Application of hyperthermia induced by superparamagnetic iron oxide nanoparticles in glioma treatment

Figures & data

Table 1 Physico-chemical properties of nanoparticles based on iron oxide and features of magnetic field applicator for the treatment of gliomas in MHT

Study	Iron oxide	[Fe3O4] × 10^5 (μg/ML)	<Dcore> (nm)	Coating	Manufacture	Magnetic field intensity (kA/m)	Magnetic field frequency (kHz)	Coil configuration	SLP/SAR (W/g)
In vitro
Shinkai et al^Citation28	Magnetite	(2–8) × 10^−4 and (2.5–10.0) × 10^−2	35	TMAG, DLPC, DOPE, 1:2:2 cationic; DLPC, DOPE, 1:1 neutral	Synthesized (nitrite oxidation method) followed by sonication method	30.6	118	Vertical coil Inner diameter: 8.5 cm Length: 21 turns	140.0
Ito et al^Citation29	Magnetite	100	35	TMAG, DLPC, DOPE, 1:2:2 cationic	Synthesized (nitrite oxidation method) followed by sonication method	30.6	118.0	Horizontal coil Inner diameter: 7 cm Length: 7 turns	N/I
Meenach et al^Citation30	Magnetite	0.0158–0.0793	20–30	PVP (PEG200MMA, PEG1000MMA, TEGDMA, PEG400DMA)	Nanostructure and amorphous materials (Los Alamos, NM) followed by free-radical polymerization	25.0	297.0	Vertical coil Inner diameter: 1.5 cm Length: 5 turns	N/I
In vivo
Yanase et al^Citation31	Magnetite	0.2 × 10^−3	35	TMAG, DLPC, DOPE, 1:2:2 cationic	Synthesized (nitrite oxidation method) followed by sonication method	30.6	118.0	Horizontal coil Inner diameter: 7 cm	N/I
Yanase et al^Citation32	Magnetite	0.075	1	TMAG, DLPC, DOPE, 1:2:2 cationic	Toda Kogyo Co, Ltd (Hiroshima) followed by sonication method	30.6	118.0	Horizontal coil Inner diameter: 7 cm	N/I
Yanase et al^Citation33	Magnetite	0.075	10	TMAG, DLPC, DOPE, 1:2:2 cationic	Toda Kogyo Co, Ltd (Hiroshima) followed by sonication method	30.6	118.0	Horizontal coil inner diameter: 7 cm	N/I
Shinkai et al^Citation34	Magnetite	0.075	10	TMAG, DLPC, DOPE, 1:2:2 cationic	Toda Kogyo Co, Ltd (Hiroshima) followed by sonication method	30.6	118.0	Horizontal coil inner diameter: 7 cm	N/I
Le et al^Citation35	Magnetite	0.05	35	Antibody-conjugated, liposomes (TMAG, DLPC, DOPE, 1:2:2 cationic)	Synthesized (nitrite oxidation method) Sonication method followed by imobilization method	30.6	118.0	Horizontal coil Inner diameter: 7 cm	96.0
Ito et al^Citation36	Magnetite	0.15	10	TMAG, DLPC, DOPE, 1:2:2 cationic	Toda Kogyo Co, Ltd (Hiroshima) followed by sonication method	30.6	118.0	Horizontal coil Inner diameter: 7 cm	N/I
Ohno et al^Citation37	Magnetite	18.3	10	CMC	Tokai Carbon Co, Ltd (Tokyo)	30.3	88.9	Horizontal coil Inner diameter: 25 cm × 25 cm	N/I
Ito et al^Citation29	Magnetite	0.075	35	TMAG, DLPC, DOPE, 1:2:2 cationic	Synthesized (nitrite oxidation method) followed by sonication method	30.6	118.0	Horizontal coil Inner diameter: 7 cm × 7 cm	N/I
Jordan et al^Citation23	Magnetite	2.016	3	Carboxydextran DDM128P6	Schering AG, Berlin, Germany	18.0	100.0	Ferromagnetic core coil	N/I
	Magnetite	2.24	15	Aminosilane MFL AS	MagForce Nanotechnologies AG, Berlin, Germany	18.0	100.0	Ferromagnetic core coil	N/I
Rabias et al^Citation39	Maghemite	2.0 × 10^4	10–12	Dextran	Synthesized (coprecipitation method)	11.0	150.0	Horizontal coil	286.0
Human
Maier-Hauff et al^Citation6	Magnetite	1.12	15	Aminosilane MFL AS	MagForce Nanotechnologies AG, Berlin, Germany	18.0	100.0	Ferrite-core applicator	N/I
Van Landeghem et al^Citation27	Magnetite	1.12	15	Aminosilane MFL AS	MagForce Nanotechnologies AG, Berlin, Germany	18.0	100.0	Ferrite-core applicator	N/I
Maier-Hauff et al^Citation7	Magnetite	1.12 × 10^5	12	Aminosilane MFL AS	MagForce Nanotechnologies AG, Berlin, Germany	15.0	100.0	Ferrite-core applicator	N/I

