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1.  Comparison of iron oxide nanoparticle and microwave hyperthermia alone or combined with cisplatinum in murine breast tumors 
Proceedings of SPIE  2011;7901:10.1117/12.876535.
Surgery, radiation and chemotherapy are currently the most commonly used cancer therapies. Hyperthermia has been shown to work effectively with radiation and chemotherapy cancer treatments. The major obstacle faced by previous hyperthermia techniques has been the inability to deliver heat to the tumor in a precise manner. The ability to deliver cytotoxic hyperthermia to tumors (from within individual cells) via iron oxide magnetic nanoparticles (mNP) is a promising new technology that has the ability to greatly improve the therapeutic ratio of hyperthermia as an individual modality and as an adjuvant therapy in combination with other modalities. Although the parameters have yet to be conclusively defined, preliminary data suggests mNP hyperthermia can achieve greater cytotoxicity (in vitro) than conventional water bath hyperthermia methods. At this time, our theory is that intracellular nanoparticle heating is more effective in achieving the combined effect than extracellular heating techniques.1 However, understanding the importance of mNP association and uptake is critical in understanding the potential novelty of the heating modality. Our preliminary data suggests that the mNP heating technique, which did not provide time for particle uptake by the cells, resulted in similar efficacy to microwave hyperthermia. mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses
Methods
One hour before nanoparticle hyperthermia, CDDP chemotherapy (5mg/kg of body mass) was delivered intraperitoneally (IP). Iron oxide nanoparticles, 7.5mg of iron per gram of tumor, were injected into MTGB flank tumors in female C3H mice immediately before activation. A 170 KHz, 400-450 Oe alternating magnetic field (AMF) was used to induce particle heating. A comparison of nanoparticle induced hyperthermia to non-nanoparticle induced hyperthermia was also made using a 915 MHz microwave generator. Treatment duration was determined by the use of the cumulative equivalent minutes (CEM) algorithm. A CEM 60 was selected as the thermal dose for all experimental groups.
Results
1) Preliminary mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses.
2) mNP hyperthermia delivered 10 minutes post mNP injection and microwave hyperthermia, with the same thermal dose, demonstrate similar treatment efficacy.
doi:10.1117/12.876535
PMCID: PMC3877302  PMID: 24386533
Iron oxide; nanoparticle; hyperthermia; microwave; AMF; chemotherapy; cisplatinum; MTGB
2.  Nanoparticle based cancer treatment: can delivered dose and biological dose be reliably modeled and quantified? 
Proceedings of SPIE  2011;7901:10.1117/12.877026.
Essential developments in the reliable and effective use of heat in medicine include: 1) the ability to model energy deposition and the resulting thermal distribution and tissue damage (Arrhenius models) over time in 3D, 2) the development of non-invasive thermometry and imaging for tissue damage monitoring, and 3) the development of clinically relevant algorithms for accurate prediction of the biological effect resulting from a delivered thermal dose in mammalian cells, tissues, and organs. The accuracy and usefulness of this information varies with the type of thermal treatment, sensitivity and accuracy of tissue assessment, and volume, shape, and heterogeneity of the tumor target and normal tissue. That said, without the development of an algorithm that has allowed the comparison and prediction of the effects of hyperthermia in a wide variety of tumor and normal tissues and settings (cumulative equivalent minutes/ CEM), hyperthermia would never have achieved clinical relevance. A new hyperthermia technology, magnetic nanoparticle-based hyperthermia (mNPH), has distinct advantages over the previous techniques: the ability to target the heat to individual cancer cells (with a nontoxic nanoparticle), and to excite the nanoparticles noninvasively with a non-injurious magnetic field, thus sparing associated normal cells and greatly improving the therapeutic ratio. As such, this modality has great potential as a primary and adjuvant cancer therapy. Although the targeted and safe nature of the noninvasive external activation (hysteretic heating) are a tremendous asset, the large number of therapy based variables and the lack of an accurate and useful method for predicting, assessing and quantifying mNP dose and treatment effect is a major obstacle to moving the technology into routine clinical practice. Among other parameters, mNPH will require the accurate determination of specific nanoparticle heating capability, the total nanoparticle content and biodistribution in the target cells/tissue, and an effective and matching alternating magnetic field (AMF) for optimal and safe excitation of the nanoparticles. Our initial studies have shown that appropriately delivered and targeted nanoparticles are capable of achieving effective tumor cytotoxicity at measured thermal doses significantly less than the understood thermal dose values necessary to achieve equivalent treatment effects using conventional heat delivery techniques. Therefore conventional CEM based thermal dose - tissues effect relationships will not hold for mNPH. The goal of this effort is to provide a platform for determining the biological and physical parameters that will be necessary for accurately planning and performing safe and effective mNPH, creating a new, viable primary or adjuvant cancer therapy.
doi:10.1117/12.877026
PMCID: PMC3877314  PMID: 24392199
Iron oxide; nanoparticle; hyperthermia; dosimetry; treatment plan; CEM; thermal therapy; thermal dose; tissue assessment
3.  Phagocytes mediate targeting of iron oxide nanoparticles to tumors for cancer therapy 
Nanotechnology has great potential to produce novel therapeutic strategies that target malignant cells through the ability of nanoparticles to get access to and be ingested by living cells. However its specificity for accumulation in tumors, which is the key factor that determines its efficacy, has always been a challenge. Here we tested a novel strategy to target and treat ovarian cancer, a representative peritoneal cancer, using iron oxide nanoparticles (IONPs) and an alternating magnetic field (AMF). Peritoneal tumors in general are directly accessible to nanoparticles administered intraperitoneally (IP), as opposed to the more commonly attempted intravenous (IV) administration. In addition, tumor-associated immunosuppressive phagocytes, a predominant cell population in the tumor microenvironment of almost all solid tumors, and cells that are critical for tumor progression, are constantly recruited to the tumor, and therefore could possibly function to bring nanoparticles to tumors. Here we demonstrate that tumor-associated peritoneal phagocytes ingest and carry IONPs specifically to tumors and that these specifically delivered nanoparticles can damage tumor cells after IONP-mediated hyperthermia generated by AMF. This illustrates therapeutic possibilities of intraperitoneal (IP) injection of nanoparticles and subsequent ingestion by tumor-associated phagocytes, to directly impact tumors or stimulate antitumor immune responses. This approach could use IONPs combined with AMF as done here, or other nanoparticles with cytotoxic potential. Overall, the data presented here support IP injection of nanoparticles to utilize peritoneal phagocytes as a delivery vehicle in association with IONP-mediated hyperthermia as therapeutic strategies for ovarian and other peritoneal cancers.
