Magnetic Solid Nanoparticles and Their Counterparts

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1		Manuel Bañobre-López	+ 4084 word(s)	4084	2022-02-28 07:49:29	\|
2	format correction	Peter Tang	Meta information modification	4084	2022-03-09 04:05:15	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14030506

Cancer is a malignant disease involving uncontrolled and rapid growth of aberrant and nonfunctional cells as a result of epigenetic and genetic modifications. These have the capacity to metastasize to distant organs of the body. Within the cancer field, magnetic nanoparticles (MNPs) have gained interest as highly functionalized tools that can be applied to diagnosis, monitorization, and therapy. Their relative straightforward synthesis, functionalization, purification, and characterization, together with their usually good biodegradability and diagnostic platform potential, confer major advantages for their use in cancer theranostics. Magnetic solid lipid nanoparticles (mSLNs) represent a new class of functional nanoplatforms that usually consist of inorganic magnetic nanoparticles incorporated in solid lipid nano-matrices and which have great applicability in the medical field.

solid lipid nanoparticles magnetic nanoparticles magnetic solid lipid nanoparticles cancer theranostics MRI-contrast agents

1. Introduction

Cancer is a malignant disease involving uncontrolled and rapid growth of aberrant and nonfunctional cells as a result of epigenetic and genetic modifications. These have the capacity to metastasize to distant organs of the body ^[1]. This heterogeneous disease ranks as a principal public health concern worldwide ^[2]. In total, 18.1 million new cancer cases were diagnosed in 2018, whilst 9.6 million deaths were related to the disease. Moreover, a 60% incidence increase in new global cancer cases is expected to occur over the next two decades, according to the World Health Organization (WHO) ^[3].

The main tool for an efficient cancer treatment is an early diagnosis, as according to WHO reports, 30% of patients could have successfully been considered cured if diagnosed at an early stage of the disease. When the tumor is identified early (in the first stages), combinations of surgery, chemotherapy, and radiotherapy are usually viable options as treatments with higher success rates and less side effects ^[4]. However, the latter occurrence of the symptoms leads quite often to a cancer diagnosis at more advanced stages—stage three or four. Then, the subscripted cancer treatment will be dependent on the type and stage of the tumor/s, in addition to the patient’s condition—older and weaker patients are normally spared treatments due to their aggressiveness—where late diagnosis (and/or surgical tumor inaccessibility) limits the treatment of cancers to chemotherapy and immunotherapy ^[4].

Several research fields are focused on finding anticancer drugs that achieve a selective phenotypic cytotoxic effect on cancer cells. These should, at the same time, stop or slow down tumor growth whilst being less toxic (or ideally innocuous) to healthy tissues ^[5]. Chemotherapeutic agents obtain different mechanisms of action depending on their pharmacophore structure and other moieties (its chemical structure). Hence, chemotherapeutics can be classified as alkylating agents (e.g., cisplatin and cyclophosphamide), anti-metabolites (e.g., methotrexate and fluorouracil), anthracyclines with DNA-binding antibiotics (e.g., doxorubicin (DOX)), topoisomerase inhibitors (e.g., etoposide), and microtubule stabilizers (e.g., paclitaxel, docetaxel) ^[4]^[6]. Although usually effective, the main drawback of these drugs is their selectivity issues, as they can usually have a phenotypic effect on the much more abundant healthy tissue as well. This can cause short and then long-term health sequels in patients and even death ^[6]^[7]^[8]^[9].

When administered intravenously, chemotherapeutics are systemically distributed and therefore can potentially reach all organs. Given its nature as a blood detoxifier—converting xenobiotics into waste products—the liver is usually specially affected by the non-selective action of the drugs ^[10]. Systemic distribution also reduces the in situ concentration of the compounds in the tumor area. They may therefore require a higher posology to achieve the desired effect, compromising their narrow therapeutic margins ^[5]^[11]^[12]. The poor pharmacokinetics, specificity, and the generation of cancer multidrug-resistance (MDR) can further reduce their therapeutic margins ^[5]^[6]^[7]^[13]. Altogether, the treatments available and the current poor success rates associated with them require smart targeted strategies to achieve chemotherapeutic selectivity in addition to better early diagnosis and in situ therapies.