Abbreviations: CMC, carboxymethylcellulose; DLPC, dilauroylphosphatidylcholine; DMA, dimethacrylate; DOPE, dioleoylphosphatidyl-ethanolamine; MHT, magnetic hyperthermia; MMA, methyl ether methacrylate; N/I, data not informed; PEG, poly (ethylene glycol); PVP, polyvinylpyrrolidone; SLP/SAR, specific loss of power or specific absorption rate; TEGDMA, triethylene glycol dimethacrylate; TMAG, N-(α-trimethylammonioacetyl)-didodecyl-D-glutamate chloride.

Table 2 Comparison of in vitro experiments performed to evaluate the technique of MHT in the treatment of gliomas

Study	In vitro preparation		MHT therapy
	Tumor cell line	Culture medium	Nanoparticle	Concentration of nanoparticle	Time incubation of nanoparticles (hours)	Cell viability		Method to assess the MHT efficacy	Nanoparticle uptake by glioma cells	Temperature reached (°C)	Time of AMF exposure (minutes)
						Before MHT	After MHT
Shinkai et al^Citation28	T-9	Dulbecco’s modified Eagle’s medium	Magnetite cationic liposomes	7.2 mg/mL	8	1.6 × 10^8 cell/mL	0 cell/mL	“Viable cell count”	55 pg/cell	42.6	60
Ito et al^Citation29	T-9	Minimum essential medium	Magnetite cationic liposomes	100 μg/mL	24	No apoptotic/necrotic cells	Apoptotic/necrotic cells	Green fluorescent dye Yo-Pro-1, propidium iodide, Vibrant apoptosis assay, flow cytometry	–	42.0	30
Meenach et al^Citation30	M059K	Dulbecco’s modified Eagle’s medium/Ham’s F-12	PEGMMA-PEGDMA with iron oxide	7.93 mg/mL	0	No cell death	Cell death – via thermoablation	Live-dead assay/fluorescence imaging	–	63.0	5

Abbreviations: AMF, alternating magnetic field; MHT, magnetic hyperthermia; PEGMMA, poly (ethylene glycol) methyl ether methacrylate; PEGDMA, poly (ethylene glycol) dymethacrylate.

Table 3 Comparison of animal models used to evaluate glioma by MHT therapy

Study	Tumor cell line	Animal	Gender	Age (weeks)	Injection site	Minimum inoculation (cells)	Days to start MHT after tumor cell inoculation	Tumor size (mm)/shape
Yanase et al^Citation31	T-9	Fisher rat F-344	Female	7–8	Subcutaneous (left femoral region)	1 × 10^6	–	3/ellipsoidal
Yanase et al^Citation32	T-9	Fisher rat F-344	Female	6–7	Subcutaneous (left femoral region)	1 × 10^7	11	13–18/ellipsoidal
Yanase et al^Citation33	T-9	Fisher rat F-344	Female	6–7	Subcutaneous (left and right femoral region)	1 × 10^7	11	13–18/ellipsoidal
Shinkai et al^Citation34	T-9	Fisher rat F-344	Female	6–7	Subcutaneous (left femoral region)	1 × 10^7	11	13–18/ellipsoidal
Ito et al^Citation36	U-251-SP	Athymic nude mice	Female	4	Right flank	3 × 10^7	–	8/–
Le et al^Citation35	U-251-SP	KSN-nu/nu nude mice	Female	4	Subcutaneous (femoral region)	–	21	10/ellipsoidal
Ohno et al^Citation37	T-9	Fisher rat F-344	Female	4	Right cerebral hemisphere	5 × 10^6	8	–
Ito et al^Citation29	T-9	Fisher rat F-344	Female	6	Subcutaneous space	1 × 10^7	–	10/–
Jordan et al^Citation23	RG-2	Fisher rat F-344	Male	–	Thalamus region	1 × 10^5	4	3–4/round
Rabias et al^Citation39	C6	Wistar rat	Male	–	Subcutaneous (anterior bregma region)	8 × 10^6	28	5–10/–

Abbreviation: MHT, magnetic hyperthermia.

