In vivo magnetic nanoparticle hyperthermia: a review on preclinical studies, low-field nano-heaters, noninvasive thermometry and computer simulations for treatment planning

Figures & data

Table 1. Potential thermometry techniques compatible with in vivo MNH, limitations and advantages.

Technique	Cost	Clinical equipment	Thermometry property	Limitations	Comments
Magnetic Resonance Imaging - MRI	$$$	Yes	$\Delta T=\frac{\phi -{\phi }_0}{\gamma \delta B_{0}TE}$;$\delta$ is the PRF change coefficient, $TE$ the echo time of the gradient echo pulse sequence, ${\phi }_0$ is the initial phase of the image at temperature $T_0,$ $\gamma$ the gyromagnetic ratio of hydrogen, $B_0$ the DC magnetic field of MRI and $\Delta T=T-T_0$ [84].	High DC fields inhibit NP magnetic moment rotation, i.e., inhibit heat generation [2].	Not applicable to MNH, but useful for MNP localization.
Computed Tomography - CT	$$$	Yes	$\Delta T=-\frac{CT(T)-{CT(T}_0)}{\alpha \left[1000+{CT(T}_0)\right]}$; where T$\left(x,y\right)=1000\frac{\mu \left(x,y\right)-{\mu }_W}{{\mu }_W}$ ; ${\mu }_W$ is the X-ray attenuation coefficient of water, while $\mu \left(x,y\right)$ is the average value in the (x,y) voxel, $\alpha$ is the volumetric expansion coefficient, and the $CT$ number (also named Hounsfield unit (HU)).	Need to use low dose ionizing radiation for safety concerns [82,83]. Although MNP localization can be determined using this technique, there is still a lack of information about its influence on the temperature dependence variation of CT image.	The method shows great promise for clinical applications if calibration can be performed and CT-based thermometry can be integrated with MNH. As far as we know, so far, there is no study showing the proof-of-concept of CT- MNH.
Ultrasound Thermal Strain Imaging - USTSI	$$	Yes	$\Delta T=\frac{c(T_0)}{2}\left(\frac{1}{{\alpha }_T-\frac{1}{c(T_0)}\frac{\partial c(T)}{\partial T}}\right)\frac{\partial (\Delta t)}{\partial z}$; ${\alpha }_T$ is the thermal expansion coefficient, c the sound velocity, $\Delta t$ the time shifts in ultrasound images due to the temperature change, $\frac{\partial (\Delta t)}{\partial z}$ the thermal strain.	Temperature calibration is strongly influenced by body movement and might show limitations due to image artifacts, animal respiration, etc.	USTSI-based thermometry during MNH was recently demonstrated using phantoms containing MNPs [77]. But there is a lack of in vivo USTSI-MNH studies to check its clinical potential.
Ultrasound Shear Wave Imaging - USSWI	$$	Yes	Monitor the non-linear changes in shear elastic properties of soft tissue that are temperature dependent.	The low frequency mechanical stimulation for generating tissue displacements might depend on MNP distribution in the tumor.	Most promising US thermometry method since the shear wave temperature dependence is not strongly influenced by motion [78]. No proof-of-concept integrating USSWI-MNH.
Magnetomotive Ultrasound Imaging – MUSI	$$	No	Can be used to monitor shear wave propagation due to MNP movement after field excitation. Since elastic properties are temperature dependent can be used as USSWI.	Particle aggregate displacement due to magnetic field excitation might not represent all the MNPs that generate heat. It might be applicable to USSWI-MNH but needs to integrate the field excitation for MUSI and the MNH in a duty-like cycle.	Not applicable to MNH in the present form, although coil design might allow RF excitation. Might be useful to MNP localization [85]. If integrated in duty cycle with MNH might be able to perform USSWI thermometry.
Magnetic Particle Imaging - MPI	$$$	No	Combines the MPI point spread function with a theoretical model that calculates the spatial decay in energy dissipation rates under magnetic field gradients using a phenomenological equation for particles relaxing by the Brownian relaxation [86].	MPI signal was shown to be temperature dependent, but SAR determination assumed particle rotation under ac field excitation (100–500 kHz), which might not contribute significantly to intra-tumoral heat generation.	Powerful technique for MNH that uses gradient fields to excite only specific ROIs inside the body. This has important MNH applications since it avoids heating of undesirable tissues, such as liver or spleen. Proof-of-concept has already been demonstrated [80], and is useful for MNP localization.
MPI Nonlinear Harmonic Ratio - MPINHR	$$$	No	The MPI signal is proportional to the time derivative of the magnetization response, $u_{\mathit{MPI}}\propto \frac{dM(t)}{dt}.$ Fourier transform of this signal allows the determination of harmonic terms, $M_{n\omega }(n\omega ).$ Temperature can in principle be obtained from the ratio of harmonics after calibration.	Theoretical models usually assume that the NP magnetization response follows the Langevin magnetization, but the time dependence of the magnetization might be more complex. Also, the influence of particle-matrix (biological environment) [87] and particle-particle interaction is not yet well understood and might have a strong influence on the harmonic signal.	Most promising technique for magnetic nanoparticle thermometry since in vitro studies suggest that the ratio of harmonic signals does not depend on particle concentration or size distribution [81]. Tuning the excitation frequency for MNP thermometry might be necessary, as well as better understanding of collective relaxation to achieve this goal.
Luminescent Nanothermometry - LNT	$	No	LNT is based on change of spectroscopic properties with temperature, as intensity in single or pair transitions, peak position shift or lifetime.	Limited to few mm in depth due to optical attenuation, even excited at the biological window. MNPs with potential for LNT are more complex since it also needs a near-infrared fluorescent part.	Might not achieve clinic, although can be used for surface tumor applications. But very interesting for preclinical studies with small tumors. Proof-of-concept of MNH-LNT has been demonstrated [79].
Photoacoustic Tomography - PAT	$$$	No	$\Delta T=\beta \frac{\Delta P}{P}$; where β is a tissue dependent constant, $\Delta P=P-P_0,$ with $P_0$ the photoacoustic signal at temperature $T_0$ [78].	Limited to few cm in depth. Generally, uses high laser pulsed light, so heat-induced effect might be mixed with laser-induced one. PAT might be useful to localize MNPs but could be limited due to low photothermal conversion efficiency (PCE) of this nanomaterial, at low laser power conditions. Increasing PCE of MNPs might be important to achieve this goal.	Might not achieve clinic because is depth-restricted, but has interesting preclinical applications although still expensive [88]. As far as we know, there is no study showing the proof-of-concept of PAT- MNH.
Infrared Thermometry - IRT	$	Yes	IRT is able to extract temperature information from the detection of thermal radiation phenomena in the infrared region.	Limited to surface temperature determination. i.e., surface tumors. Apparent temperature measurement of curved surfaces is directional dependent and influenced by external temperature [76].	If nanoparticle localization is determined using another technique (e.g., CT, MRI, etc) one might be able to integrate the surface temperature measurements with computer simulations to determine intra-tumoral thermal dose [89]. But not applicable to most clinical situations.

