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Original Article
2025
:18;
1042024
doi:
10.25259/AJC_104_2024

Targeted delivery of carboplatin via folic acid-functionalized NiFe2O4/silica nanocomposites for colon and cervical cancer therapy

, , , , ,
aDeanship of Scientific Research, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, 31441, Dammam/Saudi Arabia.
bDepartment of Stem Cell Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia
cDepartment of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi P.O. Box 59911, United Arab Emirates
dCenter for Refining and Advanced Chemicals, Research Institute, King Fahd University of Petroleum and Minerals, 31261 Dhahran, Saudi Arabia
eMaster Program of Nanotechnology, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia
fCore Research Facilitites, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
gDepartment of Nano-Medicine Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, 31441, Dammam/Saudi Arabia.

*Corresponding author: Email addresses: rjermy@iau.edu.sa, jrabindran@gmail.com (B.R. Jermy)

Received: , Accepted: ,
© 2025 Arabian Journal of Chemistry - Published by Scientific Scholar
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Abstract

Carboplatin, a platinum-based drug, offers similar mechanistic action with reduced toxicity, but is less potent than cisplatin. The present study reports the folic acid (FA)-mediated multifunctional magnetic nickel ferrite (30% NiFe2O4)/silica nanocomposite, which improves the potency of carboplatin for targeted cancer therapy. Three formulations, silica/carboplatin (Sil/Carbpt), NiFe2O4/silica/Carbpt (NiFe2O4/Sil/Carbpt), and NiFe2O4/silica/FA/Carbpt (NiFe2O4/Sil/FA/Carbpt), were formulated. NiFe2O4/silica/cisplatin (NiFe2O4/Sil/Cispt) was used for the comparative study. Additionally, 5% of FA was mixed as a composite with NiFe2O4/silica, while the carboplatin/nanocarrier ratio was maintained at 0.04. The crystallinity, textural, morphology, magnetization, and functional interactions are confirmed by various characterization techniques. The order of carboplatin release at pH 5.6 was NiFe2O4/Sil/FA/Carbpt > NiFe2O4/Sil/Carbpt > Sil/Carbpt. The diffusion mechanisms for drug release are limited to Fickian and non-Fickian diffusion mechanisms, without following the carriage (n > 0.89) or relaxation transport (n = 0.89) mechanisms. The nanoformulation cytotoxicity study of NiFe2O4/SiO2/FA/Carbpt and NiFe2O4/SiO2/Carbpt showed lower toxicity to normal cells (LC50:1054.43 µg/mL and 16542.78 µg/mL, respectively), and toxicity to colon (HCT 116, LC50:10.38 µg/mL and 8.73 µg/mL, respectively) and cervical cancer cells (HeLa LC50: 16.37 µg/mL and 11.69 µg/mL, respectively). The data show moderate toxicity, particularly in Human Foreskin Fibroblasts (HFF-1), with FA potentially enhancing the compound’s uptake. Lower LC50 values in Human colon cancer cell line (HCT116) and HELA suggest selective toxicity towards cancer cells over non-cancerous HFF-1 cells. These findings clearly indicate that silanols of NiFe2O4/SiO2 interact with FA through hydrogen bonding, while a stable amide bond between FA with Carbpt withstands the acidic/basic environment, targeting colon and cervical cancer cells.

Keywords

Carboplatin
Cisplatin
Magnetic
Multifunctional
Nickel ferrite
Targeted cancer therapy

1. Introduction

Colon cancer is one of the most common cancers that affects both men and women globally. It is the third most commonly diagnosed cancer, with an estimated 600,000 annual deaths. Conventional treatments include chemotherapy, surgical, or combination therapies. However, the drawbacks of such therapy include poor drug adsorption, dose-related toxicity, drug resistance, and a lack of selectivity between normal and cancer cells [1]. 5-Fluorouracil has been used to treat this type of cancer. However, the short half-life of such chemotherapy drugs requires multiple injections, causing frequent exposure to both normal and cancer cells [2]. Cervical cancer accounted for 570,000 cases, with an estimated 311,000 deaths among females. The standard treatment strategies include chemoradiotherapy and immunotherapy. However, the treatment remains unsatisfactory due to relapse, rapid progression to the metastasis stage, and low survival rates. For cases of relapse or metastasis, combinational chemotherapy drugs are used, including cisplatin, paclitaxel, and bevacizumab [3]. Although conventional combinational therapies are effective for cervical cancer treatment, the regimens are non-targeted, exhibit dose-related toxicity, and cause drug resistance [4,5].

Nanotechnology offers a promising solution for targeted drug delivery to the colon, improving drug penetration, release profile, bioavailability, and therapeutic efficacy at the tumor site. Several classes of nanoparticles, including polymeric, inorganic, lipid, and nanocrystalline-based drug delivery systems, have been reported [6]. In particular, the oral route of administration of nanoformulations has been reported to facilitate longer circulation half-life, reduce drug exposure, and provide a safe and effective means of treating chronic diseases [7]. However, developing a drug delivery system for the treatment of colon cancer faces several challenges due to complex physiological barriers in the human body, poor drug solubility, pH variations, and food interactions [8]. The intestinal mucus layer plays a major part in trapping and eliminating foreign particles, including toxins, pathogens, and drugs, through adhesion and spatial barriers. The fabrication of drug delivery systems requires various functional manipulations to improve drug penetration by overcoming the intestinal mucus barrier, variable physiological pH conditions (pH 5-8), and targeting cancer cells without affecting healthy cells. The development of colonic drug delivery systems can be effective based on the physiological stimulus conditions, such as colon pH, microbiota, and time. Eudragit polymer has been developed for pH-triggered drug release, while Phloral, based on a dual-triggered drug delivery system, relies on both pH and microbiota metabolism [9]. For instance, Carbpt was a chemotherapy medication used in the treatment of various cancers. The platinum-based antineoplastic agent has been developed to reduce the toxic effects associated with cisplatin. Carboplatin has been preferred over cisplatin for patients with impaired renal function, hyperhydration, and neurototoxicity [10]. Carbpt is widely used in the treatment of two types of lung cancer (small-cell lung cancer & non-small-cell lung cancer), but remains less effective for tumors arising in the gonads (ovaries), head, neck, and bladder [11]. Although Carbpt shows lesser toxicity than cisplatin at equimolar concentration, higher doses are required to treat ovarian, testicular, and lung cancers [12]. Recently, Carbpt has been encapsulated in nanocarriers with different shapes and structures [13].