doi:10.1039/c2ib20180a
PMCID: PMC3524361  PMID: 22935885
nanotechnology; ovarian cancer; peritoneal cancer; peritoneal cavity; intraperitoneal injection; intravenous injection; tumor-associated phagocytes; iron oxide nanoparticles; hyperthermia; alternating magnetic field; cytotoxic; immunosuppressive; immunostimulatory
4.  Intratumoral Iron Oxide Nanoparticle Hyperthermia and Radiation Cancer Treatment 
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 × 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 nonnanoparticle 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.
doi:10.1117/12.706302
PMCID: PMC4187389  PMID: 25301985
5.  High Therapeutic Efficiency of Magnetic Hyperthermia in Xenograft Models Achieved with Moderate Temperature Dosages in the Tumor Area 
Pharmaceutical Research  2014;31(12):3274-3288.
ABSTRACT
Purpose
Tumor cells can be effectively inactivated by heating mediated by magnetic nanoparticles. However, optimized nanomaterials to supply thermal stress inside the tumor remain to be identified. The present study investigates the therapeutic effects of magnetic hyperthermia induced by superparamagnetic iron oxide nanoparticles on breast (MDA-MB-231) and pancreatic cancer (BxPC-3) xenografts in mice in vivo.
Methods
Superparamagnetic iron oxide nanoparticles, synthesized either via an aqueous (MF66; average core size 12 nm) or an organic route (OD15; average core size 15 nm) are analyzed in terms of their specific absorption rate (SAR), cell uptake and their effectivity in in vivo hyperthermia treatment.
Results
Exceptionally high SAR values ranging from 658 ± 53 W*gFe−1 for OD15 up to 900 ± 22 W*gFe−1 for MF66 were determined in an alternating magnetic field (AMF, H = 15.4 kA*m−1 (19 mT), f = 435 kHz). Conversion of SAR values into system-independent intrinsic loss power (ILP, 6.4 ± 0.5 nH*m2*kg−1 (OD15) and 8.7 ± 0.2 nH*m2*kg−1 (MF66)) confirmed the markedly high heating potential compared to recently published data. Magnetic hyperthermia after intratumoral nanoparticle injection results in dramatically reduced tumor volume in both cancer models, although the applied temperature dosages measured as CEM43T90 (cumulative equivalent minutes at 43°C) are only between 1 and 24 min. Histological analysis of magnetic hyperthermia treated tumor tissue exhibit alterations in cell viability (apoptosis and necrosis) and show a decreased cell proliferation.
Conclusions
Concluding, the studied magnetic nanoparticles lead to extensive cell death in human tumor xenografts and are considered suitable platforms for future hyperthermic studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11095-014-1417-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s11095-014-1417-0
PMCID: PMC4224751  PMID: 24890197
CEM43T90; in vivo; iron oxide nanoparticles; magnetic hyperthermia; temperature dose
6.  Design and Application of Magnetic-based Theranostic Nanoparticle Systems 
Recently, magnetic-based theranostic nanoparticle (MBTN) systems have been studied, researched, and applied extensively to detect and treat various diseases including cancer. Theranostic nanoparticles are advantageous in that the diagnosis and treatment of a disease can be performed in a single setting using combinational strategies of targeting, imaging, and/or therapy. Of these theranostic strategies, magnetic-based systems containing magnetic nanoparticles (MNPs) have gained popularity because of their unique ability to be used in magnetic resonance imaging, magnetic targeting, hyperthermia, and controlled drug release. To increase their effectiveness, MNPs have been decorated with a wide variety of materials to improve their biocompatibility, carry therapeutic payloads, encapsulate/bind imaging agents, and provide functional groups for conjugation of biomolecules that provide receptor-mediated targeting of the disease. This review summarizes recent patents involving various polymer coatings, imaging agents, therapeutic agents, targeting mechanisms, and applications along with the major requirements and challenges faced in using MBTN for disease management.
doi:10.2174/1874764711306010007
PMCID: PMC3686518  PMID: 23795343
magnetic nanoparticles; polymeric shell; imaging agents; theranostics; therapeutic agents; hyperthermia
7.  Iron Oxide Hyperthermia And Radiation Cancer Treatment 
It is established that heat can enhance the effect of radiation cancer treatment. Due to the ability to localize thermal energy using nanoparticle hyperthermia, as opposed to other, less targeted, hyperthermia modalities, it appears such enhancement could be accomplished without complications normally associated with systemic or regional hyperthermia. This study employs non-curative (suboptimal), doses of heat and radiation, in an effort to determine the therapeutic enhancement potential for IONP hyperthermia and radiation.
Methods
MTG-B murine breast adenocarcinoma cell are inoculated into the right flanks of female CH3/HEJ mice and grown to volumes of 150mm3 +/− 40 mm3. A single dose of 15 Gy (6 MeV) radiation was uniformly delivered to the tumor. A pre-defined thermal dose is delivered by direct injection of iron oxide nanoparticles into the tumor. By adjusting the field strength of the 160 KHz alternating magnetic field (AMF) an intra-tumoral temperature between 41.5 and 43 degrees Celsius was maintained for 10min. The alternating magnetic field was delivered by a water-cooled 36mm diameter square copper tube induction coil operating at 160 kHz with variable magnet field strengths up to 450 Oe. The primary endpoint of the study is the number of days required for the tumor to achieve a volume 3 fold greater than the volume at the time of treatment (tumor regrowth delay).