Nanotechnology has evolved into a multidisciplinary field, having revolutionized many scientific and nonscientific areas since 1970, including: applied physics, materials chemistry, chemistry mechanics, robotics, medicine, and biological and electrical engineering ^[14]. In the bioscience and medicine fields, nanomaterials have a wide range of applications. In cancer therapy, for example, they have been used as diagnostic tools and as drug delivery formulations ^[15]^[16]. Their nanoscale size (1–100 nm) makes them ideal candidates for surface nano-engineering and the production of functionalized nanostructures ^[17]. Hence, they are currently being applied as drug delivery systems (DDS), sensors, and tissue engineering catalyzers, amongst others ^[18]. Due to their unique physical and optical properties and chemical stability, nanoparticles can grant selectivity to drugs for specific body/organ/tissue targeting and even for individual recognition and targeting of single cancer cells ^[15]^[19]. Hence, the nanoparticles’ characteristics can benefit the bioactivity of therapeutic compounds through the reduction of the concentration needed for a certain phenotypic outcome, potentially increasing their therapeutic margins and pharmacokinetic properties and altogether reducing their potential harmful secondary effects in healthy tissues (Figure 1) ^[14]^[18]^[19].

Figure 1. Nanomedicine applications in cancer therapy. Nanoparticles, as drug delivery systems, can enhance the drug targeting to specific body/organ/tissue or even single cancer cells through different targeting strategies (e.g., active/passive, endogenously/exogenously responsive) and different routes of administration (intravenous, oral, or intraperitoneal, among others).

Many nanoformulations have been investigated pre-clinically, yet only a minority have advanced to clinic stages ^[20]. Currently, those approved by the U.S. FDA and European Medicines Agency (EMA) ^[21] include: Abraxane ^[22], Doxil ^[23], and Patisiran/ONPATTRO ^[24]. These formulations respond to the need for creating new systems that efficiently improve drug selectivity and delivery and that help promote an accurate and safer treatment of cancer.

Within the cancer field, magnetic nanoparticles (MNPs) have gained interest as highly functionalized tools that can be applied to diagnosis, monitorization, and therapy. Their relative straightforward synthesis, functionalization, purification, and characterization, together with their usually good biodegradability and diagnostic platform potential, confer major advantages for their use in cancer theranostics ^[25]^[26]^[27]^[28]^[29]^[30]^[31]^[32]^[33]^[34]^[35]. Recently, NanoTherm^®, a new platform for the intermittent glioblastoma treatment multiform, was approved by the EMA and evidences the potential these systems have in cancer diagnosis and therapy ^[36]. Another type of nanoparticle, which is based on solid lipid nanoparticles (SLNs), has also been studied abundantly and is currently applied in cancer therapy. Here, SLNs have been used as a drug delivery system that has the potential to control the release of the loaded chemotherapy and decrease their toxicity with an enhancement of biocompatibility in comparison to inorganic or polymeric nanoparticles ^[37]^[38]^[39]^[40].

2. Magnetic Nanoparticles

MNPs are being widely studied nowadays in many areas (such as in the biomedical field), because they offer a plethora of opportunities ^[25]. Their physicochemical properties, superparamagnetic behavior, small size, and capability to promote biological interactions at the cellular and molecular level ^[25]^[26] allow MNPs to be employed as drug delivery systems ^[28]^[29], magnetic resonance imaging contrast enhancers ^[30], and hyperthermia inducers ^[31] for the treatment of cancer.

A key component of these MNPs is the metal used in their formulations. Thus, they are usually ferrites (MFe₂O₄, Ni_aZn_(1−a)Fe₂O₄, Mn_aZn_(1−a)Fe₂O₄) ^[41], metal alloys (FeCo, alnico, and permalloy), or iron-based magnetic oxides (hematite (α-Fe₂O₃), magnetite (Fe₃O₄), and maghemite (γ-Fe₂O₃)) ^[31]. The most commonly used nanoparticles in the biomedical field are superparamagnetic iron oxide nanoparticles (SPIONs), such as Fe₃O₄ and γ-Fe₂O₃, which present high biocompatibility and lower toxicity compared to other metal structures (e.g., quantum dots, gold nanoparticles, and carbon nanotubes (CNTs) may present lower biodegradation and body-elimination issues ^[25], together with increased cytotoxicity ^[32]^[41]). Their superparamagnetic properties enable a degree of control through the application of an alternating magnetic field (AMF). Here, selective application of the AMF can force the MNPs to generate local heat and promote the direct tumor ablation and/or the drug release into the desired region, ultimately avoiding invasive diagnostic and therapeutic techniques ^[32]^[33].

MNP performance is dependent on their composition, morphology, surface coating, and size of the inorganic core, all of which influence their in vivo behavior ^[25] and potential toxicity ^[41]. Studies performed in a mouse model with MNPs coated with DMSA (dimercaptosuccinic acid) revealed accumulation in the liver, spleen, and lungs without side effects ^[34]. Hence, the functionalization of the formulations’ surface with targeted ligands can be a strategy to reduce toxicity in untargeted organs, whilst also increasing the therapeutic efficacy in targeted ones ^[41].

3. Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) were first remarked upon in the early 1990s ^[42]^[43]^[44]^[45] as an upgraded alternative of the polymeric, inorganic, and liposomal nanoparticles traditionally used until then as carriers ^[40]. SLNs are colloidal nanoparticles composed of a lipid matrix, solid at both room and body temperatures ^[46], and surfactants used as stabilizing and solvating agents (Figure 2) ^[47]. Different lipid and surfactant compositions can control the size, polydispersity, surface charge, stability, and drug release profile of the formulation ^[48]. The selection of the lipids can also influence the biodegradability, stability, and affinity by drugs and other elements (metals, dyes, etc.). Commonly, fatty acids such as mono-, di-, and triglycerides, fatty alcohols, and waxes are used for the preparation of SLNs ^[49]. The small size of the formulations (ranging from 10 to 1000 nm), the large surface-to-volume ratio, and the high drug encapsulation efficiency are the key advantages of SLNs. Additionally, these formulations can potentiate the therapeutic effectiveness of hydrophobic pharmaceuticals ^[36] by improving their bioavailability, protection from biodegradation and clearance by the reticuloendothelial system (RES), and controlling the drug release rate ^[50].

Figure 2. Highlight the applications of SLNs and their major advantages. SLNs could be used as a drug carrier for both hydrophobic and hydrophilic drugs, capable of controlling the drug release, avoiding the “burst effect”, and additionally promoting a target delivery that decreases the systemic toxicity. These nanocarriers could be easily scaled up in a cost-effective manner ^[51].

4. Magnetic Solid Lipid Nanoparticles

As aforementioned, SLNs present a broad variety of advantages for the treatment of cancer. Several research groups have focused on the development of these new nanoplatforms, trying to exploit and maximize their benefits ^[52]^[53]^[54]^[55]. However, somewhat surprisingly, the magnetic material incorporation in the SLNs was not explored until quite recently.

Different metals and metal derivatives such as iron oxide, gold, and gadolinium ^[42]^[56]^[57]^[58]^[59]^[60]^[61] have been incorporated in the nanoformulations producing novel platforms with great potential in cancer therapy and tissue imaging. In particular, encapsulated iron oxide and gadolinium have been studied abundantly as magnetic delivery systems that can be guided to tumor regions and/or activated for controlled drug release and cell ablation (magnetic hyperthermia) via an external magnetic field or by endogenous stimuli such as pH changes ^[62]^[63]^[64]^[65]. In particular, iron oxide nanoparticles are considered biocompatible and safe materials and are the gold standard magnetic nanoparticles in medical research, despite the fact that they are able to cause cytotoxicity from the generation of ROS species via the Fenton reaction, which can lead to the damage of DNA, lipids, proteins, and carbohydrates ^[65]^[66].

Magnetic solid lipid nanoparticles (mSLNs) represent a new class of functional nanoplatforms that usually consist of inorganic magnetic nanoparticles incorporated in solid lipid nano-matrices and which have great applicability in the medical field ^[67]^[68]. For example, Igartua et al. ^[67] synthesized a colloidal lipid nanoparticle loaded with magnetite using a warm emulsions methodology. The preliminary small size and high entrapment efficiency of the mSLNs managed to fuse the benefits of both types of nanocarriers (SLNs and MNPs) and overcome their independent application issues. mSLNs have shown an enhanced colloidal and chemical stability and caused lower toxicity in vitro compared to the MNPs alone, as described by Müller and colleagues ^[69], and in vivo using a immunocompetent mice model as described by García-Hevia L. and co-workers ^[70]. Other groups developed mSLNs constituted with polylactide/glycolide (PLA/GA) and loaded with several different quantities of magnetite to show a controlled drug release via magnetic heating up to 42 °C ^[71].

mSLN synthesis can be achieved through different methodologies, including emulsification ultrasonic dispersion ^[72], emulsification–diffusion followed by sonication ^[73], chemical co-precipitation ^[53]^[74], and solvent evaporation ^[75]. The characterization of the resulting mSLNs allows for the elucidation of the structure of the formulation, where the metals can be embedded in the core and/or surface as described by several authors ^[73]^[74]^[75]^[76]. On the one hand, the metal nanoparticles can be embedded in the lipidic core, where the MNPs’ hydrophobic surface shows chemical affinity by the lipid matrix to yield mSLNs. For the mSLN surface, different surfactants can be used during the synthesis to confer colloidal stability and solvation in water. A schematic representation of mSLNs can be seen in Figure 3.

Figure 3. Schematic structure of magnetic solid lipid nanoparticles (mSLNs) and their application in cancer theranostics. Due to the properties of magnetic nanoparticles (MNPs), mSLNs can be used for diagnostic purposes (e.g., MRI application) and cancer therapy via magnetic hyperthermia. Moreover, magnetic hyperthermia in mSLNs offers an extra level of control over the drug release into the region of interest, ultimately increasing the cytotoxicity for cancer cells in comparison with SLNs or MNPs alone.