Niosomes, non-ionic surfactant-based vesicles in their dehydrated form, have been reported to exhibit better therapeutic efficiency compared to hydrated niosomes for targeted drug delivery to the colon. However, the use of such a delivery system is often limited by the rapid drug clearance, low bioavailability, and difficulty in controlling drug release [14]. Therefore, delivery drugs to the colon often requires the integration of multiple delivery techniques to improve the efficacy of targeted drug delivery. Ugorji et al. developed a composite of 5-Fluorouracil-leucovorin-loaded proniosomes encapsulated in the Eudragit polymer and studied it against HCT-116 cell line. The formulation showed lower drug release under simulated gastric pH of 1.2 (about 11%), at pH 6.8, and more than 80% release at pH 7.4 [2]. The proniosomes/Eudragit combination also showed colon-specific in vitro cytotoxicity. The application of liposomes in the treatment of colon cancer has attracted considerable attention due to their similar membrane features and high biocompatibility [15]. The combination of acidity-triggered rational membrane peptide (ATRAM), liposome, and Platycodin D2 (saponin) was found to target the tumor site in colorectal cancer xenografts and reactivate apoptosis, leading to cancer cell death [16]. Plant lectin protein (peanut agglutinin), the topoisomerase I inhibitor (Irinotecan hydrochloride), and the chemodrug (capecitabine) loaded liposome were reported to enhance apoptosis in vivo and inhibit colorectal cancer cell proliferation [17].

A composite of liposome and biodegradable polymer poly lactic-co-glycolic acid (PLGA) has been reported to be effective for targeted cisplatin release for the treatment of cervical cancer. Firstly, cisplatin was functionalized with PLGA by the double emulsion solvent evaporation technique, then encapsulated in anti–vascular endothelial growth factor (anti-VEGF) antibody conjugated liposomes antibody-conjugated liposomes. The therapeutic efficiency of the formulation was studied using 3D cell culture and in vivo using tumor-bearing mice. The formulation showed a significant anti-tumor effect and exhibit cytotoxicity to cells that express VEGF [18]. Cisplatin loaded on estrogen-modified liposomes with a diameter of 100 nm showed high colloidal stability (a zeta potential value of -19 mV) and a high cisplatin encapsulation efficiency (47.7%) for the treatment of cervical cancer. The formulation was reported to exhibit dose-dependent cytotoxic effects and specific internalization in HeLa cells. The in vivo study showed target-specific accumulation at the tumor site and exhibited tumor inhibition [19].

Mesoporous silica (MSN) has attracted significant research attention in targeted cancer therapy due to its large textural characteristics [20]. The large surface area enables the impregnation of magnetic Fe3O4, Quantum dots, and encapsulates a high percentage of drug payloads and ligands, including FA [21-23]. Capecitabine loaded on glycosylated MSN, capped with chitosan polymer sensitive to pH and lectin receptors, was prepared using immersion (solvent) and impregnation techniques. The formulation showed high capecitabine loading (∼180 mg/g) due to the presence of a large surface area, pore diameter (8.12 nm), and pore volume (0.73 cm3/g). An in vitro study using HCT 116 cell lines showed pH-based drug release and higher uptake of capecitabine-loaded nanoformulation in colon cells [24]. The silane-functionalized MSN loaded with catechin and coated with pH stimuli polymer Eudragit-S100 was found to be effective in treating colorectal cancer. After silylation, the catechin-loaded formulation showed less drug release compared to plain MSN (52% in 2 h vs. 79% in 2 h). The kinetic release profile of catechin over developed nanoformulation is shown to adhere to the Korsmeyer-Peppas model with storage stability over 3 months [25].

The shape, particle size, and textural features of porous silica play a key role in bioavailability and cell internalization [26]. Recently, the synthesis and characterization of monodispersed silica have gained attention in the fields of nanomedicine and photonic biosensors [27]. Batch-to-batch reproducible silica has been applied as standards for instrument calibration and circuit fabrication [28]. Monodisperse, uniform-sized silica particles have been synthesized through various techniques, such as Stober [29], fluoride, seeded growth [28], sonochemical [30], ionic liquids [31], fly ash [32], polymeric microspheres [33], and hydrothermal synthesis [34]. We have recently shown the potential of such monodispersed spherical silica for anti-cancer and antibacterial applications [35-38]. Targeted delivery of active platinum-based drugs to colon and cervical cancer cells, avoiding toxicity to normal cells, can improve treatment efficacy, reduce drug exposure to healthy tissues, and enhance bioavailability. To date, the integration of a multifunctional magnetic nickel ferrite/monodispersed spherical silica composite functionalized with FA as pH stimuli nanocarrier has not been reported. In this study, we have developed nickel ferrite/monodispersed silica-based multifunctional pH-responsive nanoformulation suitable for colon and cervical drug delivery.

2. Materials and Methods

2.1. Synthesis

2.1.1. Synthesis of Nickel ferrite nanoparticles

The stoichiometric amounts of nickel nitrate and iron nitrate salts were completely dissolved in de-ionized water, followed by stirring. The solution was then heated at 95oC for 45 min. Afterward, the pH of the solution was adjusted to 7 using 25% ammonia solution. After mixing, the pH was further adjusted to 7 using NH3. The solution was then heated at 115oC for 1 h and subsequently at 375oC until the gel formed. Finally, the obtained powder sample was calcinated at 500°C for 4 h to obtain nickel ferrite nanoparticles [39].

2.1.2. Synthesis of NiFe2O4/Sil

For this, 0.74 g of nickel nitrate and 1.03 g of iron nitrate salt were weighed and added to silica (1.4g), then mixed well using a mortar and pestle. The mixture was then calcined at 850°C for 6 h at a heating rate of 5°C/min.

2.1.3. Synthesis of NiFe2O4/Sil/FA/Carbpt

For this, 50 mg of FA was dissolved in 5 mL phosphate buffer solution (PBS) (pH 7) and added dropwise to 1000 mg of NiFe2O4/Sil. After mixing the composite, a dry paste was obtained, which was then dried at room temperature. FA-loaded NiFe2O4/Sil was then loaded with carboplatin at a drug-to-NiFe2O4/Sil/FA ratio of 0.05 in 10 mL of normal saline solution (NSS) solution. The mixture was stirred overnight under ice-cool conditions and then filtered to obtain NiFe2O4/Sil/FA/Carbpt. The filtrate, obtained after washing with 5 mL PBS solution, was analyzed to determine the remaining Carbpt using diffuse reflectance UV-Vis spectroscopy measurement [40].