Results
Preliminary results suggest the addition of a modest IONP hyperthermia to 15 Gy radiation achieved an approximate 50% increase in tumor regrowth delay as compared to a 15 Gy radiation treatment alone. The therapeutic effects of IONP heat and radiation combined were considered additive, however in mice that demonstrated complete response (no tumor present after 30 days), the effect was considered superadditive or synergistic. Although this data is very encouraging from a multimodality cancer therapy standpoint, additional temporal and dose related information is clearly necessary to optimize the therapy.
doi:10.1117/12.810035
PMCID: PMC4208073  PMID: 25346582
Iron oxide; nanoparticle; AMF; adenocarcinoma; transmission electron microscopy; TEM; murine; MTG-B; HT-29
8.  An in vivo transmission electron microscopy study of injected dextran-coated iron-oxide nanoparticle location in murine breast adenocarcinoma tumors versus time 
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.
doi:10.1117/12.809868
PMCID: PMC4187245  PMID: 25301988
Iron oxide nanoparticle; hyperthermia; tumor; cancer; transmission electron microscopy; IONP; MTG-B; HT-29
9.  Local hyperthermia for esophageal cancer in a rabbit tumor model: Magnetic stent hyperthermia versus magnetic fluid hyperthermia 
Oncology Letters  2013;6(6):1550-1558.
Magnetic-mediated hyperthermia (MMH) is a promising local thermotherapy approach for cancer treatment. The present study investigated the feasibility and effectiveness of MMH in esophageal cancer using a rabbit tumor model. The therapeutic effect of two hyperthermia approaches, magnetic stent hyperthermia (MSH), in which heat is induced by the clinical stent that is placed inside the esophagus, and magnetic fluid hyperthermia (MFH), where magnetic nanoparticles are applied as the agent, was systematically evaluated. A rabbit esophageal tumor model was established by injecting VX2 carcinoma cells into the esophageal submucosa. The esophageal stent was deployed perorally into the tumor segment of the esophagus. For the MFH, magnetic nanoparticles (MNPs) were administered to the rabbits by intratumoral injection. The rabbits were exposed under a benchtop applicator using an alternative magnetic field (AMF) with 300 kHz frequency for the hyperthermia treatment. The results demonstrated that esophageal stents and MNPs had ideal inductive heating properties upon exposure under an AMF of 300 kHz. MSH, using a thermal dose of 46°C with a 10-min treatment time, demonstrated antitumor effects on the rabbit esophageal cancer. However, the rabbit esophageal wall is not heat-resistant. Therefore, a higher temperature or longer treatment time may lead to necrosis of the rabbit esophagus. MFH has a significant antitumor effect by confining the heat within the tumor site without damaging the adjacent normal tissues. The present study indicates that the two hyperthermia procedures have therapeutic effects on esophageal cancer, and that MFH may be more specific than MSH in terms of temperature control during the treatment.
doi:10.3892/ol.2013.1618
PMCID: PMC3833863  PMID: 24260045
magnetic mediated hyperthermia; esophageal cancer; magnetic nanoparticles; esophageal stent; alternative magnetic field
10.  Nanotechnologies for Noninvasive Measurement of Drug Release 
Molecular pharmaceutics  2013;11(1):24-39.
A wide variety of chemotherapy and radiotherapy agents are available for treating cancer, but a critical challenge is to deliver these agents locally to cancer cells and tumors while minimizing side effects from systemic delivery. Nanomedicine uses nanoparticles with diameters in the range of ~1–100 nm to encapsulate drugs and target them to tumors. The nanoparticle enhances local drug delivery effciency to the tumors via entrapment in leaky tumor vasculature, molecular targeting to cells expressing cancer biomarkers, and/or magnetic targeting. In addition, the localization can be enhanced using triggered release in tumors via chemical, thermal, or optical signals. In order to optimize these nanoparticle drug delivery strategies, it is important to be able to image where the nanoparticles distribute and how rapidly they release their drug payloads. This Review aims to evaluate the current state of nanotechnology platforms for cancer theranostics (therapeutic and diagnostic particles) that are capable of noninvasive measurement of release kinetics.
doi:10.1021/mp400419k
PMCID: PMC4050079  PMID: 24215280
theranostic nanomedicine; quantitative drug delivery; imaging delivery; cancer
11.  Comparison of microwave and magnetic nanoparticle hyperthermia radiosensitization in murine breast tumors 
Proceedings of SPIE  2011;7901:10.1117/12.876515.
Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and an appropriately matched noninvasive alternating magnetic field (AMF). To explore the tumor radiosensitization potential of mNP hyperthermia we used a syngeneic mouse breast cancer model, dextran-coated 110 nm hydrodynamic diameter mNP and a 169 kHz / 450 Oe (35.8 kA/m) AMF. Intradermally implanted (flank) tumors (150 ± 40 mm3) were treated by injection of 0.04 ml mNP (7.5 mg Fe) / cm3 into the tumor and an AMF (35.8 kA/m and 169 kHz) exposure necessary to achieve a CEM (cumulative equivalent minute) thermal dose of 60 (CEM 60). Tumors were treated with mNP hyperthermia (CEM 60), radiation alone (15 Gy, single dose) and in combination. Compared to the radiation and heat alone treatments, the combined treatment resulted in a greater than two-fold increase in tumor regrowth tripling time (tumor treatment efficacy). None of the treatments resulted in significant normal tissue toxicity or morbidity. Studies were also conducted to compare the radiosensitization effect of mNP hyperthermia with that of microwave-induced hyperthermia. The effects of incubation of nanoparticles within tumors (to allow nanoparticles to be endocytosed) before application of AMF and radiation were determined. This preliminary information suggests cancer cell specific hyperthermia (i.e. antibody-directed or anatomically-directed mNP) is capable of providing significantly greater radiosensitization / therapeutic ratio enhancement than other forms of hyperthermia delivery.