Table 2. Preclinical studies that show the effect of MNH (alone) in the treatment of solid tumors.

Preclinical Study	Treated Animals	Solid Tumor Model (Tumor size)	Nanocarrier (magnetic core size)	$H$^a[kA.m^−1]	$f$[kHz]	SLPin vitro	Amount of Injected NP^b	Tumoral Heating	Days after MNH^c	Biological Outcome
Jordan et al. 1997 [10]	n = 13	C3H mammary carcinoma (120–400 mm^3)	#P6: Fe3O4-Dextran (3.1 ± 0.7 nm)	6.8	520	160 W.g^−1(NP)	10.5 μg(Fe).mm^−3(tumor)	47 ± 1 °C for 30 min	60	Inhibition of tumor growth ration (44% of PR^d)
Hilger et al. 2001 [11]	n = 10	MX-1 adenocarcinoma (299 ± 158 mm^3)	Fe3O4 (10 nm)	6.5	400	211 W.g^−1(NP)	(70 ± 30) μg(NP).mm^−3(tumor)	71 ± 8 °C	—	Tumor shrinkage after MNH and CR^e
Johannsen et al. 2005 [12]	n = 12	Dunning R3327 Prostate (740 mm^3)	Fe3O4-aminosilan core-shell (15 nm)	12.6	100	160 W.g^−1(NP)	60 mg(NP).cm^−3(tumor)	50 °C for 30 min	10	Inhibition of tumor growth ratio (44.1–50.9% of PR)
Ito et al. 2006 [13]	—	B16, MM46, Os515, Vx-7, T-9	Fe3O4-Cationic Liposomes (10 nm)	30.6	118	—	—	43–45 °C for 20 min	28	CR (T-9 glioma) + antitumor immune response
Dennis et al. 2009 [14]	n = 4	MTG-B mammary (180 ± 40 mm^3)	Fe3O4-Dextran (BNF) ($\sim$ 50 nm)	43.8	150	81 ± 2 W.g^−1(Fe)	(4.98 ± 0.03) mg(Fe).cm^−3(tumor)	40.5–55 °C for 15 min	60	75% of CR
Hou et al. 2009 [15]	n = 6	Colorectal (CT26) (D = 0.7 − 1.2 cm)	Magnetic Hydroxyapatite (mHAP) (20–50 nm)	3.8	—	—	160 mg(NP).ml^−1(Fluid)	45–46 °C for 20 min/day (9 days)	15	100% of CR
Lee et al. 2011 [16]	n = 3	U87MG human brain (100 mm^3)	CoFe2O4-MnFe2O4 core-shell (15 nm)	37.3	500	2280 W.g^−1(NP)	0.75 μg(NP).mm^−3(tumor)	—	26	100% of CR
Candido et al. 2014 [17]	n = 6	UM-SCC14A oral carcinoma (200 − 250 mm^3)	ɣ-Fe2O3 Tripolyphosphate (8 nm)	3.2	1000	—	7 × 101^4 Particles.ml^−1(Fluid)	—	7	100% of CR
Kossatz et al. 2015 [18]	n = 26	MDA-MB-231 breast adenocarcinoma (100 − 250 mm^3)	MF66-N6L, MF66-DOX or MF66-N6LDOX (Fe3O4 core with 12 ± 3 nm)	15.4	435	500 W.g^−1(Fe)	2.5 μg(Fe).mm^−3(tumor)	41.7 °C for 60 min/day (2 days)	28	50% of CR: animals with a tumoral reduction to less than 20% of the initial volume
Liu et al. 2015 [19]	n = 2	MCF-7 breast cancer ($\sim$ 500 mm^3)	Fe3O4 ferrimagnetic vortex-domain Nanorings (70 nm)	31.8	400	1500 W.g^−1(NP)	300 μg(NP).cm^−3(tumor)	44 ± 0.5 °C for 10 min	40	100% of CR
Alphandéry et al. 2017 [20]	n = 10	Intracranial U87-Luc GBM (3 − 25 mm^3)	Chains of Magnetosomes ($\sim$45 nm)	23.9	198	57 ± 6 W.g^−1(Fe)	1–13 μg(Fe).mm^−3(tumor)	ΔT = 28.5 °C 30 min/day (15 days)	150	40% of CR in the 35th day after MNH (all tumors with 3 mm^3)
Jang et al. 2018 [21]	—	Hep3B subcutaneous ($\sim$ 1000 mm^3)	Mg013-γFe2O3 (7 nm ± 10%)	12.3	99	2300–3900 W.g^−1(NP)	1.15 mg(NP).ml^−1(Fluid)	50.2 °C for 15 min	14	100% of CR
Ma et al. 2019 [22]	n = 5	4T1 orthotopic mouse breast cancer (60 mm^3)	Fe3O4-Pd Janus (15 nm)	23.9	300	—	6.0 μg(Fe).g^−1(tumor)	35.6–42 °C for 8 min	18	Inhibition of tumor growth ratio (48.6% of PR)
Mai et al. 2019 [23]	n = 6	A431 epidermoid carcinoma (80–100 mm^3)	Iron Oxide Nanocubes (TR-cubes) (19 nm)	11	110	157.2–247 W.g^−1(Fe)	0.7 mg(Fe) per animal	ΔT = 15 °C 30 min/day (3 days)	$\sim$ 35	Inhibition of tumor growth ratio