2.2. Characterization of spinel ferrite

The phase, texture, morphological, magnetic, and stability characteristics were analyzed using X-ray diffraction (XRD) (Rigaku Benchtop Miniflex XRD), Brunauer-Emmett-Teller (BET) (Micromeritics, ASAP 2020), diffuse reflectance UV-Visible spectroscopy, scanning electron microscopy-energy-dispersive X-ray (SEM-EDX), transmission electron microscopy (TEM), thermogravimetric analysis-differential thermal analysis (TGA-DTA), and vibrating sample magnetometer (VSM) analysis.

2.3. Drug delivery using dialysis membrane technique

The Carbpt release study was performed using the dialysis membrane (MWCO = 14,000 Da) technique. Before the study, the calibration was performed using 5-30 µg/mL concentrations at a specific λmax of cisplatin. Then, 15mg of the nanoformulation-containing membrane was placed in 25 mL of PBS solution, maintained at 37°C. The pH of buffer was varied at 2.0, 5.6, 7.4, and 9.0, respectively. At specific intervals, 5 mLthe of the solution was withdrawn for analysis and replaced with an equal quantity of fresh PBS solution. The study was conducted in duplicate.

2.4. In vitro study

2.4.1. Cell culture and treatment

Following our previously cultured method [41], colorectal cancer (HCT116; ATCC® CCL-247™), cervical cancer (HELA; ATCC® CCL-2™), and human foreskin fibroblast (HFF-1; ATCC® SCRC-1041™) cells were cultured in complete Dulbecco’s modified Eagle’s Medium (DMEM) at 37°C and in a 5% CO2 environment. A 96-well plate (Thermo Fisher, Waltham, MA, USA) was seeded with 15 × 103 cells/well. When the wells reached 75% cell confluence, 2.5, 5, 20, and 40 µg/mL of nanoformulations, cisplatin or carboplatin were added over the cells for 24 h. Then MTT (3-(4, 5-Dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium Bromide) cell survival assay was used to estimate the relative growth inhibition compared to control cells.

2.4.2. MTT assay

MTT assay was used to measure the cell viability, following previously published protocol [41]. Briefly, MTT was added to control and treated cells in the 96-well plate for 3 h at 37°C. After washing with PBS, the crystalized formazan dye was solubilized using isopropanol and HCl. The optical density (OD) of the solubilized dye was measured at 570 nm using a 96-well plate reader (Tecan Infinite® 200 PRO, Männedorf, Switzerland). Each treatment was represented as the percentage of cell survival compared to the control, by comparing the measured OD with that of the control.

2.4.3. Statistical analysis

A two tailed t-test was used to assess the statistically significant of the MTT cell viability assay data (P values <0.05) from a minimum of three independent sets of experiments conducted in triplicates.

3. Results and Discussion

3.1. Structure and morphology

FA, an important vitamin B ligand, has been used in targeted cancer therapy to bind with cancer cells [42]. Figures 1(a-e) shows the XRD analysis of carboplatin, FA, Sil/Carbpt, NiFe2O4/Sil/Carbpt, and NiFe2O4/Sil/FA/Carbpt. The XRD pattern of FA alone showed the presence of several crystalline peaks between 20-50° with peak maxima at 26.8° (Figure 1a). Similarly, carboplatin alone showed several crystalline peaks between 20-60° (Figure 1b). The loading of Carbpt on Sil showed only the presence of a broad amorphous silica peak at 22.6° without the crystalline peaks of Carbpt. Aghmiouni and Khoee stated that the disappearance of the crystal structure of Carbpt after loading on MSN indicates a well-dispersed drug interaction with hydroxyl groups without recrystallization inside the mesoporous cavities [43]. The nanocomposite formation of nickel ferrite with silica exhibited several crystalline peaks indexed to (hkl) planes of (220), (311), (400), (422), and (511). In the case of NiFe2O4/SS/FA/Carbpt, the crystalline peaks of both FA and carboplatin disappeared, indicating nanotransformations, while the distinct spinel ferrite phase indicated the presence of a pure phase without any impurities. The silica support also induced a similar nanoformation of carboplatin. This indicates the specific role of silica nanocarrier in altering the crystal properties of the adsorbed carboplatin and FA.

XRD analysis of (a) Carboplatin, (b) FA, (c) Sil/Carbpt. (d) NiFe2O4/Sil/Carbpt, and (e) NiFe2O4/Sil/FA/Carbpt.
Figure 1.
XRD analysis of (a) Carboplatin, (b) FA, (c) Sil/Carbpt. (d) NiFe2O4/Sil/Carbpt, and (e) NiFe2O4/Sil/FA/Carbpt.

The nitrogen adsorption-desorption technique was used to determine the textural changes (surface area and pore size distributions) of the nanoformulation after spinel ferrite, FA, and carboplatin loading onto silica (Figures 2a-f). Silica without modifications showed a type IV isotherm with H2 hysteresis loop, indicating the formation of mesopore, with surface area of 170 m2/g (Table 1). The pore size distribution of Sil was uniform with an average pore diameter of 8.3 nm and a pore volume of 0.35 cm3/g. Nickel ferrite alone exhibited inherent mesoporous characteristics with surface area of 55 m2/g. In case of NiFe2O4/Sil nanocomposite formation, the surface area decreased to 29 m2/g (83% reduction), with a pore volume of 0.12 cm3/g (57% reduction). Meanwhile, the pore diameter increased to 17 nm (approximately a two-fold increase). This increase in pore diameter suggests the deposition of NiFe2O4 on the external pore surface of Sil, thereby contributing to the enlargement of external pore mouth. After loading with FA and carboplatin, the surface area of NiFe2O4/Sil/FA/Carbpt composite was of 35 m2/g, with pore volume of 0.15 cm3/g and pore diameter of 16.5 nm.