On the other hand, the metal nanoparticles can be confined in the mSLN surface. Hsu and Su ^[66] synthesized a new platform that conjugated magnetic heating with a controlled release of the encapsulated drugs (tetracaine) using lipid matrices with γ-Fe₂O₃ particles on their surface. γ-Fe₂O₃ could then be energized using an external magnetic field, generating enough heat to induce direct thermotherapy as well as to stimulate the release of the loaded drugs in the surrounding tissues. They applied an alternating magnetic field of 60 kA/m at 25 kHz to obtain an increase in temperature of 13 °C in 20 min (up to absolute values of 50 °C). Approximately 35% of the encapsulated tetracaine was released from the mSLNs in 20 min of exposure to the alternating magnetic field ^[66].

Another example of MNPs loaded in SLNs with applicability in controlled drug release was explored by Pang et al. Here, MNPs were first coated with oleic acid and then loaded in the SLNs. Ibuprofen was chosen as a model drug to be also loaded within the mSLNs due to its well-known pharmacological properties. They observed a drug encapsulation efficiency of 80%, and the interaction between the encapsulated MNPs with magnetic hyperthermia application promoted a controlled release from the nanoformulation. They concluded that magnetite-loaded SLNs are viable alternatives as drug delivery systems ^[72]. Moreover, Oliveira and colleges developed mSLNs with PTX encapsulated via the emulsification–diffusion method. The data showed a 67% encapsulation efficiency, as well as an in vitro drug release rate increase when the temperature was raised from 25 to 43 °C by magnetic hyperthermia. They concluded that the lipid layer played a key role in the controlled drug release mechanism in response to a temperature increase. Similarly, they demonstrated that PTX-loaded mSLNs are promising systems to increase the drug bioavailability, potentially improving future cancer treatments ^[73]. Using the same approach, Abidi et al. observed a gradual release of albendazole from mSLNs, which reach 84% after 36 h. Their data confirmed these mSLNs as fast and high-efficiency drug delivery systems ^[77].

Recently, Ahmadifard and co-workers also developed chitosan-coated mSLNs, loaded with letrozole (LTZ), via a modified solvent evaporation–ultrasonic combination method. With this system, 90.1% of the drug was encapsulated, whereas 50% was released after application of a low-frequency pulsed magnetic field (LFPME) at 50 Hz for 1 h, in comparison with the non-LFPME application where the same amount of drug was released in 12 h. Similar to previous reports, their results demonstrated a promising strategy to induce a localized temperature through a magnetic field and a control of chemotherapy treatment in drug-resistant cancers via LTZ release from a nano delivery system ^[74].

Ghiani et al. synthesized a novel nano-sized contrast agent composed of gadolinium (III) complexes on the surface of solid lipid nanoparticles with a particle size around 50 nm. The developed paramagnetic solid lipid nanoparticles (pSLNs) demonstrated good stability. For MRI studies, IGROV-1 ovarian carcinoma-bearing BALB/c nu/nu mice were used. In vivo MRI revealed an enhancement of the T₁ signal in the tumor region, in particular when folate, used as a targeting ligand, was used to functionalize the nanoparticles’ surface (through intravenous injection). Biodistribution studies in C57BL/6 mice showed an accumulation of pSLNs in the liver, highlighting the need for adjusting the approach in order to enhance the rate of hepatic clearance ^[78].

A recent published work by Rocha et al. describe the synthesis of a novel hybrid magnetic nanocomposite (mHNCs-DOX) which simultaneously incorporates a chemotherapeutic drug (DOX), superparamagnetic iron oxide NPs as a T₂-contrast agent (Fe₃O₄) and paramagnetic manganese oxide NPs (MnO) as a T₁-MRI contrast agent ^[79]. Dual T₁/T₂ MRI performance and additional thermo-chemotherapy capability were observed in vitro in triple-negative breast carcinoma cells (Hs578t cancer cell line) ^[79]. Table 1 further summarizes representative studies involving mSLNs for cancer treatment/theranostics.

Table 1. 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.	^[80]
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).	^[81]
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.	^[70]
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.	^[82]
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.	^[62]
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.	^[83]
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.	^[78]
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.	^[84]
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.	^[75]
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.	^[53]

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.

Altogether, the mSLNs have been demonstrated to be promising tools because of their good biocompatibility ^[65]^[66]^[73], improvement of thermo-responsiveness compared to SLNs ^[62], efficiency in targeting tumors ^[68]^[75], and their high drug encapsulation efficiency. Furthermore, these nanosystems allow the application of magnetic hyperthermia as a means to provide thermal therapy and control drug release ^[52]^[66]^[75], in addition to being used as MRI contrast agents ^[68]^[75]. Still, there are only few studies involving tests in vivo, highlighting the need to validate the performance of these nanocarriers in more biological complex systems.

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