doi:10.1117/12.876515
PMCID: PMC3877316  PMID: 24392200
Hyperthermia; radiation; nanoparticle; microwave; AMF; radiosensitization; intracellular hyperthermia
12.  Hyperthermic potentiation of cisplatin by magnetic nanoparticle heaters is correlated with an increase in cell membrane fluidity 
Magnetic fluid hyperthermia as a cancer treatment method is an attractive alternative to other forms of hyperthermia. It is based on the heat released by magnetic nanoparticles subjected to an alternating magnetic field. Recent studies have shown that magnetic fluid hyperthermia-treated cells respond significantly better to chemotherapeutic treatment compared with cells treated with hot water hyperthermia under the same temperature conditions. We hypothesized that this synergistic effect is due to an additional stress on the cellular membrane, independent of the thermal heat dose effect that is induced by nanoparticles exposed to an alternating magnetic field. This would result in an increase in Cis-diammine-dichloroplatinum (II) (cDDP, cisplatin) uptake via passive transport. To test this hypothesis, we exposed cDDP-treated cells to extracellular copper in order to hinder the human cell copper transporter (hCTR1)-mediated active transport of cDDP. This, in turn, can increase the passive transport of the drug through the cell membrane. Our results did not show statistically significant differences in surviving fractions for cells treated concomitantly with magnetic fluid hyperthermia and cDDP, in the presence or absence of copper. Nonetheless, significant copper-dependent variations in cell survival were observed for samples treated with combined cDDP and hot water hyperthermia. These results correlated with platinum uptake studies, which showed that cells treated with magnetic fluid hyperthermia had higher platinum uptake than cells treated with hot water hyperthermia. Changes in membrane fluidity were tested through fluorescence anisotropy measurements using trimethylamine-diphenylhexatriene. Additional uptake studies were conducted with acridine orange and measured by flow cytometry. These studies indicated that magnetic fluid hyperthermia significantly increases cell membrane fluidity relative to hot water hyperthermia and untreated cells, and hence this could be a factor contributing to the increase of cDDP uptake in magnetic fluid hyperthermia-treated cells. Overall, our data provide convincing evidence that cell membrane permeability induced by magnetic fluid hyperthermia is significantly greater than that induced by hot water hyperthermia under similar temperature conditions, and is at least one of the mechanisms responsible for potentiation of cDDP by magnetic fluid hyperthermia in Caco-2 cells.
doi:10.2147/IJN.S38842
PMCID: PMC3593770  PMID: 23493492
magnetic nanoparticles; synergistic effect; hot water hyperthermia; surviving fraction; viability ratio
13.  Nanotechnology 
Executive Summary
Objective
Due to continuing advances in the development of structures, devices, and systems with a length of about 1 to 100 nanometres (nm) (1 nm is one billionth of a metre), the Medical Advisory Secretariat conducted a horizon scanning appraisal of nanotechnologies as new and emerging technologies, including an assessment of the possibly disruptive impact of future nanotechnologies.
The National Cancer Institute (NCI) in the United States proclaimed a 2015 challenge goal of eliminating suffering and death from cancer. To help meet this goal, the NCI is engaged in a concerted effort to introduce nanotechnology “to radically change the way we diagnose, treat and prevent cancer.” It is the NCI’s position that “melding nanotechnology and cancer research and development efforts will have a profound, disruptive effect on how we diagnose, treat, and prevent cancer.”
Thus, this appraisal sought to determine the systemic effects of nanotechnologies that target, image and deliver drugs, for example, with respect to health human resources, training, and new specialties; and to assess the current status of these nanotechnologies and their projected timeline to clinical utilization.
Clinical Need: Target Population and Condition
Cancer is a heterogeneous set of many malignant diseases. In each sex, 3 sites account for over one-half of all cancers. In women, these are the breast (28%), colorectum (13%) and lungs (12%). In men, these are the prostate (28%), lungs (15%), and the colorectum (13%).
It is estimated that 246,000 people in Ontario (2% of the population) have been diagnosed with cancer within the past 10 years and are still alive. Most were diagnosed with cancer of the breast (21%), prostate (20%), or colon or rectum (13%).
The number of new cancer cases diagnosed each year in Ontario is expected to increase from about 53,000 in 2001 to 80,000 in 2015. This represents more than a 50% increase in new cases over this period. An aging population, population growth, and rising cancer risk are thought to be the main factors that will contribute to the projected increase in the number of new cases.
The Technology Being Reviewed - Medical Advisory Secretariat Definition of Nanotechnology
First-Generation Nanotechnologies
Early application of nanotechnology-enabled products involved drug reformulation to deliver some otherwise toxic drugs (e.g., antifungal and anticancer agents) in a safer and more effective manner.
Examples of first-generation nanodevices include the following:
liposomes;
albumin bound nanoparticles;
gadolinium chelate for magnetic resonance imaging (MRI);
iron oxide particles for MRI;
silver nanoparticles (antibacterial wound dressing); and
nanoparticulate dental restoratives.
First-generation nanodevices have been in use for several years; therefore, they are not the focus of this report.
Second-Generation Nanotechnologies
Second-generation nanotechnologies are more sophisticated than first- generation nanotechnologies, due to novel molecular engineering that enables the devices to target, image, deliver a therapeutic agent, and monitor therapeutic efficacy in real time. Details and examples of second-generation nanodevices are discussed in the following sections of this report.
Review Strategy
The questions asked were as follows:
What is the status of these multifunctional nanotechnologies? That is, what is the projected timeline to clinical utilization?
What are the systemic effects of multifunctional nanodevices with integrated applications that target, image, and deliver drugs? That is, what are the implications of the emergence of nanotechnology on health human resources training, new specialties, etc.?
The Medical Advisory Secretariat used its usual search techniques to conduct the literature review by searching relevant databases. Outcomes of interest were improved imaging, improved sensitivity or specificity, improved response rates to therapeutic agents, and decreased toxicity.
Results
The search yielded 1 health technology assessment on nanotechnology by The Centre for Technology Assessment TA-Swiss and, in the grey literature, a technology review by RAND. These, in addition to data from the National Cancer Institute (United States) formed the basis for the conclusions of the review.
With respect to the question as to how soon until nanotechnology is used in patient care, overall, the use of second-generation nanodevices, (e.g., quantum dots [QDs]), nanoshells, dendrimers) that can potentially target, image, and deliver drugs; and image cell response to therapy in real time are still in the preclinical benchwork stage.
Table 1 summarizes the projected timelines to clinical utilization.
Summary of Timelines to Clinical Use*
NCI refers to National Cancer Institute; QD, quantum dot.
Medical Advisory Secretariat Estimated Timeline for Ontario
Upon synthesizing the estimated timelines from the NCI, the Swiss technology assessment and the RAND reports (Figure 1), it appears that:
the clinical use of separate imaging and therapeutic nanodevices is estimated to start occurring around 2010;
the clinical use of combined imaging and therapeutic nanodevices is estimated to start occurring around 2020;
changes in the way disease is diagnosed, treated and monitored are anticipated; and
the full (and realistic) extent of these changes within the next 10 to 20 years is uncertain.