Nitrogen adsorption-desorption isotherm of (a) Sil, (b) NiFe2O4, (c) NiFe2O4/Sil, (d) NiFe2O4/Sil/FA/Carbpt and pore size distributions of (e) Sil and (f) NiFe2O4/Sil/FA/Carbpt.
Figure 2.
Nitrogen adsorption-desorption isotherm of (a) Sil, (b) NiFe2O4, (c) NiFe2O4/Sil, (d) NiFe2O4/Sil/FA/Carbpt and pore size distributions of (e) Sil and (f) NiFe2O4/Sil/FA/Carbpt.
Table 1. Textural properties of NiFe2O4, Sil, NiFe2O4/Sil and NiFe2O4/Sil/FA/Carbpt.
NCs BET surface area (m2/g)

Pore volume

(cm3/g)

 Average pore size (nm)
NiFe2O4 55 0.19 14
Sil 170 0.35 8.3
NiFe2O4/Sil 29 0.12 17
NiFe2O4/Sil/FA/Carbpt 35 0.15 16.5

Figure 3 shows the diffuse reflectance spectra of Carbpt alone, FA, Sil/Carbpt, NiFe2O4/Sil/Carbpt, and NiFe2O4/Sil/FA/Carbpt. The variation in the chemical state of NiFe2O4, carboplatin, and FA on Sil was studied using UV-visible spectroscopy. Carbpt and FA in their free states exhibited a strong absorption at 280 nm and 370 nm, respectively (Figures 3a and b) [44]. Carbpt loading on Sil shows a strong absorption at about 220 nm, indicating the presence of tetrahedrally coordinated siloxane bonding in Sil. The coordination of Carbpt on Sil was evidenced by the extension of the absorption peaks corresponding to Carbpt at 260 and 340 nm, respectively (Figure 3c). In the case of NiFe2O4/Sil/Carbpt and NiFe2O4/Sil/FA/Carbpt, the characteristic peaks of Carbpt were observed along with peaks corresponding to the nickel ferrite spinel, extending up to 700 nm (Figures 3d and e). This demonstrates the successful formation of the nanocomposite of nickel ferrite, FA, and Carbpt on monodispersed silica.

Diffuse reflectance spectroscopy of (a) Carboplatin, (b) FA, (c) Sil/Carbpt. (d) NiFe2O4/Sil/Carbpt, and (e) NiFe2O4/Sil/FA/Carbpt.
Figure 3.
Diffuse reflectance spectroscopy of (a) Carboplatin, (b) FA, (c) Sil/Carbpt. (d) NiFe2O4/Sil/Carbpt, and (e) NiFe2O4/Sil/FA/Carbpt.

To confirm the interaction of nickel ferrite with Sil, elemental mapping of the formulation was performed using scanning electron microscopy with energy-dispersive X-ray spectroscopy. Figures 4(a-e) show the SEM-EDS and high resolution (HR)-TEM images of NiFe2O4/Sil/FA/Carbpt. The SEM-EDX micrograph of the formulation reveals agglomerated chunks. The sample shows an intense distribution of NiFe2O4 across the Sil surface (Figures 4a and b). Figures 4(c-e) display the high resolution transmission electron microscopy (HR-TEM). images of NiFe2O4/Sil/FA/Carbpt. The presence of monodispersed form silica confirms the stabilization of particle size and shape even after the functionalization of nickel ferrite, FA, and carboplatin. The presence of nickel ferrite as chucks on the external surface of Sil was confirmed with a d-spacing value of 0.251 nm (as per the pattern of fringes) (Figures 4c-e). To investigate the phases of NiFe2O4 and Carbpt, scanning transmission electron microscopy (STEM) analysis was performed. Individual nanoparticles of nickel ferrite and carboplatin were clearly captured, as shown in Figures 4(f-i). The nickel ferrite nanoparticles appear as small, agglomerated clusters (Figures 4f-h), while a homogeneous distribution of carboplatin is confirmed by the distributed dots (Figures 4i).

(a, b) SEM-EDS image of NiFe2O4/Sil/FA/Carbpt, (c-e) HRTEM and (f-i) STEM images of NiFe2O4/Sil/FA/Carbpt.
Figure 4.
(a, b) SEM-EDS image of NiFe2O4/Sil/FA/Carbpt, (c-e) HRTEM and (f-i) STEM images of NiFe2O4/Sil/FA/Carbpt.

3.2. Drug delivery study

Carboplatin has been widely used to treat ovarian, small cell lung cancer, and squamous cell carcinomas. The anti-cancer efficacy of Carbpt is primarily due to its interaction with DNA, inhibiting cell proliferation. We selected Carbpt for in vitro studies on colon and cervical cancer, considering its lower toxicity and fewer side effects compared to cisplatin. The encapsulation and loading capacity of Carbpt were 78% and 3.9%, respectively. The pH of cervical cancer is approximately 5-6, while the pH of colon cancer ranges from 7.4 to 9.0. Gastric intestinal pH is highly acidic between 1.2-2.0, whereas normal physiological pH occurs at 7.4. After internalization, the presence of FA enhances the interaction with the folate receptor, and the pore opening leads to drug release under various physiological environments. FA acts as a capping agent. To investigate the pH-dependent Carbpt release, an in vitro release study was performed using three formulations: Sil/Carbpt, NiFe2O4/Sil/Carbpt, and (e) NiFe2O4/Sil/FA/Carbpt at different pH conditions (2.0, 5.6, 7.4, 9.0) at 37°C (Figure 5). At a gastric pH 2.0, a lower Carbpt release (11%, 6.3% and 16% at 72 h) was observed for Sil/Carbpt, NiFe2O4/Sil/Carbpt, and NiFe2O4/Sil/FA/Carbpt. Under cervical pH conditions (pH 5.6), a higher Carbpt release was observed from multifunctional NiFe2O4/Sil/FA/Carbpt (68%, 72 h) and NiFe2O4/Sil/Carbpt (44%, 72 h) compared to the silica-alone functionalized carboplatin formulation, Sil/Carbpt (19%, 72 h). However, at a pH closer to that of colon cancer (pH 9.0), the Carbpt release from NiFe2O4/Sil/FA/Carbpt decreased to less than 15%, demonstrating the reduced disintegration and the gatekeeper role of FA, which safeguards the release of the drug from the pores of Sil. At this pH of 9, silica alone showed a higher Carbpt release of about 18%. However, the slower drug release from NiFe2O4/Sil/FA/Carbpt is advantageous as it reduces the dose-dependent Carbpt toxicity by extending the drug release duration. At normal physiological pH 7.4, a similarly slow Carbpt release (24% for 72 h) was observed, indicating effective drug encapsulation without leakage. Lin et al. has observed that the particle shape affects the transit time in colon, thereby influencing the therapeutic effect on the target site [44]. The larger particles’ transit time was reported to be shorter than smaller particles. The attractive feature of silica is that the morphology, particle size, and porosity features (spherical, cubic, microsphere, nanorods) can be controlled and varied based on the Stober synthesis strategies [45]. It has been observed that nanocarriers (cubosomes) with a high interfacial area exhibit burst release, while bulk nanocarriers (cubics) with longer length scales enable sustained drug release [46]. In the case of silica-based drug release study, it has been reported that hexagonal-shaped silica has controlled drug release than open cubic phase silica [47]. Polymeric nanocomposite formation with biocompatible polymers such as chitosan and polyethylene glycol induces pH stimuli-responsive drug release [48]. However, silica-based nanoemulsion consisting of carboxymethyl cellulose, graphene quantum dots, and starch, due to the interactive effect of nanoemulsion, was reported to exhibit pH stimuli 5-fluorouracil release [49]. In a similar stance, our study also observed pH-based Carbpt release without such polymer wrapping technique, indicating the importance of the interactive effect between carboplatin and FA dispersed on monodispersed spherical silica.

