160 kHz and 400 - 550 Oe. Tumor growth was monitored daily using standard 3-D caliper measurement technique and formula. specific Mouse tumors were heated using a cooled, 36 mm diameter square copper tube induction coil which provided optimal heating in a 1 cm wide region in the center of the coil. Double dextran coated 80 nm iron oxide nanoparticles (Triton Biosystems) were used in all studies. Intra-tumor, peri-tumor and rectal (core body) temperatures were continually measured throughout the treatment period. Results: Preliminary in vivo nanoparticle-AMF hyperthermia (167 KHz and 400 or 550 Oe) studies demonstrated dose responsive cytotoxicity which enhanced the effects of external beam radiation. AMF associated eddy currents resulted in nonspecific temperature increases in exposed tissues which did not contain nanoparticles, however these effects were minor and not injurious to the mice. These studies also suggest that iron oxide nanoparticle hyperthermia is more effective than non-nanoparticle tumor heating techniques when similar thermal doses are applied. Initial electron and light microscopy studies of iron oxide nanoparticle and AMF exposed tumor cells show a rapid uptake of particles and acute cytotoxicity following AMF exposure.

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