Table 5.

Magnetic solid lipid nanoparticles (mSLNs) as drug delivery systems and theranostic agents against cancer.

mSLN (Particle Size) + Surface Modification	Drug + Cancer Model	Results	Ref
Wax-mSLNs (200 nm). Surface modification is not mentioned.	Drug: DOX. Cancer model: murine melanoma B16f10, Hs578t, and Dox-resistance cell lines (t84 and HCT-15).	Efficacy studies showed that DOX delivery in combination with 1 h of MH promoted a significant cytotoxic effect in vitro in melanoma cell lines compared to a treatment in which no MH was supplied (~5% vs. ~50%, respectively, when using 1 µg DOX/mL of DOX-mSLNs). Similar results were obtained in 3D in vitro using melanoma spheroids. The same dual treatment approach was applied to DOX-resistant cell lines obtaining approximately 40% of cell viability reduction.	[186]
Wax-mSLNs (250–300 nm). Surface modification is not mentioned.	Drug: OncoA. Cancer model: human lung carcinoma cell line (A549 cell line).	mSLNs showed an outstanding performance as a T2-contrast agent in MRI (r2 > 800 mm−1 s−1). In vitro, the combination of co-loaded MNPs and OncoA with MH greatly decreased the cell viability (virtually 0% vs. 53% when performed without MH application) at the same 40 µg OncoA/mL and 25 µg Fe/mL doses).	[187]
Wax-mSLNs (200 nm). Surface modification is not mentioned.	Drug: DOX. MH: 224 kHz, 13 A, 27.6 W for 1 h for in vitro 174.5 kHz, 23 mT for 1 h for in vivo. Cancer model: murine malignant melanoma cells (B16F10 cell line); C57BL/6 mice (8–10 weeks old) were subcutaneously injected in interscapular region of mice with 5 × 105 B16F10 cells.	mSLNs-DOX showed higher cytotoxicity activity than free DOX in the whole range of DOX concentration tested both in vitro and in vivo. In vitro, a remarkable enhanced cytotoxicity was obtained when cells were exposed to the combination of chemotherapy (0.5 µ/mL) and 1 h MH (40% of viable cells vs. 85% without MH). Under a higher incubation concentration of mLNVs-DOX (1 μg DOX/mL), the results showed a cytotoxicity virtually to 100% under a combination of mLNVs-DOX with MH. In vivo, the dual treatment promoted the slowest tumor growth and smallest tumor volume, which was on average 3 and 2.1-fold smaller than the saline and free-DOX groups. Regarding imaging capability, T2-MRI relaxation times of animal tumors treated with mSLNs were on average over 15% shorter than those of control animals injected only with saline.	[176]
Sor-mag-SLN (250 nm). Surface modification is not mentioned.	Drug: Sor. Cancer model: liver cancer model (HepG2 cell line).	The nanocarriers showed a loading efficiency of 90% and stability in an aqueous environment. Moreover, the developed nanoparticles presented a good cytocompatibility with a high antiproliferative effect against the cancer cells (40% higher in comparison to control group). This effect was associated with the capability of these nanocarriers to be specifically accumulated in the tumor region and the application of a local AMF.	[188]
Mag-SLN (150 nm). Surface modification is not mentioned.	Cancer model: myeloid leukemia cancer model (HL-60/wt cell lines; L-60/adr with MRP1 = ABCC1 over-expression; HL-60/vinc with P-glycoprotein = ABCB1 over-expression), leukemia cancer model (Jurkat T-cells), and glioblastoma cancer model (U251 cell line).	The developed nanoparticles showed promising results in the context of cancer therapy, in particular against drug-resistant cell lines. The mag-SLN revealed higher cytotoxicity against resistance cell lines in comparison to DOX alone when under an AMF. Moreover, the data showed that the cells treated with a dual treatment presented an increase of nuclei fragmentation and condensed chromatin. The mag-SLNs plus MH presented apoptotic and necrotic activities. The authors proposed that the production of ROS was the cause of the higher cytotoxicity observed in the cells treated with the particles.	[168]
LMNV (100 nm). Surface modification is not mentioned.	Drug: TMZ. Cancer model: glioblastoma cancer model (U-87 cell line) and brain-endothelial cell model (bEnd.3 cell lines, an immortalized mouse BEC line).	In vitro results showed that lipid-based magnetic nanovectors presented a good loading capacity with a sustained release profile of the encapsulated chemotherapeutic drug. Moreover, a complete drug release was observed after the exposure to (i) low pH (4.5), (ii) increased concentration of hydrogen peroxide (50 µM), and (iii) increased temperature achieved through the application of an AMF. The authors noted that these nanovectors could be used as a potential hyperthermia agent, since they managed to increase apoptotic levels and decrease proliferative rates when a magnetic field of 20 mT and 750 kHz was applied, increasing the temperature to 43 °C. During in vitro tests, the capacity of LMNVs to cross the BBB was observed, where after 24 h of exposure, 40% of LMNVs were able to translocate inside the glioblastoma cells.	[189]