Medical Advisory Secretariat Estimated Timeline for the Clinical Use of Second-Generation Nanodevices in Ontario
With respect to the question on potential systemic effects of second-generation nanodevices (i.e., the implications of the emergence of these nanodevices on health human resources training, new specialties etc.), Table 2 summarizes the findings from the review.
Potential Systemic Effects Caused by Second Generation Nanodevices*
MRI indicates magnetic resonance imaging; PSA, prostate-specific antigen; QD, quantum dot.
Uncertainties Not Addressed in the Literature
The United States National Nanotechnology Initiative (NNI) funds a variety of research in the economic, ethical, legal, and cultural implications of the use of nanotechnology, as well as the implications for science, education and quality of life.
There are many uncertainties that are sparsely or not addressed at all in the literature regarding second generation nanodevices. These include the following:
long-term stability and toxicology of nanodevices;
cost-effectiveness of nanodevices;
refinement of specific targeting;
effects on hospitals, physician/nurse training, creation/removal of specialties; and
that pertaining to the question, where does disease begin if therapy is applied before the symptoms have appeared?
PMCID: PMC3379172  PMID: 23074489
14.  Surface engineering of iron oxide nanoparticles for targeted cancer therapy 
Accounts of chemical research  2011;44(10):853-862.
Conspectus
Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired biological response. Of the nanomaterials studied, iron oxide nanoparticles have emerged as one of top candidates for cancer therapy due to their intrinsic superparamagnetism that enables no-invasive magnetic resonance imaging (MRI) and biodegradability favorable for in vivo application. A therapeutic superparamagnetic iron oxide nanoparticle (SPION) typically consists of three primary components: an iron oxide nanoparticle core that serves as both a carrier for therapeutics and contrast agent for MRI, a coating on the iron oxide nanoparticle that promotes favorable interactions between the SPION and biological system, and a therapeutic payload that performs designated function in vivo. Often, a targeting ligand is also included in the design that recognizes the receptors over-expressed on cancer cells. The body is a highly complex system that imposes multiple physiological and cellular barriers to foreign objects. Thus, the success of a therapeutic SPION largely relies on the proper design of the iron oxide core to ensure MRI detectability and more critically, the coating to render the ability to bypass these barriers.
Strategies to bypass the physiological barriers such as liver, kidneys, and spleen, involve tuning the overall size and surface chemistry of the SPION to maximize blood half-life and facilitate the navigation in the body. Strategies to bypass cellular barriers include the use of targeting agents to maximize uptake of the SPION by cancer cells, and employing materials that promote desired intracellular trafficking and enable controlled drug release.
The payload can be genes, proteins, chemotherapy drugs, or a combination of them. Each therapeutic requires a specific coating design to maximize the loading and achieve effective delivery and release. In this Account, we discuss the primary design parameters in developing therapeutic SPIONs with a focus on surface coating design to overcome the barriers imposed by the body’s defense system and provide examples of how these design parameters have been implemented to produce therapeutic SPIONs for specific therapeutic applications.
Although there are still challenges to be addressed, SPIONs show great promise in successful diagnosis and treatment of the most devastating cancers. Once critical design parameters have been optimized, these nanoparticles, combined with imaging modalities, can serve as a truly multi-functional theranostic agent that not only performs a therapeutic function, but provides instant treatment feedback for the physician to adjust the treatment plan.
doi:10.1021/ar2000277
PMCID: PMC3192288  PMID: 21528865
15.  Theranostic applications of nanomaterials in cancer: Drug delivery, image-guided therapy and multifunctional platforms 
Applied biochemistry and biotechnology  2011;165(7-8):1628-1651.
Successful cancer management depends on accurate diagnostics along with specific treatment protocols. Current diagnostic techniques need to be improved to provide earlier detection capabilities, and traditional chemotherapy approaches to cancer treatment are limited by lack of specificity and systemic toxicity. This review highlights advances in nanotechnology that have allowed the development of multifunctional platforms for cancer detection, therapy, and monitoring. Nanomaterials can be used as MRI, optical imaging, and photoacoustic imaging contrast agents. When used as drug carriers, nanoformulations can increase tumor exposure to therapeutic agents and result in improved treatment effects by prolonging circulation times, protecting entrapped drugs from degradation, and enhancing tumor uptake through the EPR effect as well as receptor-mediated endocytosis. Multiple therapeutic agents such as chemotherapy, antiangiogenic, or gene therapy agents can be simultaneously delivered by nanocarriers to tumor sites to enhance the effectiveness of therapy. Additionally, imaging and therapy agents can be co-delivered to provide seamless integration of diagnostics, therapy and follow-up, and different therapeutic modalities such as chemotherapy and hyperthermia can be coadministered to take advantage of synergistic effects. Liposomes, metallic nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes, and quantum dots are examples of nanoformulations that can be used as multifunctional platforms for cancer theranostics. Nanomedicine approaches in cancer have great potential for clinically translatable advances that can positively impact the overall diagnostic and therapeutic process, and result in enhanced quality of life for cancer patients. However, a concerted scientific effort is still necessary to fully explore long-term risks, effects, and precautions for safe human use.
doi:10.1007/s12010-011-9383-z
PMCID: PMC3239222  PMID: 21947761
nanocarriers; multifunctional nanoparticles; theranostics; cancer; nanomaterials; image-guided therapy
16.  Biodegradable magnesium nanoparticle-enhanced laser hyperthermia therapy 
Background
Recently, nanoparticles have been demonstrated to have tremendous merit in terms of improving the treatment specificity and thermal ablation effect on tumors. However, the potential toxicity and long-term side effects caused by the introduced nanoparticles and by expelling them out of the body following surgery remain a significant challenge. Here, we propose for the first time to directly adopt magnesium nanoparticles as the heating enhancer in laser thermal ablation to avoid these problems by making full use of the perfect biodegradable properties of this specific material.
Methods
To better understand the new nano “green” hyperthermia modality, we evaluated the effects of magnesium nanoparticles on the temperature transients inside the human body subject to laser interstitial heating. Further, we experimentally investigated the heating enhancement effects of magnesium nanoparticles on a group of biological samples: oil, egg white, egg yolk, in vitro pig tissues, and the in vivo hind leg of rabbit when subjected to laser irradiation.
Results
Both the theoretical simulations and experimental measurements demonstrated that the target tissues injected with magnesium nanoparticles reached much higher temperatures than tissues without magnesium nanoparticles. This revealed the enhancing behavior of the new nanohyperthermia method.
Conclusion
Given the unique features of magnesium nanoparticles – their complete biological safety and ability to enhance heating – which most other advanced metal nanoparticles do not possess, the use of magnesium nanoparticles in hyperthermia therapy offers an important “green” nanomedicine modality for treating tumors. This method has the potential to be used in clinics in the near future.
doi:10.2147/IJN.S34902
PMCID: PMC3431971  PMID: 22956872
laser thermal therapy; heating enhancer; biodegradability; nanohyperthermia; bioheat transfer
17.  Multifunctional polymeric nanoparticles doubly loaded with SPION and ceftiofur retain their physical and biological properties 
Background
Advances in nanostructure materials are leading to novel strategies for drug delivery and targeting, contrast media for magnetic resonance imaging (MRI), agents for hyperthermia and nanocarriers. Superparamagnetic iron oxide nanoparticles (SPIONs) are useful for all of these applications, and in drug-release systems, SPIONs allow for the localization, direction and concentration of drugs, providing a broad range of therapeutic applications. In this work, we developed and characterized polymeric nanoparticles based on poly (3-hydroxybutyric acid-co-hydroxyvaleric acid) (PHBV) functionalized with SPIONs and/or the antibiotic ceftiofur. These nanoparticles can be used in multiple biomedical applications, and the hybrid SPION–ceftiofur nanoparticles (PHBV/SPION/CEF) can serve as a multifunctional platform for the diagnosis and treatment of cancer and its associated bacterial infections.
Results
Morphological examination using transmission electron microscopy (TEM) showed nanoparticles with a spherical shape and a core-shell structure. The particle size was evaluated using dynamic light scattering (DLS), which revealed a diameter of 243.0 ± 17 nm. The efficiency of encapsulation (45.5 ± 0.6% w/v) of these polymeric nanoparticles was high, and their components were evaluated using spectroscopy. UV–VIS, FTIR and DSC showed that all of the nanoparticles contained the desired components, and these compounds interacted to form a nanocomposite. Using the agar diffusion method and live/dead bacterial viability assays, we demonstrated that these nanoparticles have antimicrobial properties against Escherichia coli, and they retain their magnetic properties as measured using a vibrating sample magnetometer (VSM). Cytotoxicity was assessed in HepG2 cells using live/dead viability assays and MTS, and these assays showed low cytotoxicity with IC50 > 10 mg/mL nanoparticles.
Conclusions
Our results indicate that hybrid and multifunctional PHBV/SPION/CEF nanoparticles are suitable as a superparamagnetic drug delivery system that can guide, concentrate and site–specifically release drugs with antibacterial activity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12951-015-0077-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12951-015-0077-5
PMCID: PMC4334767
PHBV; SPION; Ceftiofur; Polymeric nanoparticles; Drug delivery; Superparamagnetic nanoparticles
18.  Stability of antibody-conjugated gold nanoparticles in the endo-lysosomal nanoenvironment: Implications for non-invasive radiofrequency-based cancer therapy 
The use of non-invasive radiofrequency (RF) electric fields as an energy source for thermal activation of nanoparticles within cancer cells could be a valuable addition to the emerging field of nano-mediated cancer therapies. Based on investigations of cell death through hyperthermia, and offering the ability for total body penetration by RF fields, this technique is thought to compliment and possibly out-perform existing nano-heat-treatments that utilize alternative heat production via optical or magnetic stimuli. However, it remains a challenge to understand fully the complex RF-nanoparticle-intracellular interactions before full system optimization can be engineered. Herein we have shown that liver cancer cells can selectively internalize antibody-conjugated gold nanoparticles (AuNPs) through receptor-mediated endocytosis, with the nanoparticles predominantly accumulating and aggregating within cytoplasmic endo-lysosomes. After exposure to an external RF field, non-aggregated AuNPs absorbed and dissipated energy as heat causing thermal damage to the targeted cancer cells. We also observed that RF absorption and heat dissipation is dependent on solubility of AuNPs in the colloid, which is pH dependent. Furthermore, by modulating endo-lysosomal pH it is possible to prevent intracellular AuNP aggregation and enhance thermal cytotoxicity in hepatocellular cancer cells.
doi:10.1016/j.nano.2012.02.001
PMCID: PMC3392470  PMID: 22349096
pH; radiofrequency; gold nanoparticles; lysosomotropics; hyperthermia; cancer
19.  Magnetic Fluid Hyperthermia for Bladder Cancer: A Preclinical Dosimetry Study 
Purpose
This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with Magnetic Fluid Hyperthermia (MFH), performed by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model.
Materials and Methods
The bladders of twenty-five female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42°C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fiberoptic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterization method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions.
Results
Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen ≥1°C/min to a steady-state of 42°C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder.
Conclusion
These data demonstrate that our MFH system with magnetite-based nanoparticles provide well-localized heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues.
doi:10.3109/02656736.2013.834384
PMCID: PMC4261618  PMID: 24050253
bladder cancer; hyperthermia; nanoparticle heating; iron oxide; thermal dosimetry
20.  Iron oxide nanoparticle hyperthermia and chemotherapy cancer treatment 
The benefit of combining hyperthermia and chemotherapy to treat cancer is well established. However, combined therapy has not yet achieved standard of care status. The reasons are numerous and varied, however the lack of significantly greater tumor cell sensitivity to heat (as compared to normal cells) and the inability to deliver heat to the tumor in a precise manner have been major factors. Iron oxide nanoparticle (IONP) hyperthermia, alone and combined with other modalities, offers a new direction in hyperthermia cancer therapy via improved tumor targeting and an improved therapeutic ratio. Our preliminary studies have demonstrated tumor cell cytotoxicity (in vitro and in vivo) with IONP heat and cisplatinum (CDDP) doses lower than those necessary when using conventional heating techniques or cisplatinum alone. Ongoing studies suggest such treatment could be further improved through the use of targeted nanoparticles.
