**3. Nanoferrites functionalized and functional groups for drug delivery in cancer**

Non-functionalized nanoferrites (non-coating material on their surface) seems to be not optimal for drug delivery application. Surface energy minimization processes can promote agglomeration, percolation as well as other unwanted effects. Some of the most common problems whit this kind of nanosystems are [12]:


To deal with these problems, nanoparticles have been coating with organic or inorganic molecules (functionalization). The surface engineering of ferrites could be accomplished during nanoparticle synthesis (in-situ) or after this (ex-situ). A detailed review of the coating and functionalization strategies was reported for nanoparticles in drug delivery applications by Pinelli et al. [70]. The surface functionalization procedure and choice of appropriate solvent are crucial factors for obtaining nanoferrites. Here, the repulsive interactions among nanoparticles prevent agglomerations [71]. Moreover, functionalization promotes several advantages such as stable dispersions, biocompatibility, biodegradability, and reduced toxicity. Usually, functionalized nanoparticles loaded with drugs adopt covalent/ noncovalent interaction methods. Conjugation of a drug to a carrier by nonbiodegradable linkages results in: changing the drug chemical units, reducing drug efficacy, and displaying relevant side effects. The drug remains unharmed by using physical adsorption for drug conjugation, and no changes occur in the chemical units and the controlled drug release behavior. In this case, the idea deals with functionalized nanoparticles that have an opposite electrical charge to the cancer

### *Ferrites - Synthesis and Applications*

drug to promote the electrostatic interaction [42]. Moreover, surface functionality gives significant strength to bind and adsorb cancer drugs using specific functional groups. The characterization techniques for studying the functional groups attached to nanoparticles for drug delivery applications have been reported previously [12].

Some examples of functional groups commonly used to functionalized nanoferrites in drug delivery applications are:


The functionalization can allows high drug encapsulation, stabilizes the nanocarrier, and reaches the cancer site-specific. Furthermore, the coating uses to reach the target cells without getting removed by the reticuloendothelial system of the body and to have a capable surface for keeping the drug unharmed until reaching the location of interest. The performance enhancement achieves through functionalization with suitable ligands that will bind to the aimed receptors of pathological tissues. The size of the nanocarrier has paramount importance for rendering it absorbable by tumor tissues [68]. The inclusion of active targeting functionalities results in drug accumulation within tumors, tumor cells, or immune cells and allows for reduced dosages due to specificity. Functionalized ferrite nanoparticles have been used for: a) imitate ligand binding to receptors, b) for initiation of cellular signaling, c) for increased stimulation of immune cells to better infiltrate and extinguish immunosuppressive tumors [73]. Commonly, the pH of cancer cells (tumor) is acidic ranging between 4 and 5. It is due to the presence of lactic acid, which starts due to inefficient consumption of glucose [74]. On the other hand, the pH in an extracellular matrix or bloodstream is natural (pH = 7) [75]. This difference in pH offers to fabricate functionalized nanoparticles as a pH-sensitive trigger for drug delivery applications.

The most popular drugs for cancer delivery applications, using ferrites as nanocarriers are: Doxorubicin [58], 5-Fluorouracil [21], Docetaxel [76], Hesperidin and Eugenol [60], Curcumin [77], Tamoxifen [55], Cisplatin [78], Nilotinib [79], Camptothecin [38], and Telmisartan [20]. Hydrophobicity of the orally administered drugs for cancer treatments has low systemic bioavailability [80]. It produces low water solubility and can cause serious adverse effects [62].

Among functionalized nanoferrites investigated to load cancer drugs, one can find:

1.Zinc ferrite functionalized with Polyethylene Glycol (PEG) and chitosan loaded with Curcumin [80]. Chitosan takes cationic amine functional groups, at low pH, which would involve an ionic gelation process with polyanions to form nanoparticles. It is used as an effective drug carrier, where the reactive amine groups on the chitosan side chain are used for functional group modifications. The hydrophobically modified chitosan improves the encapsulation efficiency of the carrier towards the hydrophobic drugs [34].