^a$H$-field rms values; ^bIn all these studies the amount of nanoparticles (NP) was intratumorally injected; ^cTime period that the animals were followed after MNH treatment; ^dPR: Partial Remission, i.e., re-growth of the local tumor tissue exposed to heat; ^eCR: Complete Remission, i.e., no re-growth of the local tumor tissue exposed to heat;.

Figure 1. In several preclinical studies reported on the literature, the experimental setups for in vivo MNH are out of the clinical safe-limit region (some much more than others): at the graph the dashed and shaded areas delimits, respectively, the Atkinson¹ and Dutz-Hergt² thresholds to prevent harmful non-localized heating regime due to eddy currents. The points correspond to the ordered pair of the experimental values for frequency $f$ (in kHz) and amplitude $H$ (in kA.m⁻¹ and Oe) of the AMF for the reports presented in Table 2.

Table 3. Some mono-core and multicore nano-heaters (from 2008 to 2019), targeted for better SLP performance with in vivo MNH.

Study	Material	Type	Core size (obtained by)	Multicore size (obtained by)	$H$^a[kA.m^−1]	$f$[kHz]	$H\times f$ [A.m^−1s^−1]	SLPin vitro	Fluid Volume (concentration)	Temperature rise	Heating time
Dennis C.L. et al., 2008 [152]	ɣ-Fe2O3 (core) Dextran (shell)	Cluster of BNF core-shell nanoparticles (NPs)	44 ± 13 nm (AUC^b) and 50 nm (HRTEM^c)	92 ± 14 nm (PCS^d)	86	150	1.3 × 10^10	1075 W.g^−1(Fe)	– (3200 mg(Fe).ml^−1)	–	–
Lartigue L. et al., 2012 [153]	ɣ-Fe2O3	Cluster of ɣ-Fe2O3 cores forming a NF^e structure	10.5 nm (XRD^f)	24 nm (HRTEM)	25	520	1.3 × 10^10	$\sim$1500 W.g^−1(Fe)	300 μl (4.8 mg(Fe).ml^−1)	from 37 °C to $\sim$ 65 °C	$\sim$ 28 s
Hugounenq P. et al., 2012 [154]	ɣ-Fe2O3	Cluster of ɣ-Fe2O3 cores forming a NF structure	11 nm (XRD)	42 nm (HRTEM)	11	400	4.4 × 10^9	500 W.g^−1(Fe)	300 μl (2.8 mg(Fe).ml^−1)	–	–
Liu X.L. et al., 2014 [155]	MnFe2O4	Polymeric nanospheres loaded with MnFe2O4 NPs	18.0 ± 0.9 nm (HRTEM) 17.03 nm (XRD)	106 nm (DLS)	4	435	1.7 × 10^9	332 W.g^−1(Fe+Mn)	1 ml (0.3 mg(Fe+Mn).ml^−1)	from 30 °C to 45 °C	800 s
Dennis C.L. et al., 2015 [156]	ɣ-Fe2O3 (core) Dextran (shell)	Cluster of BNF core-shell NPs	$\sim$ 50 nm (HRTEM)	126 nm (DLS^g)	40	150	6.0 × 10^9	$\sim$550 W.g^−1(Fe)	1 ml (11 mg(Fe).ml^−1)	–	30 s
Shubitidze F. et al., 2015 [157]	ɣ-Fe2O3	IONPs^h with saccharide chains in a NF structure	2–5 nm (HRTEM)	20–40 nm (HRTEM)	$\sim$ 35.8	164	5.9 × 10^9	$\sim$190 W.g^−1(Fe)	1 ml (5 mg(Fe).ml^−1)	–	–