Methods
In vivo: IONPs (5mg of iron per gram of tumor) were administered into MTG-B flank tumors in female C3H-HEJ mice directly after cisplatinum chemotherapy (0.1ml/kg of body mass) was intraperitoneally injected. An 160 KHz, 350–450 Oe AMF (alternating magnetic field) was used to induce particle heating.
In vitro: Mouse mammary adenocarcinoma cells (MTG-B) cells were grown and exposed to IONP hyperthermia and cisplatinum. IONPs not associated with cells were removed by washing prior to heat induction by an AMF field. Acute cell survival, via trypan blue assay, was used to quantify the level of cytotoxicity.
Results
In vitro studies, using IONP + cisplatinum, have demonstrated promising cytotoxicity enhancement. Ongoing studies are being pursued to further define the mechanism of action, temporal associations and pathophysiology of combined IONP hyperthermia and chemotherapy treatment. Preliminary in vivo IONP /cisplatinum studies have shown a tumor growth delay/volume reduction greater than either modality alone at comparable doses. Further enhancement of this treatment success appears to depend on a better understanding of IONP dose and tumor cell association, chemotherapy dose and administration technique, the spatial and temporal treatment relationship of the two modalities and optimal AMF - IONP coupling.
doi:10.1117/12.810024
PMCID: PMC4208066  PMID: 25346581
Iron oxide; nanoparticle; AMF; chemotherapy; cisplatinum; murine; MTG-B; HT-29
21.  Limitations of Adenoviral Vector-Mediated Delivery of Gold Nanoparticles to Tumors for Hyperthermia Induction 
The open nanomedicine journal  2009;2:10.2174/1875933500902010027.
Novel combinatorial treatment strategies are desired to achieve tumor eradication. In this regard, nanotechnology and gene therapy hold the potential to expand the available tumor treatment options. In particular, gold nanoparticles (AuNPs) have been utilized for hyperthermic tumor cell ablation. Similarly, adenoviral (Ad) vectors have been utilized for targeting, imaging, and cancer gene therapy. Thus, to combine AuNP-mediated hyperthermia with Ad vector-based gene therapy, we have previously coupled AuNPs to Ad vectors. Herein we tested the capability of these AuNP-coupled Ad vectors for hyperthermic tumor cell ablation. Towards this end, we compared absorption characteristics of different sized AuNPs and determined that in our system 20 nm diameter AuNPs are suitable for laser induced hyperthermic tumor cell killing. In addition, we observed that AuNPs outside and inside the cell contribute differentially towards hyperthermia induction. Unfortunately, due to the limitation of delivery of required amounts of AuNPs to cells, we observed that AuNP-coupled Ad vectors are unable to kill tumor cells via hyperthermia. However, with future technological advances, it may become possible to realize the potential of the multifunctional AuNP-coupled Ad vector system for simultaneous targeting, imaging, and combined hyperthermia and gene therapy of tumors.
doi:10.2174/1875933500902010027
PMCID: PMC3882004  PMID: 24403982
Gold nanoparticles; hyperthermia; tumor treatment; adenovirus
22.  Simulating Magnetic Nanoparticle Behavior in Low-field MRI under Transverse Rotating Fields and Imposed Fluid Flow 
In the presence of alternating-sinusoidal or rotating magnetic fields, magnetic nanoparticles will act to realign their magnetic moment with the applied magnetic field. The realignment is characterized by the nanoparticle’s time constant, τ. As the magnetic field frequency is increased, the nanoparticle’s magnetic moment lags the applied magnetic field at a constant angle for a given frequency, Ω, in rad/s. Associated with this misalignment is a power dissipation that increases the bulk magnetic fluid’s temperature which has been utilized as a method of magnetic nanoparticle hyperthermia, particularly suited for cancer in low-perfusion tissue (e.g., breast) where temperature increases of between 4°C and 7°C above the ambient in vivo temperature cause tumor hyperthermia. This work examines the rise in the magnetic fluid’s temperature in the MRI environment which is characterized by a large DC field, B0. Theoretical analysis and simulation is used to predict the effect of both alternating-sinusoidal and rotating magnetic fields transverse to B0. Results are presented for the expected temperature increase in small tumors (~1 cm radius) over an appropriate range of magnetic fluid concentrations (0.002 to 0.01 solid volume fraction) and nanoparticle radii (1 to 10 nm). The results indicate that significant heating can take place, even in low-field MRI systems where magnetic fluid saturation is not significant, with careful The goal of this work is to examine, by means of analysis and simulation, the concept of interactive fluid magnetization using the dynamic behavior of superparamagnetic iron oxide nanoparticle suspensions in the MRI environment. In addition to the usual magnetic fields associated with MRI, a rotating magnetic field is applied transverse to the main B0 field of the MRI. Additional or modified magnetic fields have been previously proposed for hyperthermia and targeted drug delivery within MRI. Analytical predictions and numerical simulations of the transverse rotating magnetic field in the presence of B0 are investigated to demonstrate the effect of Ω, the rotating field frequency, and the magnetic field amplitude on the fluid suspension magnetization. The transverse magnetization due to the rotating transverse field shows strong dependence on the characteristic time constant of the fluid suspension, τ. The analysis shows that as the rotating field frequency increases so that Ωτ approaches unity, the transverse fluid magnetization vector is significantly non-aligned with the applied rotating field and the magnetization’s magnitude is a strong function of the field frequency. In this frequency range, the fluid’s transverse magnetization is controlled by the applied field which is determined by the operator. The phenomenon, which is due to the physical rotation of the magnetic nanoparticles in the suspension, is demonstrated analytically when the nanoparticles are present in high concentrations (1 to 3% solid volume fractions) more typical of hyperthermia rather than in clinical imaging applications, and in low MRI field strengths (such as open MRI systems), where the magnetic nanoparticles are not magnetically saturated. The effect of imposed Poiseuille flow in a planar channel geometry and changing nanoparticle concentration is examined. The work represents the first known attempt to analyze the dynamic behavior of magnetic nanoparticles in the MRI environment including the effects of the magnetic nanoparticle spin-velocity. It is shown that the magnitude of the transverse magnetization is a strong function of the rotating transverse field frequency. Interactive fluid magnetization effects are predicted due to non-uniform fluid magnetization in planar Poiseuille flow with high nanoparticle concentrations.
doi:10.1016/j.jmmm.2010.03.029
PMCID: PMC2901184  PMID: 20625540
Magnetic nanoparticles; MRI; rotating magnetic field; interactive magnetization; magnetic particle imaging
23.  Studies on Preparation of Photosensitizer Loaded Magnetic Silica Nanoparticles and Their Anti-Tumor Effects for Targeting Photodynamic Therapy 
Nanoscale Research Letters  2009;4(5):400-408.