Cumulative percentage release of Carbpt from Sil/Carbpt, NiFe2O4/Sil/Carbpt and NiFe2O4/Sil/FA/Carbpt under different pH conditions using dialysis membrane technique: (a) cervical cancer microenvironment (pH 5.6), (b) colon cancer microenvironment (pH 9.0), (c) normal physiological condition (pH 7.4), and (d) simulated gastric fluid (pH 2.0).
Figure 5.
Cumulative percentage release of Carbpt from Sil/Carbpt, NiFe2O4/Sil/Carbpt and NiFe2O4/Sil/FA/Carbpt under different pH conditions using dialysis membrane technique: (a) cervical cancer microenvironment (pH 5.6), (b) colon cancer microenvironment (pH 9.0), (c) normal physiological condition (pH 7.4), and (d) simulated gastric fluid (pH 2.0).

Figure 6(a) shows the STEM mapping details of the atomic distribution of overlapped Ni, Fe, Si, and Pt in NiFe2O4/Sil/Carbpt. The analysis confirms the cohabitation of nickel ferrite and carboplatin (Pt) on the silica matrix. The homogeneous distribution highlights the advantage of a large surface area of monodispersed silica, and the presence of all four elements confirms the purity of the NiFe2O4/Sil/Carbpt sample. Figure 6(b) presents the Thermogravimetric analysis (TGA) of NiFe2O4/Sil/FA. TGA confirms the interaction between FA and the nanocarrier, providing information about the decomposition of components from the NiFe2O4/Sil/FA nanocarrier. Up to a temperature of approximately 150°C the decomposition curve shows an initial weight loss corresponding to the evaporation of physically adsorbed water and the dehydration of spherical silica from the porous matrix. FA undergoes the thermal disintegration between 250°C and 350°C (8%). The extended weight loss indicates the thermal stability of FA within the silica matrix.

(a-f) Multifunctional Carbpt interactive NiFe2O4/Sil/FA smart selective drug delivery system for Colon and Cervical Cancer Treatment. (a) STEM mapping of atomic distribution of overlapped Ni, Fe, Si and Pt in NiFe2O4/Sil/Carbpt. (b) Thermogravimetric analysis (TGA) of NiFe2O4/Sil/FA. (c) FTIR spectra of NiFe2O4/Sil, NiFe2O4/Sil/Carbpt and NiFe2O4/Sil/FA/Carbpt. (d, e) UV-visible spectra of carbpt adsorption and release effect on NiFe2O4/Sil over a time duration of 0.25-48 h. (f) Nanocomposite bond formation between NiFe2O4/Sil, folic acid and Carbpt.
Figure 6.
(a-f) Multifunctional Carbpt interactive NiFe2O4/Sil/FA smart selective drug delivery system for Colon and Cervical Cancer Treatment. (a) STEM mapping of atomic distribution of overlapped Ni, Fe, Si and Pt in NiFe2O4/Sil/Carbpt. (b) Thermogravimetric analysis (TGA) of NiFe2O4/Sil/FA. (c) FTIR spectra of NiFe2O4/Sil, NiFe2O4/Sil/Carbpt and NiFe2O4/Sil/FA/Carbpt. (d, e) UV-visible spectra of carbpt adsorption and release effect on NiFe2O4/Sil over a time duration of 0.25-48 h. (f) Nanocomposite bond formation between NiFe2O4/Sil, folic acid and Carbpt.

Figure 6(c) shows the Fourier transform infrared (FTIR) spectra of NiFe2O4/Sil, NiFe2O4/Sil/Carbpt and NiFe2O4/Sil/FA/Carbpt. NiFe2O4/Sil displays sharp and broad elongated peaks at 1611 and 3334 cm-1, corresponding to the hydroxyl O-H bending and Si-OH of silica [50]. NiFe2O4/Sil/Carbpt shows the characteristic carboplatin functional groups at 2905 and 2990 cm-1. A reduction in the Si-OH peak of silica indicates the interaction between carboplatin and silica. In case of FA and carbopt functionalization in NiFe2O4/Sil/FA/Carbpt, additional peaks at 1684 cm-1 (carbonyl) and 1520 cm-1 (NH bending) confirm the formation of amide bonds. Furthermore, an extension of the absorption peak was observed at 3325 cm-1, indicating the formation of additional hydrogen and NH bonds, leading to new elongated stretching peaks. Figure 6(d) shows the Carbpt adsorption effect on NiFe2O4/Sil over a time duration of 0.25-48 h. Carboplatin exhibits a peak maximum at approximately 213 nm with a shoulder peak at 231 nm. The presence of high textural characteristics (as shown in Table 1) facilitates the pore accessibility of nanosized Carbpt, leading to the reduction in the Carbpt peaks. After interaction with FA and Carbpt, NiFe2O4/Sil/FA/Carbpt shows an additional band at around 285 nm, confirming the interaction between FA with carboplatin. Interestingly, a systematic increase in carboplatin and FA release is confirmed by UV spectra analysis, with release times ranging from 0.25 to 48 h (Figure 6e).