*Nanoferrites-Based Drug Delivery Systems as Adjuvant Therapy for Cancer Treatments.… DOI: http://dx.doi.org/10.5772/intechopen.100225*


Proteins are promising carriers for drug delivery applications. The main advantages are the abundance of active sites, improved biocompatibility, easy availability, and pH-dependent swelling behavior. The last one allows the programmed release of the cytotoxic agent in response to the acidic cancer microenvironment [82].

DFT calculations demonstrated Cisplatin on graphene oxide can be adsorbed by the functionalized nanoferrites. Here, hydrogen bonds forming with hydroxyl and epoxy functional groups. It involves the formation of the amide bond between Cisplatin and the COOH functional group of graphene oxide. In the case of glutaraldehyde, the functional group is CHO, which formed the amide bond between Cisplatin and the CHO functional group [18].

### **4. Drugs loaded on functionalized nanoferrites for cancer treatments**

Drug-loading of nanoparticles plays an essential role in drug delivery systems. There are several ways through which the drug can load with the functionalized nanoparticle:


The second key point in functionalized nanoparticles design is the necessity to provide the nanoparticles with specific properties. The interaction with the external environment in the human body increases the targeting action towards determined sites [70].

Drug-loading involves several variables such as the solvent type and amount of it, the temperature, time of loading, and the drug-loading capacity. The most popular solvent for drug-loading is water (see **Table A2**). Less popular solvents involved in drug-loading are ethanol, dichloromethane, and saline solution. Usually, the solvent quantity varies from 1 *ml*to 200 *ml*. The drug-loading capacity represents the amount of drug loader per unit weight of the nanoparticle. Drug-loading represents the percentage of the nanoparticle mass that is due to the encapsulated drug. Loading capacity can calculate by the amount of total entrapped drug divided by the total nanoparticle weight. The drugloading values reported for nanoferrites ranging from 0.016 [64] to 3.3 [63]. These values correspond to cobalt ferrite loaded with Doxorubicin and Docetaxel, respectively. The loading-drug temperature ranges from 4°C [54] to 55°C [33].

From **Table A2** many reports did not include the drug-loading solvent, the solvent quantity, and the drug loading capacity. The efficiency of drug-loading measure by a high-performance liquid chromatography system (HPLC) [30] or ultraviolet–visible spectroscopy (UV–Vis) [18]:

$$Drug - loading \% = \frac{\text{total amount of drug} - \text{free amount of drug}}{\text{total amount of drug}} \times 100 \tag{1}$$

The free amount of the drug is measure by the absorbance of the supernatant in a UV–Vis spectrophotometer at the maximum wavelength of the dissolved drug. The nanoferrites can magnetically remove from the solution instead of the centrifugation process. The maximum wavelength for anticancer drugs are: Doxorubicin at 479 *nm* [23], Curcumin at 425 *nm* [34], Camptothecin at 480 *nm*, [68], 5-Fluorouracil at 266 *nm* [21], Cisplatin at 300 *nm* [18], Imanitib at 260 *nm* [31], Telmisartan at 296 *nm* [20], and Tamoxifen at 250 *nm* [55].

The time of loading is one of the essential factors in drug-loading. **Figure 2** shows a summary of the drug-loading efficiency results reported in the literature. The highest efficiency for drug-loading (98,3%) is reporting for calcium ferrite loaded with Curcumin in ethanol solvent at 100 *mL* with a drug-loading capacity of 0.4, at room temperature for 3 *h* [34]. The lowest efficiency for drug-loading (8,4%) is reporting for cobalt ferrite. It is loaded with Docetaxel in 10 *mL* of dichloromethane at room temperature for 1 *h*.

#### **Figure 2.**

*Summary of the drug-loading percentage as a function of the time reported in the literature. All the data plotted are shown in Table A2.*

*Nanoferrites-Based Drug Delivery Systems as Adjuvant Therapy for Cancer Treatments.… DOI: http://dx.doi.org/10.5772/intechopen.100225*

Other alternatives for drug-loading of nanoferrites composites include:

