**5. Drug delivery of functionalized nanoferrites for cancer treatments**

Conventional drug delivery methods rely on the absorption of drugs and transport across biological membranes through diffusion and systemic transport. The targeted drug delivery, on the contrary, focuses on enhancing the concentration of the chemotherapeutic drug in the disease parts of the body [87]. The drug release studies, usually, are realized in simulated physiological conditions and measured by HPLC [30] or UV–Vis spectra [88]. For UV–vis spectrophotometer, the percentage of release drug is given by [49]:

$$Drug\ release \% = \frac{amount\ of\ release\ drug}{amount\ of\ loaded\ drug} \times 100\tag{2}$$

The drug release mechanisms evaluate with different models, such as zero-order, first-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell. A detailed explanation of these five mathematical models to investigate drug release kinetic on *in-vitro* release data was reported by Jafari *et al.* [75]. The best mathematical model with a high correlation coefficient determines the suitable mathematical model and confirms drug release kinetics. Some results reported in the literature are summarized next:


polymer. The release data for pH 5.8 and pH 7.4 fits well with the Higuchi model indicating a surface diffusion mechanism, in other words, the diffusion of the surface-bound [60].


The efficiency *in-vitro* tumor-targeted drug delivery of the nanoferrites loaded with anticancer drugs is evaluated by fluorescence microscopy imaging [58]. Here, the authors used human cancer cell lines as: MCF-7, A-549 [81], A431 [37], SKOV-3, MDA-MB-231 [61], SK-BR3 [33], MDA-MB-231, MCF-10A [90] in a culture media which is incubate in presence of the nanoferrites. Moreover, cytotoxicity determines the efficiency of the formulation [51]. The cytotoxic effect of the nanoformulation tests the cell viability (MTT) assay. It evaluated the ability of viable cells to reduce MTT to formazan crystals. The following equation used to calculate the % of cell viability is [91]:

$$\% \text{@Cell viability} = \frac{\text{average sample read}}{\text{average control read}} \text{x100} \tag{3}$$

*In-vivo* antitumor therapy came tests in mice. Here, hepatoma cell lines (H22) inoculate into the back of the hind leg through subcutaneous injection. When the size of the tumor was grown to about 40 mm3 were treated with the drug-loading nanoferrites. All the formulations were injected intravenously through the tail of mice. The tumor inhibition rates could be determined by fluorescence microscopy [67]:

$$Tumpor\ inhibition\ rates = 1 - \frac{tumor\ volume\ with\ drug\ group}{tumor\ volume\ in\ control\ group} \mathbf{x100} \tag{4}$$

Nanoferrites have got importance in terms of biological applications due to their physicochemical properties. To enhance their cancer therapeutic effect stimuliresponsive combine treatments have been developed:

• *Magnetic hyperthermia therapy.* Here, drug release may be activated applying an external alternating magnetic field which transforms electromagnetic energy into heat and induces the drug carrier to release its contents into the target site [34, 36, 57]. The combined techniques can enhance the therapeutic effect by increasing the blood flow and improving the oxygen supply to the tumor sites when increasing the temperature of the tumor sites from 37*°C* to hyperthermia temperature 42–45°C. This phenomenon can also enhance the drug delivery efficacy and increase the drug dosage to the target tumor sites. To determine the intracellular drug delivery of ferrite nanoparticles load with anticancer drugs, which were placed in dialysis membrane tubes and dialyzed at 37*°C* with different pHs [22].

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


Usually, drug delivery is dramatically pH-dependent. Most of the papers reported in the literature studied the influence of pH on the release behavior of the carrier. pH variations at different physiological situations trigger a controlled delivery of drugs at different sites. The pH-responsive drug release under three conditions of simulated gastric fluid (pH 1.2), cancer microenvironment (pH 5.4), and simulated body fluid (pH 7.4) during a determined time [61]. **Table A3** shows the influence of the pH on the release efficiency of the carrier. From there, in all cases, the acidic pH stimuli the rate of drug delivery. **Table 2** shows the drug release percentage at cancer microenvironment conditions for nanoferrite formulations. The time of drug release is one of the essential factors in drug delivery. **Figure 3**


#### **Table 2.**

*Summary of drug delivery conditions and results reported in the literature for ferrite nanoparticles loaded with anticancer drugs (system). The main conditions are the cancer microenvironments (pH), the time (t), and the temperature (T) of release. The drug release (DR) percentage measures the efficiency of the process.*

#### **Figure 3.**

*Summary of the drug delivery efficiency as a function of the time reported in the literature. All the data plotted are shown in Table 2 and A3.*

shows a summary of the drug delivery efficiency results reported in the literature. The highest efficiency for drug delivery (97%) is reporting for magnesium-cobalt ferrite loaded with 5-fluorouracil for 48 h [21]. The lowest efficiency for drug delivery (8,9%) was reported for magnetite load with Curcumin for 37 h.

## **6. Conclusions**

Recent advances reviewed on synthetic routes for the obtention of nanoferrites for drug delivery applications. The most popular ferrite is magnetite obtained by chemical coprecipitation method with sizes ranging from 20 nm to 30 nm, and spherical shape. Moreover, it reviews the magnetic properties of ferrite nanoparticles. Often, the nanoferrites are superparamagnetic. Coated the nanoparticle's surface with organic or inorganic molecules makes the nanostructures optimal for drug delivery applications. Functionalization reduces the agglomeration and toxicity of the nanoferrites. Physical adsorption among the functional groups of the cancer drugs and the coated molecules on the nanoparticles preserve the chemical structure of the medicament. Oncology drugs were detailed for drug delivery applications. The most popular solvent for drug-loading is water. It discussed the influence of parameters such as: pH, temperature, and time on drug-loading.

It reviewed the main drug release mechanisms for investigating pharmacokinetics. The release mechanism is highly dependent on the pH, the type of drug, and the nanocarrier. It discussed the stimuli-responsive combine treatments for cancer drug delivery applications. Some challenges persist:


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