The structure of FA consists of a bicyclic pteridine ring, attached through a methylene bridge (-CH2-) to p-aminobenzoic acid, followed by an amide bond connecting glutamic acid, which contains a functionally active carboxylic acid group. Emtiazi et al. reported the covalent conjugation of FA with magnetic/diphenylalanine peptide-derived nanotubes by a carbodiimide coupling mechanism [51]. In the present case, the NiFe2O4/Sil nanocarrier consists of various types of silanol groups, including isolated, vicinal, and geminal silanols, which facilitate interaction with FA. Specifically, the presence of isolated hydroxyl groups in silanol and terminal silanol groups in vicinal and geminal silanols can induce hydrophilic property, allowing the formation of hydrogen bonds with the amine functional group of FA (NH2/NH) (A, A’). Carboplatin consists of a Platinum atom attached to two amine groups (NH3) (B) and two chelating ligands that form a bidentate cyclobutene-1,1-dicarboxylate ligand via carboxylate groups. During the formation of the nanocomposite between NiFe2O4/Sil, FA, and Carbpt, hydrogen bonds are proposed to form between the silanol groups of NiFe2O4/Sil and the amine group of FA, while amide bond formation occurs due to condensation between the amine group of Carbpt and the carbonyl group of FA (BB’) (Figure 6f). Due to the resonance characteristics of the amide bond, it becomes strong and rigid, similar to the structure of proteins, which can withstand the acidic and basic conditions of the colon and cervix. The presence of FA facilitates the selective interaction of NiFe2O4/Sil/FA/Carbpt with the receptor of cancer cells, while reducing the toxic effect on normal cells.

3.3. Kinetics of carboplatin drug release using Korsmeyer-Peppas model

The Carboplatin drug release profiles at different pH were examined using the Korsmeyer-Peppas model, expressed using the Eq. (1):

(1)
R   % = k t n

Where R% is the Carboplatin drug percentage release at time (t), k and n are the kinetic rate constant and the release exponent, respectively. The kinetic parameters with their 95% confidence intervals have been presented in Table 2.

Table 2. Kinetic parameters for Carbpt drug release from three nanocarriers Sil, NiFe2O4/Sil, and NiFe2O4/Sil/FA.
Carboplatin k/h-n n
NiFe2O4/Sil; pH 2.0 3.4216 ± 0.2480 0.1637 ± 0.0319
NiFe2O4/Sil; pH 5.6 3.9773 ± 0.4974 0.5424 ± 0.0543
NiFe2O4/Sil; pH 7.4 2.4405 ± 0.9040 0.3634 ± 0.1422
NiFe2O4/Sil; pH 9.0 1.7026 ± 0.0868 0.1535 ± 0.0227
NiFe2O4/Sil/FA; pH 2.0 4.9475 ± 0.3176 0.2497 ± 0.0284
NiFe2O4/Sil/FA; pH 5.6 25.5458 ± 0.9694 0.2177 ± 0.0169
NiFe2O4/Sil/FA; pH 7.4 16.5960 ± 2.2181 0.1031 ± 0.0569
NiFe2O4/Sil/FA; pH 9.0 4.6009 ± 0.4066 0.2466 ± 0.0387
Sil; pH 2.0 1.5775 ± 1.2032 0.4979 ± 0.1944
Sil; pH 5.6 1.6971 ± 0.4841 0.4841 ± 0.0867
Sil; pH 7.4 1.1197 ± 0.4119 0.6166 ± 0.1074
Sil; pH 9.0 11.9033 ± 1.2408 0.1254 ± 0.0453

For NiFe2O4/Sil, the rate of Carbpt release, determined by the release constant, is enhanced at acidic and neutral pH. However, at pH = 9.0, the rate of drug release is lower than at the other pH values. On the other hand, the release exponent (n) signified a Fickian (0.16, 0.36, 0.15 < 0.45) and non-Fickian (0.45 < 0.54 < 0.89) for pH values of 2.0, 7.4, 9.0, and 5.6, respectively. Similarly, for NiFe2O4/Sil/FA, the effect of pH on the rate of drug release followed the same pattern with NiFe2O4/Sil, with the highest rate of drug release recorded at low acidic conditions (pH = 5.6) and the lowest recorded at alkaline pH. The drug release mechanism followed the Fickian diffusion mechanism at all pH conditions (n < 0.45). In contrast, the pH effect on the rate of Sil alone and Carbpt drug release followed a trend opposite to that of NiFe2O4/Sil and NiFe2O4/Sil/FA. Alkaline pH (pH = 9.0) enhanced the drug release rate almost 10 times than in acidic and neutral pH conditions. The release exponent (n) for the neutral (pH = 7.4) and acidic (pH = 2.0 and 5.6) pH signified a non-Fickian diffusion mechanism, while at alkaline pH (9.0), the drug release followed the Fickian diffusion mechanism. Among the three nanoformulations, NiFe2O4/Sil/FA had the highest drug release rate at acidic and neutral pH, while Sil alone had the highest rate at alkaline pH. The diffusion mechanisms for all drug releases were limited to Fickian and non-Fickian diffusion mechanisms, without following the carriage (n > 0.89) or relaxation transport (n = 0.89) mechanisms.

3.4. Magnetic properties

In the nickel ferrite system, Fe3+ ions occupy the tetrahedral (A) and octahedral (B) sites, while Ni2+ ions occupy the octahedral sites. The anti-parallel alignment of the magnetic moments of ions in the A and B sites leads to the ferrimagnetic property of NiFe2O4. As such, crystalline bulk nickel ferrite achieves a higher saturation magnetization, ranging from 40-60 emu/g [52]. The saturation magnetic properties of nickel ferrite are also influenced by the particle size and the presence of non-magnetic surface layers [53]. For instance, nickel ferrite magnetic nanoparticles exhibit superparamagnetism when the particle size is below 30-15 nm [54,55]. Nickel ferrite loaded on MCM-41 and SBA-15 has been reported to show a lower emu/g. In our case, we observed the formation of nickel ferrite nanoparticles with superparamagnetic properties with a saturation magnetization of about 8 emu/g (Figure 7). This suggests the formation of nanoscale nickel ferrite, leading to lower saturation magnetization due to surface effects, such as spin canting and the presence of silica surface layers.

Magnetic property of NiFe2O4/Sil nanocomposite.
Figure 7.
Magnetic property of NiFe2O4/Sil nanocomposite.

3.5. In vitro study

The anticancer activity of the controls (cisplatin, carboplatin, and NiFe2O4/Sil) and nanoformulations (NiFe2O4/Sil/Carbpt, NiFe2O4/Sil/Cpt, and NiFe2O4/Sil/FA/Carbpt) was assessed using HFF-1, Colon, and Cervical cells (Figures 8a-c).

Curve response showing the cytotoxic activities of drugs on (a) HFF-1, (b) HCT-116, and (c) HELA cells. The average of three independent measurements was graphed as a logarithmic dose-response curve. The nanocomposite includes NiFe2O4/Sil, NiFe2O4/Sil/Carbpt, NiFe2O4/Sil/FA/Carbpt, and Sil/Cpt, respectively.
Figure 8.
Curve response showing the cytotoxic activities of drugs on (a) HFF-1, (b) HCT-116, and (c) HELA cells. The average of three independent measurements was graphed as a logarithmic dose-response curve. The nanocomposite includes NiFe2O4/Sil, NiFe2O4/Sil/Carbpt, NiFe2O4/Sil/FA/Carbpt, and Sil/Cpt, respectively.