Das R. et al., 2016 [158]	Ag (core) Fe3O4 (shell)	Core-shell (Ag/Fe3O4) NPs forming a NF	Core: 45 ± 10 nm (XRD) Shell: 40 nm (XRD)	120 ± 10 nm (HRTEM)	63.66	310	2.0 × 10^10	167 W.g^−1(NP)	– (2 mg(NP).ml^−1)	from $\sim$ 22 °C to $\sim$ 50 °C	300 s
Rodrigues H.F. et al., 2017 [76]	MnFe2O4	Cluster of MnFe2O4 cores coated with a DMSA	15 ± 3 nm (HRTEM) and 14.1 ± 2.1 nm (XRD)	64.2 nm (DLS)	17.5	301	5.3 × 10^9	128 W.g^−1(NP)	90 μl ($\sim$ 26 mg(NP).ml^−1)	from 25 °C to 50 °C	30 s
Soleymani M. et al., 2017 [159]	Mn-perovskite La1-xSrxMnO3	Core-Shell NPs La0.73Sr0.27MnO3	54 nm (HRTEM)	Not applicable	2.7	120	3.2 × 10^8	25.5 W.g^−1(NP)	1 ml (100 mg(NP).ml^−1)	from 20 °C to 50 °C	$\sim$ 20 s
Hemery G. et al., 2017 [160]	ɣ-Fe2O3	Cluster of ɣ-Fe2O3 PEGylated cores	14.5 ± 3.4 nm (HRTEM)	29.1 ± 4.4 nm (HRTEM)	10	755	7.6 × 10^9	265 W.g^−1(Fe)	1 ml (3 mg(Fe).ml^−1)	from 37 °C to $\sim$ 67 °C	5 s
Gavilan H. et al., 2017 [161]	ɣ-Fe2O3	ɣ-Fe2O3 NPs (coated with Citric Acid) forming a NF	23.7 ± 0.2 nm (XRD)	58 ± 11 nm (HRTEM)	23.8	419	1.0 × 10^10	$\sim$440 W.g^−1(Fe)	–	–	–
Phong P.T. et al., 2017 [162]	Mn0.5Zn0.5Fe2O4	Nanosized mixed ferrite Mn0.5Zn0.5Fe2O4	14 nm (XRD) and 15 nm (HRTEM)	Not applicable	6.4	178	1.1 × 10^9	28.38 W.g^−1(NP)	1 ml (3 mg(NP).ml^−1)	from 30 °C to $\sim$ 45 °C	1500s
Bender P. et al., 2018 [163]	ɣ-Fe2O3 and Fe3O4	Cluster of IONPs (FeraSpin^TMR)	6 nm (HRTEM) and 9 nm (XRD)	18–56 nm (SAXS^i)	7	934	6.5 × 10^9	226.99 ± 7.32 W.g^−1(Fe)	– (5 mg(Fe).ml^−1)	–	–
He S. et al., 2018 [164]	ZnxFe3−xO4	Core-Shell NPs Zn0.3Fe2.7O4-SiO2	22 nm (HRTEM)	Not applicable	13	380	4.9 × 10^9	1010 W.g^−1(Fe)	– (1 mg(Fe).ml^−1)	from $\sim$ 20 °C to $\sim$ 46 °C	180 s
Bender P. et al., 2019 [165]	ɣ-Fe2O3	Cluster of ɣ-Fe2O3 cores coated with a dextran	5–15 nm (XRD)	39.0 ± 0.3 nm (HRTEM)	7	934	6.5 × 10^9	289 W.g^−1(Fe)	– (5 mg(Fe).ml^−1)	–	–
Curcio A. et al., 2019 [166]	ɣ-Fe2O3	Core-shell (ɣ-Fe2O3-CuS) IONPs forming a NF	25.5 ± 2.7 nm (HRTEM)	120.4 ± 7.3 nm (HRTEM)	14.35	471	6.8 × 10^9	$\sim$500 W.g^−1(Fe)	100 µL ($\sim$ 2.8 mg(Fe).ml^−1)	From $\sim$ 25 °C to 55 °C	300 s
Sol-Fernandez S. et al., 2019 [167]	MnFe2O4	Mn-IONPs coated with DMSA forming a NF	17.0 ± 1.6 nm (HRTEM) and 12 nm (XRD)	67 nm (DLS)	47	96	4.5 × 10^9	689 W.g^−1(Fe+Mn)	1 ml (1 mg(Fe+Mn).ml^−1)	from $\sim$ 22 °C to $\sim$ 35 °C	300 s
Ognjanovic M. et al., 2019 [168]	–	Cluster of IONPs coated with poly(acrylic acid)	13.5 ± 1.2 nm (HRTEM)	24.8 ± 4.4 nm (HRTEM)	15.95	252	4.0 × 10^9	478 W.g^−1(NP)	1 ml (5 mg(NP).ml^−1)	from 25 °C to 55 °C	60 s
Mai et al., 2019 [23]	–	Iron Oxide Nanocubes (TR-cubes)	19 nm (HRTEM)	–	11	110	1.2 × 10^9	157–247 W.g^−1(Fe)	100 µL (3 mg(Fe).ml^−1)	from 25 °C to 55 °C	1800s