Table 4 Comparison of different treatment protocols used in animal models with glioma

Study	Animals groups/number	Main tumor length (mm)	Fe3O4 weight administrated	Time to AMF application after Fe3O4 administration (hours)	Maximum therapeutic temperaturea (°C)	Time to reach the therapeutic temperature (minutes)	Time of AMF application per session (minutes)	Number of AMF applications per group	Method to assess the MHT	Combined therapy
Yanase et al^Citation31	3/5	3	3 μg/150 μL	N/I	≅45	20	60	1 and 3	“Tumor take”	No
Yanase et al^Citation32	4/10–13	13–18	3 mg/400 μL	24	≅44	15	30	1, 2, and 3	Berlin blue counter-stained with Kernechtrot or HE,	No
Yanase et al^Citation33	2/8, 21	13–18	3 mg/400 μL	24	≅45	10	30	3	“Tumor volume” “Tumor volume”, HE, Immunohistochemistry (CD3, CD4, CD8, and NK)	No
Shinkai et al^Citation34	4/5	13–18	3 mg/400 μL	N/I	≅44	15	30	1, 2, and 3	HE, Immunohistochemistry (CD3, CD4, CD8, and NK)	No
Le et al^Citation35	2/5	10	0.5 mg/100 μL	24	≅43	20	30	3	Immunohistochemistry (G22–FML)	No
Ito et al^Citation36	4/5	8	3 mg/200 μL	24	≅46	3	30	1	Immunohistochemistry (TNF-α), TNF-α ELISA	TNF-α gene therapy
Ohno et al^Citation37	3/5	N/I	N/I	24	≅44.4	N/I	30	1 and 3	HE, Berlin blue, “Survival rate”, Berlin blue counterstained with Kernechtrot or HE	No
Ito et al^Citation29	4/5	10	3 mg/400 μL	24	≅45	4	30	1, 2, and 3	HE, Immunohistochemistry (HSP70), TUNEL	HSP 70 gene therapy
Jordan et al^Citation23	10/12	3–4	1.8 mol/L 2.0 mol/L	0	39, 43–47	10	40	1	Prussian blue/immunohistochemistry (PCNA and GFAP)	No
Rabias et al^Citation39	2/–	5–10	3 mg/150 μL	0	N/I	N/I	20	1	HE	No

Note:

a Maximum temperature reached in a period of application of AMF.

Abbreviations: AMF, alternating magnetic field; ELISA, enzyme-linked immunosorbent assay; GFAP, glial fibrillary acidic protein; HE, hematoxylin-eosin; HSP, heat shock protein; MHT, magnetic hyperthermia; N/I, data not informed; NK, natural killer; PCNA, proliferating cell nuclear antigen; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling. HE, hematoxylin-eosin; N/I, data not informed.

Table 5 Case reports and results of the autopsies of three patients with glioblastoma who received MHT therapy

Patient	Sex	Age (years)	Glioblastoma	Primary treatment line	Secondary treatment line	Amount of magnetic liquid instilled (mL)	Intratumoral temperature (°C)	Survival after hyperthermia (months)	Brain mass (g)	Autopsya	Average rate of mitosis/proliferationb
P1	Male	41	Left Frontoparietal	Surgery, radiotherapy, and chemotherapy	Radiotherapy and six sessions of hyperthermia	4.5	49.5	7.9	1.780	Signs of transtentorial and subfalcial herniation	1.2 ± 0.1/0.0625 μm^2/10.3 ± 1.4%
P2c	Male	57	Left Temporo-occipital	Untreated	–	4.2	–	–	1.610	Signs of transtentorial herniation	1.3 ± 0.3/0.0625 μm^2/15.3 ± 2.5%
P3	Male	69	Left Temporal	Surgery and radiotherapy	Chemotherapy and six sessions of hyperthermia	4.6	65.6	2.1	1.640	Generalized edema with transtentorial and tonsillar herniation	1.2 ± 0.3/0.0625 μm^2/11.8 ± 1.8%

Notes:

a All lesions showed aspects of solid tumor with necrosis and hemorrhage, and all autopsies demonstrated multifocal deposition of magnetic nanoparticles, particularly within the geographic necrosis, as the morpho-histological aspects were similar among patients expressing GFAP in one third of the tumor cells and S100 in most cells;

b There was no difference between surgical biopsies of patients 1 and 3 regarding the rate of mitosis and proliferation;

c The patient died of pneumonia 14 days after instillation of the magnetic fluid.

Source: Van Landeghem et al.²⁷

Abbreviations: GFAP, glial fibrillary acidic protein; MHT, magnetic hyperthermia.

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