NiFe2O4/Sil/Cpt was used for comparative purposes. Both cisplatin (Cpt) alone and cisplatin-bound nanoformulation NiFe2O4/Sil/Cpt exhibited significant toxicity against normal HFF-1 cells, indicating the non-selective nature of the raw chemo drug. Interestingly, a significant difference in the LC50 value was observed between cisplatin, carboplatin, and their nanoformulations, NiFe2O4/Sil/Carbpt and NiFe2O4/Sil/FA/Carbpt (Table 3). With respect to the cytotoxicity of carboplatin, NiFe2O4/Sil/Cpt, NiFe2O4/Sil/FA/Carbpt, and control nanocarrier alone, NiFe2O4/Sil exhibited a lower LC50 value towards HFF-1, suggesting a lower toxicity towards normal cells. Conversely, the nanoformulation exhibited significant toxicity against colon and cervical cells (HeLa and HCT 116). The nanoformulation NiFe2O4/Sil/FA/Carbpt showed excellent cytotoxicity comparable to the cisplatin-based nanoformulation NiFe2O4/Sil/Cpt and cisplatin alone. The sensitivity of NiFe2O4/Sil/Carbpt and NiFe2O4/Sil/FA/Carbpt to HeLa and HCT 116 cells was higher than that of HFF-1. These results suggest the selective toxicity of NiFe2O4/Sil/FA/Carbpt towards colon and cervical cancer cells over normal cells. The cell viability of HFF-1 cells remained relatively high even at the higher concentrations of nanoformulations. However, cisplatin-bound NiFe2O4/Sil/Cispt displayed higher sensitivity towards both normal HFF-1 cells and HeLa/HCT 116 cells.

Table 3. LC50 of the drugs on HFF-1, HCT116, and HELA cells. The results are presented with an average standard deviation of three independent measurements and p-value.
Nanoformulations HFF-1
 HCT116
 HELA
LC50 STD p value LC50 STD p value LC50 STD p value
NiFe2O4/SiO2/Carbpt 16542.78 3060.58 0.0145 8.73 0.64 0.0013 11.69 0.73 0.0062
NiFe2O4/SiO2/FA/Carbpt 1054.43 175.68 0.0145 10.38 0.56 0.0003 16.37 1.55 0.0008
NiFe2O4/SiO2/Cpt 59.81 0.19 0.0225 6.76 0.30 0.0043 5.50 0.23 0.0092
NiFe2O4/SiO2 5199.44 240.85 0.0000 4.20 0.69 0.0043 3.09 0.20 0.0092
Cisplatin 69.19 0.34 0.0225 10.87 0.55 0.0016 6.83 0.20 0.0067
Carboplatin 167649139.97 5426.17 0.5415 25772.56 3890.81 0.0011 131960.84 17783.95 0.0008

The cell morphology images of HFF-1, HeLa, and HCT 116 cells were recorded after 24 h of treatment with 40µg/mL of the following: A, Control; B, NiFe2O4/Sil/Carbpt; C, NiFe2O4/Sil/FA/Carbpt; D, NiFe2O4/Sil/Cispt; E, NiFe2O4/Sil; F, Cisplatin; and G, Carboplatin. The small black dots represent the nanoparticles, and the brown debris indicates dead cells (Figures 9-11). In vitro cytotoxic activity was evaluated by MTT assay using HeLa, HCT116, and the non-tumorigenic cell line HFF-1. Analysis of LC50 values across these three cell lines (HFF-1, HCT116, and HELA) reveals distinct toxicity profiles for the various treatments. Notably, Carbpt exhibited the highest LC50 values in both HFF-1 and HeLa cell lines, indicating lower toxicity compared to other treatments. In contrast, NiFe2O4/SiO2/Cispt showed the lowest LC50 values (59.81µg/mL for HFF-1, 6.76 µg/mL for HCT116, and 5.50 µg/mL for HeLa), suggesting a high level of toxicity, particularly in HCT116 and HeLa. Overall, the results highlight that cisplatin and NiFe2O4/SiO2/Cpt are among the most toxic treatments, even in non-tumorigenic cell line HFF-1, while carboplatin exhibits relatively lower toxicity across the tested cell lines.

Cell morphology images of HFF-1 cells after 24 h of treatment with 40 µg/mL of (a) Control, (b) NiFe2O4/Sil/Carbpt, (c) NiFe2O4/Sil/FA/Carbpt, (d) NiFe2O4/Sil/Cpt, (e) NiFe2O4/Sil, (f) Cisplatin, (g) Carboplatin. The small black dots are the nanoparticles, and the brown debris is the dead cells.
Figure 9.
Cell morphology images of HFF-1 cells after 24 h of treatment with 40 µg/mL of (a) Control, (b) NiFe2O4/Sil/Carbpt, (c) NiFe2O4/Sil/FA/Carbpt, (d) NiFe2O4/Sil/Cpt, (e) NiFe2O4/Sil, (f) Cisplatin, (g) Carboplatin. The small black dots are the nanoparticles, and the brown debris is the dead cells.
Cell morphology images of HELA cells after 24 h of treatment with 20 µg/mL of (a) Control, (b) NiFe2O4/Sil/Carbpt, (c) NiFe2O4/Sil/FA/Carbpt, (d) NiFe2O4/Sil/Cpt, (e) NiFe2O4/Sil, (f) Cisplatin, (g) Carboplatin. The small black dots are the nanoparticles, and the brown debris is the dead cells.
Figure 10.
Cell morphology images of HELA cells after 24 h of treatment with 20 µg/mL of (a) Control, (b) NiFe2O4/Sil/Carbpt, (c) NiFe2O4/Sil/FA/Carbpt, (d) NiFe2O4/Sil/Cpt, (e) NiFe2O4/Sil, (f) Cisplatin, (g) Carboplatin. The small black dots are the nanoparticles, and the brown debris is the dead cells.
Cell morphology images of HCT116 cells after 24 h of treatment with 20 µg/mL of (a) Control, (b) NiFe2O4/Sil/Carbpt, (c) NiFe2O4/Sil/FA/Carbpt, (d) NiFe2O4/Sil/Cpt, (e) NiFe2O4/Sil, (f) Cisplatin, (g) Carboplatin. The small black dots are the nanoparticles, and the brown debris is the dead cells.
Figure 11.
Cell morphology images of HCT116 cells after 24 h of treatment with 20 µg/mL of (a) Control, (b) NiFe2O4/Sil/Carbpt, (c) NiFe2O4/Sil/FA/Carbpt, (d) NiFe2O4/Sil/Cpt, (e) NiFe2O4/Sil, (f) Cisplatin, (g) Carboplatin. The small black dots are the nanoparticles, and the brown debris is the dead cells.