(–) The information was not reported by the authors; ^a$H$-field rms values; ^bAUC: Analytical ultracentrifugation; ^cHRTEM: High resolution transmission electron microscopy; ^dPCS: hydrodynamic diameter by Photon Correlation Spectroscopy; ^eNF: Nanoflower, i.e., NPs clustering in a flower-like structure; ^fXRD: Powder x-ray diffraction; ^gDLS: Dynamic light scattering; ^hIONPs: Iron oxide nanoparticles; ⁱSAXS: small-angle x-ray scattering.

Figure 2. In several in vitro studies reported on the literature, the experimental MNH setups are out of the clinical safe-limit region (some much more than others): in the graph the dashed and shaded areas delimit, respectively, the Atkinson¹ and Dutz-Hergt² thresholds to prevent harm in human applications (minimizing the off-target heating due to eddy currents). The points correspond to the ordered pair of the experimental values for frequency $f$ (in kHz) and amplitude $H$ (in kA.m⁻¹ and Oe) of the AMF for each work presented in Table 3.

Table 4. Computer simulations for in vivo MNH.

Computational Study	Geometric modeling for animal			Thermal dose	MNP concentration	${\dot{Q}}_{\mathit{SIM}}$	${\dot{Q}}_{\hspace{0.17em}\text{EXP}\hspace{0.17em}}$	${\mathit{SLP}}_{\mathit{SIM}}$	${\mathit{SLP}}_{\hspace{0.17em}\text{Exp}\hspace{0.17em}}$	$H$^a	$f$	Maximum temperature
	Body	Tumor	MNP^b distribution		[mg.ml^−1]	[W.m^−3]	[W.m^−3]	[W.g^−1]	[W.g^−1]	[KA.m^−1]	[KHz]	[ºC]
Pavel et al. 2008 [172]	Cube	Spherical	Spherical	No	10	6 × 10^9	–	6 × 10^5	–	14.5	170	42.5
Pavel et al. 2009 [173,174]	No	Spherical	spherical	No	10–10.5	(6.8–7.5) × 10^9	–	–	–	7	200	–
Lebrun et al. 2013 [55]	Parallelepiped	Micro-CT	Pixel dependent	CEM43	–	1.5 × 10^4 − 2.9 × 10^6	9.8 × 10^5	–	–	–	190	55
Attaluri et al. 2015 [39]	Spherical shell	Spherical	Spherical	CEM43	–	4.6 × 10^5	–	–	–	24	155	–
Lebrun et al. 2016 [56]	Modeled from a mouse obtained from a Micro-CT	Micro-CT	Pixel dependent	$\Omega$	–	–	–	–	–	–		–
Pearce et al. 2017 [175]	Box	Ellipsoidal	Spherical	CEM43	1.25	9 × 10^9	1 × 10^6	–	–	32.5	162	57
Rodrigues H.F. et al., 2017 [76]	Ellipsoidal	Ellipsoidal	Spherical	No	26	3.9 × 10^6	3.3 × 10^6	150	128	17.5	310	50
Li et al. 2019 [176]	Cylindrical	Spherical	Spherical	CEM43	5	–	–	–	–	5	100	43
Jin et al. 2019 [177]	Spherical shell	Spherical	Spherical	$\Omega$	–	Gaussian distribution	–	–	–	–	300	54.5

The dash (–) means that the information/quantity was not specified/reported by the authors in the paper; ^a$H$-field rms values; ^bMNP: magnetic nanoparticle.