Gd(III)-loaded pSLNs were modified with with cellular receptors, DSPE-PEG2000-folate.	Cancer model: murine macrophage model (Raw 264.7 cell line), lymphoma cancer model (U937 cell line), and human ovarian adenocarcinoma (IGROV-1 cell line). Female Balb/C nu/nu were subcutaneously injected with 1 × 107 of IGROV-1 cells.	The data showed that pSLNs could effectively internalize in in vitro and in vivo models. Moreover, the authors detected the nanoparticles’ T1-MRI signal, at least after 30 min post-injection. The cytotoxic studies showed a decrease in cell viability when the loaded Gd(III) concentration increased within the pSLN (below 50% of viable cells). The results also demonstrated that Gd(III)-loaded pSLNs could efficiently target the cancer cells and due to the EPR effect in conjunction with its targeting properties allowed a higher internalization capacity. Moreover, they could be used as a molecular imaging tool. A macrophage uptake experiment in vivo showed that the nanoparticles could avoid the macrophage internalization and circulate for at least 6 h, increasing altogether the tumor uptake. However, the authors noted an excessive accumulation in the liver with slow elimination rates after performing the biodistribution study.	[184]
Sor-Mag-SLNs (300 nm). Surface modification is not mentioned.	Drug: Sor. Cancer model: liver cancer model (HepG2 cell line).	The results showed an increase of the cytotoxic effects of sorafenib. Using an external magnetic field, it was possible to guide and improve the drug effect in the desired area. Quantitative evaluation of cell mortality indicated 95% of cell death compared to the control (5%). Moreover, the authors mentioned that the nanocarriers could be an effective approach to reduce the undesired side effects of chemotherapeutic drugs and improve their pharmacokinetic properties.	[190]
Nut-Mag-SLNs (180 nm) were loaded with fluorescenin-PEG-DSPE (FITC-PEG-DSPE).	Drug: Nut. Cancer model: glioblastoma cancer model (U-87 cancer cell line) and brain endothelial cell model (bEnd.3 cell lines, an immortalized mouse BEC line).	Nut-Mag-SLNs presented a good colloidal stability and could efficiently cross an in vitro blood–brain barrier model. The authors observed that the nanovectors were magnetically activated, enabling their pass through the BBB, and could also deliver the drug loads to glioblastoma cells. Moreover, they observed an enhanced antitumor activity as they obtained a 50% reduction in the metabolic activity with lower drug concentrations. Increased pro-apoptotic activity was also noted. These nanocarriers presented several advantages compared to the free drug in overcoming several limitations in glioblastoma treatments, for instance, (i) Nut-Mag-SLNs could cross the BBB, (ii) Nut-Mag-SLNs had the ability to be magnetically guided to the tumor region, and (iii) the nanoparticles showed a powerful inhibition of cancer cell proliferation while increasing the pro-apoptotic activity.	[181]
mSLNs (180 nm). Surface modification is not mentioned.	Cancer model: colon cancer model (HT-29 cell line).	By applying magnetic hyperthermia, results showed that mSLNs could constantly maintain the maximum temperature achieved (46 °C, in 40 min) during 1 h of exposure to a magnetic field (250 kHz and 4 kA/m). These results translated into a decrease in cell viability after magnetic treatment (up to 52% comparatively to 100% of control group). Interestingly, no cytotoxic effect was observed if only one (but not both) of the components was used alone for treatment.	[165]

Mag-SLN (mSLN): magnetic solid lipid nanoparticles; Sor: sorafenib; MRP1: multidrug resistance-associated protein 1; TMZ: temozolomide; BBB: blood–brain barrier; pSLNs: paramagnetic solid lipid nanoparticles; AMF: alternating magnetic field; DSPE: 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine; PEG: poly(ethylene glycol); EPR effect: enhanced permeability and retention effect; Nut: Nutlin; DOX: doxorubicin; OncoA: oncocalyxone A.