The treatments NiFe2O4/SiO2/FA/Carbpt and NiFe2O4/SiO2/Carbpt exhibit distinct toxicity profiles across the cell lines (HFF-1, HCT116, and HeLa). NiFe2O4/SiO2/Carbpt had LC50 values of 16542.78 µg/mL for HFF-1, 10.38 µg/mL for HCT116, and 16.37 µg/mL for HeLa. NiFe2O4/SiO2/FA/Carbpt had LC50 values of 1054.43 µg/mL for HFF-1, 10.38 µg/mL for HCT116, and 16.37 µg/mL for HeLa. These values indicate moderate toxicity, particularly in HFF-1, where the LC50 suggests a significant effect on cell viability. The addition of FA appears to influence the compound’s interaction with the cells, potentially enhancing uptake or efficacy, especially in HCT116 and HeLa, where the LC50 values remain lower compared to HFF-1, indicating selective toxicity towards cancer cells.

The LC50 values in this study were in line with those observed in previous studies on cisplatin and carboplatin formulations. For example, the reported LC50 of cisplatin in different cell lines typically ranges from 5 to 20 µg/mL, consistent with the values observed here for NiFe₂O₄/SiO₂/Cpt. The lower toxicity of Carboplatin in both cancer and normal cells, as observed here, supports its clinical use, especially when compared to the more aggressive cisplatin. These findings align with earlier studies that suggest carboplatin can be an alternative to cisplatin, making it a safer option in many clinical contexts, particularly for patients requiring prolonged treatment or those with sensitive normal tissues [56].

The findings in this study align with earlier work demonstrating that drug-loaded nanoparticles, such as NiFe₂O₄/SiO₂, can enhance the therapeutic efficacy of conventional chemotherapy agents like cisplatin and carboplatin. For instance, Ranasinghe et al. and Maliyakkal et al. reported that nanoparticle formulations of cisplatin enhanced its therapeutic efficacy in various cancer cell lines, showing that the incorporation of nanoparticles can reduce toxicity in normal cells while increasing the concentration of the drug in tumor cells [57,58]. These studies support the conclusion that NiFe₂O₄/SiO₂/Cpt and NiFe₂O₄/SiO₂/FA/Carbpt exhibit selective toxicity towards cancer cells over normal cells, consistent with the observed data in this study. Targeted drug delivery systems such as these can increase the drug’s accumulation in cancer cells while minimizing exposure to healthy tissues, as demonstrated in studies on other nanoparticle-based formulations [59].

The inclusion of FA in the nanoformulation, particularly in NiFe₂O₄/SiO₂/FA/Carbpt, plays a significant role in the selective targeting of cancer cells, as FA receptors are often overexpressed in tumor cells. This is corroborated by previous studies where folate-conjugated nanoparticles have shown enhanced uptake in folate receptor-positive cancer cell lines. For example, Miranda et al. demonstrated that folate-conjugated nanoparticles increased drug uptake specifically in tumor cells, leading to higher cytotoxicity in cancer cells while reducing off-target effects on normal cells [60]. Further, magnetic/folate-targeted approach enhances the therapeutic potential of drug-loaded nanoparticles in specific tumor types [61].

4. Conclusions

Developing a targeted drug delivery system (DDS) for colon and cervical is complicated due to pH variation. Folate is overexpressed in cervical and colon cancer. For the first time, carboplatin as effective a cisplatin has been developed by identifying the dual role of FA targeting folate receptor and amide bond interaction ability with carboplatin based on multifunctional DDS. Systematically, pH, magnetic, and FA-based monodispersed spherical silica was prepared, characterized, and studied for sustained Carbpt release for the treatment of colon and cervical cancer. The study showed that FA-facilitated amide bond formation between carboplatin helps to stabilize the formulation in basic and acidic media of cancers. The physico-chemical characteristics confirm the transformation of crystalline to nanosize Carbpt, FA on silica. Deposition of NiFe2O4 at the external pore surface of silica and distribution of Carbpt were confirmed using BET and HRTEM analysis. The presence of silica as a nanocomposite induces a superparamagnetic effect with a magnetic saturation value of 8 emu/g. The nanocarrier based on 30% NiFe2O4/spherical silica/FA formulation showed a cervical pH stimuli carboplatin release at pH 5.6, while slow release at colon pH 7.4. The diffusion mechanisms for all the drug release are limited to Fickian and non-Fickian diffusion mechanisms, without following the carriage (n > 0.89) or relaxation transport (n = 0.89) mechanisms. The comparative toxicity profiles of cisplatin and carboplatin and their respective nanoformulations, demonstrating that NiFe₂O₄/SiO₂/Cpt and NiFe₂O₄/SiO₂/FA/Carbpt show selective toxicity against cancer cells (HeLa and HCT116), while minimizing damage to normal cells (HFF-1). The dual role of FA enhances the nanoformulation’s targeting and carboplatin release capabilities, making it a promising candidate for cancer therapy with reduced side effects.

Acknowledgment

The author BRJ would like to acknowledge the research grant funded by the Research, Development, and Innovation “ Authority (RDIA) - Kingdom of Saudi Arabia - with grant number (12968-iau-2023-iau-R-3-1-HW-). The author B.Rabindran Jermy also acknowledge Institute for Research and Medical Consultations (IRMC), IAU for providing state of art facilities.

CRediT authorship contribution statement

Vijaya Ravinayagam: Conceptualization, methodology, writing – original draft, review & editing. Munther Alomari: Methodology, formal analysis, validation, writing – original draft. Gazali Tanimu: Methodology, formal analysis, writing – original draft. Ammar Ali AlAbdullatif: Methodology, formal analysis, validation. H. Dafalla: Methodology, formal analysis, validation. B. Rabindran Jermy: Conceptualization, methodology, formal analysis, validation, writing, review & editing, funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Declaration of Generative AI and AI-assisted technologies in the writing process

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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