Figure 3. In vivo MNH treatment planning algorithm. MRI – Magnetic Resonance Imaging, CT – Computed Tomography, US – Ultrasound, US-SW – Shear wave ultrasound, MPI – Magnetic Particle Imaging, FMT - Fluorescence Molecular Tomography, * Technique useful only for preclinical studies.

Saccomandi P, Schena E, Silvestri S. Techniques for temperature monitoring during laser-induced thermotherapy: an overview. Int J Hyperthermia. 2013;29(7):609–619.

 PubMed Web of Science ®Google Scholar

Jordan A, Wust P, Fahling H, et al. Inductive heating of ferrimagnetic particles and magnetic fluids: physical evaluation of their potential for hyperthermia. Int J Hyperthermia. 1993;9(1):51–68.

 PubMed Web of Science ®Google Scholar

Mahnken AH, Bruners P. CT thermometry: will it ever become ready for use? Int J Clin Pract. 2011;65:1–2.

 PubMed Web of Science ®Google Scholar

Fani F, Schena E, Saccomandi P, et al. CT-based thermometry: an overview. Int J Hyperthermia. 2014;30(4):219–227.

 PubMed Web of Science ®Google Scholar

Hadadian Y, Uliana JH, Oliveira Carneiro AA, et al. A novel theranostic platform: integration of magnetomotive and thermal ultrasound imaging with magnetic hyperthermia. IEEE Trans Biomed Eng. 2020. DOI: 10.1109/TBME.2020.2990873

 PubMed Web of Science ®Google Scholar

Lewis MA, Staruch RM, Chopra R. Thermometry and ablation monitoring with ultrasound. Int J Hyperthermia. 2015;31(2):163–181.

 PubMed Web of Science ®Google Scholar

Oh J, Feldman MD, Kim J, et al. Detection of magnetic nanoparticles in tissue using magneto-motive ultrasound. Nanotechnology. 2006;17(16):4183–4190.

 PubMed Web of Science ®Google Scholar

Dhavalikar R, Rinaldi C. Theoretical predictions for spatially-focused heating of magnetic nanoparticles guided by magnetic particle imaging field gradients. J Magn Magn Mater. 2016;419:267–273.

 PubMed Web of Science ®Google Scholar

Tay ZW, Chandrasekharan P, Chiu-Lam A, et al. Magnetic particle imaging-guided heating in vivo using gradient fields for arbitrary localization of magnetic hyperthermia therapy. ACS Nano. 2018;12(4):3699–3713.

 PubMed Web of Science ®Google Scholar

Wells J, Löwa N, Paysen H, et al. Probing particle-matrix interactions during magnetic particle spectroscopy. J Magn Magn Mater. 2019;475:421–428.

 Web of Science ®Google Scholar

Weaver JB, Rauwerdink AM, Hansen EW. Magnetic nanoparticle temperature estimation. Med Phys. 2009;36(5):1822–1829.

 PubMed Web of Science ®Google Scholar

Ortgies DH, Teran FJ, Rocha U, et al. Optomagnetic nanoplatforms for in situ controlled hyperthermia. Adv Funct Mater. 2018;28(11):1704434.

 Web of Science ®Google Scholar

Fatima A, Kratkiewicz K, Manwar R, et al. Review of cost reduction methods in photoacoustic computed tomography. Photoacoustics. 2019;15:100112–100137.

 Web of Science ®Google Scholar

Rodrigues HF, Capistrano G, Mello FM, et al. Precise determination of the heat delivery during in vivo magnetic nanoparticle hyperthermia with infrared thermography. Phys Med Biol. 2017;62(10):4062–4082.

 PubMed Web of Science ®Google Scholar

Capistrano G, Rodrigues HF, Zufelato N, et al. Non-invasive intratumoral thermal dose determination during in vivo magnetic nanoparticle hyperthermia: combining surface temperature measurements and computer simulations. Manuscript submitted for publication. 2020.

 Google Scholar

Jordan A, Scholz R, Wust P, et al. Effects of magnetic fluid hyperthermia (MFH) on C3H mammary carcinoma in vivo. Int J Hyperth. 1997;13(6):587–605.

 PubMed Web of Science ®Google Scholar

Hilger I, Andrä W, Hergt R, et al. Electromagnetic heating of breast tumors in interventional radiology: in vitro and in vivo studies in human cadavers and mice. Radiology. 2001;218(2):570–575.

 PubMed Web of Science ®Google Scholar

Johannsen M, Thiesen B, Jordan A, et al. Magnetic fluid hyperthermia (MFH)reduces prostate cancer growth in the orthotopic Dunning R3327 rat model. Prostate. 2005;64(3):283–292.