Abstract
As a fast developing alternative of traditional therapeutics, photodynamic therapy (PDT) is an effective, noninvasive, nontoxic therapeutics for cancer, senile macular degeneration, and so on. But the efficacy of PDT was compromised by insufficient selectivity and low solubility. In this study, novel multifunctional silica-based magnetic nanoparticles (SMNPs) were strategically designed and prepared as targeting drug delivery system to achieve higher specificity and better solubility. 2,7,12,18-Tetramethyl-3,8-di-(1-propoxyethyl)-13,17-bis-(3-hydroxypropyl) porphyrin, shorted as PHPP, was used as photosensitizer, which was first synthesized by our lab with good PDT effects. Magnetite nanoparticles (Fe3O4) and PHPP were incorporated into silica nanoparticles by microemulsion and sol–gel methods. The prepared nanoparticles were characterized by transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy and fluorescence spectroscopy. The nanoparticles were approximately spherical with 20–30 nm diameter. Intense fluorescence of PHPP was monitored in the cytoplasm of SW480 cells. The nanoparticles possessed good biocompatibility and could generate singlet oxygen to cause remarkable photodynamic anti-tumor effects. These suggested that PHPP-SMNPs had great potential as effective drug delivery system in targeting photodynamic therapy, diagnostic magnetic resonance imaging and magnetic hyperthermia therapy.
Graphical Abstract
Novel multifunctional photosensitizer loaded magnetic silica nanoparticles were strategically prepared with low toxicity, good biocompatibility and remarkable photodynamic anti-tumor efficacy. The nanoparticles were believed to be of great value as drug delivery system in targeting photodynamic therapy, diagnostic magnetic resonance imaging and magnetic hyperthermia therapy.
doi:10.1007/s11671-009-9254-5
PMCID: PMC2893856  PMID: 20596490
Targeting photodynamic therapy; Photosensitizer; Silica; Magnetic nanoparticles; Tumor
24.  Magnetic resonance imaging contrast of iron oxide nanoparticles developed for hyperthermia is dominated by iron content 
Purpose
Magnetic iron oxide nanoparticles (MNPs) are used as contrast agents for magnetic resonance imaging (MRI) and hyperthermia for cancer treatment. The relationship between MRI signal intensity and cellular iron concentration for many new formulations, particularly MNPs having magnetic properties designed for heating in hyperthermia, is lacking. In this study, we examine the correlation between MRI T2 relaxation time and iron content in cancer cells loaded with various MNP formulations.
Materials and methods
Human prostate carcinoma DU-145 cells were loaded with starch-coated bionised nanoferrite (BNF), iron oxide (Nanomag® D-SPIO), Feridex™, and dextran-coated Johns Hopkins University (JHU) particles at a target concentration of 50 pg Fe/cell using poly-D-lysine transfection reagent. T2-weighted MRI of serial dilutions of these labelled cells was performed at 9.4 T and iron content quantification was performed using inductively coupled plasma mass spectrometry (ICP-MS). Clonogenic assay was used to characterise cytotoxicity.
Results
No cytotoxicity was observed at twice the target intracellular iron concentration (~100 pg Fe/cell). ICP-MS revealed highest iron uptake efficiency with BNF and JHU particles, followed by Feridex and Nanomag-D-SPIO, respectively. Imaging data showed a linear correlation between increased intracellular iron concentration and decreased T2 times, with no apparent correlation among MNP magnetic properties.
Conclusions
This study demonstrates that for the range of nanoparticle concentrations internalised by cancer cells the signal intensity of T2-weighted MRI correlates closely with absolute iron concentration associated with the cells. This correlation may benefit applications for cell-based cancer imaging and therapy including nanoparticle-mediated drug delivery and hyperthermia.
doi:10.3109/02656736.2014.913321
PMCID: PMC4327906  PMID: 24773041
Magnetic iron oxide nanoparticles; magnetic nanoparticle hyperthermia; magnetic resonance imaging; cancer
25.  Development of Novel Magnetic Nanoparticles for Hyperthermia Cancer Therapy 
Proceedings of SPIE  2011;7901:790115-.
Advances in magnetic nanoparticle hyperthermia are opening new doors in cancer therapy. As a standalone or adjuvant therapy this new modality has the opportunity significantly advance thermal medicine. Major advantages of using magnetic magnetite (Fe3O4) nanoparticles are their highly localized power deposition and the fact that the alternating magnetic fields (AMF) used to excite them can penetrate deeply into the body without harmful effect. One limitation, however, which hinders the technology, is the problem of inductive heating of normal tissue by the AMF if the frequency and fields strength are not appropriately matched to the tissue. Restricting AMF amplitude and frequency limits the heat dose which can be selectively applied to cancerous tissue via the magnetic nanoparticle, thus lowering therapeutic effect. In an effort to address this problem, particles with optimized magnetic properties must be developed. Using particles with higher saturation magnetizations and coercivity will enhance hysteresis heating increasing particle power density at milder AMF strengths and frequencies. In this study we used oil in water microemulsions to develop nanoparticles with zero-valent Fe cores and magnetite shells. The superior magnetic properties of zero-valent Fe give these particles the potential for improved SAR over pure magnetite particles. Silane and subsequently dextran have been attached to the particle surface in order to provide a biocompatible surfactant coating. The heating capability of the particles was tested in-vivo using a mouse tumor model. Although we determined that the final stage of synthesis, purification of the dextran coated particles, permits significant corrosion/oxidation of the iron core to hematite, the particles can effectively heat tumor tissue. Improving the purification procedure will allow the generation Fe/Fe3O4 with superior SAR values.
doi:10.1117/12.876514
PMCID: PMC3947375  PMID: 24619487
Magnetic Nanoparticle; Ferrofluid; Hyperthermia; Tumor; Cancer; Synthesis

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