 PubMed Web of Science ®Google Scholar

Ito A, Honda H, Kobayashi T. Cancer immunotherapy based on intracellular hyperthermia using magnetite nanoparticles: a novel concept of “heat-controlled necrosis” with heat shock protein expression. Cancer Immunol Immunother. 2006;55(3):320–328.

 PubMed Web of Science ®Google Scholar

Dennis CL, Jackson AJ, Borchers JA, et al. Nearly complete regression of tumors via collective behavior of magnetic nanoparticles in hyperthermia. Nanotechnology. 2009;20(39):395103.

 PubMed Web of Science ®Google Scholar

Hou C-H, Hou S-M, Hsueh Y-S, et al. The in vivo performance of biomagnetic hydroxyapatite nanoparticles in cancer hyperthermia therapy. Biomaterials. 2009;30(23–24):3956–3960.

 PubMed Web of Science ®Google Scholar

Lee J-H, Jang J, Choi J, et al. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nat Nanotechnol. 2011;6(7):418–422.

 PubMed Web of Science ®Google Scholar

Candido N, Calmon M, Taboga S, et al. High efficacy in hyperthermia-associated with polyphosphate magnetic nanoparticles for oral cancer treatment. J Nanomed Nanotechnol. 2014;5:206.

 Google Scholar

Kossatz S, Grandke J, Couleaud P, et al. Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery. Breast Cancer Res. 2015;17:66.

 PubMed Web of Science ®Google Scholar

Liu XL, Yang Y, Ng CT, Zhao LY, et al. Magnetic vortex nanorings: a new class of hyperthermia agent for highly efficient in vivo regression of tumors. Adv Mater Weinheim. 2015;27(11):1939–1944.

 PubMed Web of Science ®Google Scholar

Alphandéry E, Idbaih A, Adam C, et al. Chains of magnetosomes with controlled endotoxin release and partial tumor occupation induce full destruction of intracranial U87-Luc glioma in mice under the application of an alternating magnetic field. J Control Release. 2017;262:259–272.

 PubMed Web of Science ®Google Scholar

Jang J, Lee J, Seon J, et al. Giant magnetic heat induction of magnesium-doped γ-Fe2O3 superparamagnetic nanoparticles for completely killing tumors. Adv Mater. 2018;30(6):1704362.

 Web of Science ®Google Scholar

Ma X, Wang Y, Liu X-L, et al. Fe3O4–Pd Janus nanoparticles with amplified dual-mode hyperthermia and enhanced ROS generation for breast cancer treatment. Nanoscale Horiz. 2019;4(6):1450–1459.

 Web of Science ®Google Scholar

Mai BT, Balakrishnan PB, Barthel MJ, et al. Thermoresponsive iron oxide nanocubes for an effective clinical translation of magnetic hyperthermia and heat-mediated chemotherapy. ACS Appl Mater Interfaces. 2019;11(6):5727–5739.

 PubMed Web of Science ®Google Scholar

Dennis CL, Jackson AJ, Borchers JA, et al. The influence of collective behavior on the magnetic and heating properties of iron oxide nanoparticles. J Appl Phys. 2008;103(7):07A319.

 Web of Science ®Google Scholar

Lartigue L, Hugounenq P, Alloyeau D, et al. Cooperative organization in iron oxide multi-core nanoparticles potentiates their efficiency as heating mediators and MRI contrast agents. ACS Nano. 2012;6(12):10935–10949.

 PubMed Web of Science ®Google Scholar

Hugounenq P, Levy M, Alloyeau D, et al. Iron oxide monocrystalline nanoflowers for highly efficient magnetic hyperthermia. J Phys Chem C. 2012;116(29):15702–15712.

 Web of Science ®Google Scholar

Liu XL, Choo ESG, Ahmed AS, et al. Magnetic nanoparticle-loaded polymer nanospheres as magnetic hyperthermia agents. J Mater Chem B. 2014;2(1):120–128.

 PubMed Web of Science ®Google Scholar

Dennis CL, Krycka KL, Borchers JA, et al. Internal magnetic structure of nanoparticles dominates time-dependent relaxation processes in a magnetic field. Adv Funct Mater. 2015;25(27):4300–4311.

 Web of Science ®Google Scholar

Shubitidze F, Kekalo K, Stigliano R, et al. Magnetic nanoparticles with high specific absorption rate of electromagnetic energy at low field strength for hyperthermia therapy. J Appl Phys. 2015;117(9):094302.

 PubMed Web of Science ®Google Scholar

Das R, Rinaldi-Montes N, Alonso J, et al. Boosted hyperthermia therapy by combined AC magnetic and photothermal exposures in Ag/Fe3O4 nanoflowers. ACS Appl Mater Interfaces. 2016;8(38):25162–25169.

 PubMed Web of Science ®Google Scholar

Soleymani M, Edrissi M, Alizadeh AM. Tailoring La1-xSrxMnO3 (0.25 ≤x≤ 0.35) nanoparticles for self-regulating magnetic hyperthermia therapy: an in vivo study. J Mater Chem B. 2017;5(24):4705–4712.

 PubMed Web of Science ®Google Scholar

Hemery G, Genevois C, Couillaud F, et al. Monocore vs. multicore magnetic iron oxide nanoparticles: uptake by glioblastoma cells and efficiency for magnetic hyperthermia. Mol Syst Des Eng. 2017;2(5):629–639.

 Web of Science ®Google Scholar

Gavilán H, Sánchez EH, Brollo MEF, et al. Formation mechanism of maghemite nanoflowers synthesized by a polyol-mediated process. ACS Omega. 2017;2(10):7172–7184.

 PubMed Web of Science ®Google Scholar

Phong PT, Nam PH, Manh DH, et al. Mn0.5Zn0.5Fe2O4 nanoparticles with high intrinsic loss power for hyperthermia therapy. J Magn Magn Mater. 2017;433:76–83.

 Web of Science ®Google Scholar

Bender P, Fock J, Hansen MF, et al. Influence of clustering on the magnetic properties and hyperthermia performance of iron oxide nanoparticles. Nanotechnology. 2018;29(42):425705.

 PubMed Web of Science ®Google Scholar

He S, Zhang H, Liu Y, et al. Maximizing specific loss power for magnetic hyperthermia by hard-soft mixed ferrites. Small. 2018;14(29):1800135.

 Web of Science ®Google Scholar

Bender P, Honecker D, Fernández Barquín L. Supraferromagnetic correlations in clusters of magnetic nanoflowers. Appl Phys Lett. 2019;115(13):132406.

 Web of Science ®Google Scholar

Curcio A, Silva AKA, Cabana S, et al. Iron oxide nanoflowers @ CuS hybrids for cancer tri-therapy: interplay of photothermal therapy, magnetic hyperthermia and photodynamic therapy. Theranostics. 2019;9(5):1288–1302.

 PubMed Web of Science ®Google Scholar

Del Sol-Fernández S, Portilla-Tundidor Y, Gutiérrez L, et al. Flower-like Mn-doped magnetic nanoparticles functionalized with αvβ3-integrin-ligand to efficiently induce intracellular heat after alternating magnetic field exposition, triggering glioma cell death . ACS Appl Mater Interfaces. 2019;11(30):26648–26663.

 PubMed Web of Science ®Google Scholar

Ognjanović M, Radović M, Mirković M, et al. 99mTc-, 90Y-, and 177Lu-labeled iron oxide nanoflowers designed for potential use in dual magnetic hyperthermia/radionuclide cancer therapy and diagnosis. ACS Appl Mater Interfaces. 2019;11(44):41109–41117.

 PubMed Web of Science ®Google Scholar

Pavel M, Gradinariu G, Stancu A. Study of the optimum dose of ferromagnetic nanoparticles suitable for cancer therapy using MFH. IEEE Trans Magn. 2008;44(11):3205–3208.

 Web of Science ®Google Scholar

Pavel M, Stancu A. Study of the optimum injection sites for a multiple metastases region in cancer therapy by using MFH. IEEE Trans Magn. 2009;45(10):4825–4828.

 Web of Science ®Google Scholar

Pavel M, Stancu A. Ferromagnetic nanoparticles dose based on tumor size in magnetic fluid hyperthermia cancer therapy. IEEE Trans Magn. 2009;45(11):5251–5254.

 Web of Science ®Google Scholar

LeBrun A, Manuchehrabadi N, Attaluri A, et al. MicroCT image-generated tumour geometry and SAR distribution for tumour temperature elevation simulations in magnetic nanoparticle hyperthermia. Int J Hyperthermia. 2013;29(8):730–738.

 PubMed Web of Science ®Google Scholar

Attaluri A, Kandala SK, Wabler M, et al. Magnetic nanoparticle hyperthermia enhances radiation therapy: a study in mouse models of human prostate cancer. Int J Hyperthermia. 2015;31(4):359–374.

 PubMed Web of Science ®Google Scholar

LeBrun A, Ma R, Zhu L. MicroCT image based simulation to design heating protocols in magnetic nanoparticle hyperthermia for cancer treatment. J Therm Biol. 2016;62(Pt B):129–137.

 PubMed Web of Science ®Google Scholar

Pearce JA, Petryk AA, Hoopes PJ. Numerical model study of in vivo magnetic nanoparticle tumor heating. IEEE Trans Biomed Eng. 2017;64(12):2813–2823.

 PubMed Web of Science ®Google Scholar

Li J, Yao H, Lei Y, et al. Numerical simulation of magnetic fluid hyperthermia based on multiphysics coupling and recommendation on preferable treatment conditions. Curr Appl Phys. 2019;19(9):1031–1039.

 Web of Science ®Google Scholar

Tang Y, Flesch RCC, Jin T. Numerical method to evaluate the survival rate of malignant cells considering the distribution of treatment temperature field for magnetic hyperthermia. J Magn Magn Mater. 2019;490:165458.

 Web of Science ®Google Scholar