An in vitro characterization and cytotoxic evaluation of mesoporous delivery of celecoxib on anticancer activity

Peer Review Article | Open Access | Published 2nd April 2025

An in vitro characterization and cytotoxic evaluation of mesoporous delivery of celecoxib on anticancer activity

Sayani Bhattacharyya¹*, Reena Inas Fernandaes*² | EJPPS | 301 (2025) | https://doi.org/10.37521/ejpps30105 | Click to download pdf

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Abstract

Celecoxib has opened new avenues for its potential efficacy in the treatment of colorectal cancer. The low solubility of the drug is a major concern for its efficacy. The present research explores the possibility of enhancing the solubility of the drug using a mesoporous delivery system. A commercially available mesoporous silica (Syloid 244FP) was used as a carrier to load celecoxib by the solvent evaporation method. Three different formulations were prepared varying drug/silica ratio. The formulations were evaluated for drug loading, particle size, surface morphology, solid-state characterization, and drug release study. Cytotoxicity study was conducted on cancer cell lines. The formulations were found to be nano-sized, with a high loading of drugs in the porous network of silica. The dissolution efficiency of celecoxib in the formulations was improved remarkably. Formulation with the highest drug/silica ratio was found to be the best in terms of dissolution. The solid-state behaviour studies of the best formulation exhibited compatibility and amorphization of the drug and the same was further proved by surface morphology study. Surface area analysis study further proved the high loading of the drug in the silica. The cytotoxicity study revealed a significant reduction in the number of viable cancer cells following administration of the best formulation in comparison to the pure drug and standard drug doxorubicin. Hence it can be concluded that mesoporous nanoparticles loaded with celecoxib can make a valuable contribution to enhancement of solubility and anticancer activity.

Keywords: Celecoxib, Mesoporous silica, Colon Cancer, dissolution, nanoparticles

1.Introduction

Celecoxib, a cyclooxygenase 2 inhibitor has been repurposed for its new indication as a chemotherapeutic agent in the treatment of cancers of the colon, lung, prostate, breast, stomach, head, and neck, and adenoma polyposis¹. It acts by hindering the biosynthesis of Prostaglandins and diminishing the proliferation and angiogenesis of cancerous cells².

Celecoxib regardless of having remarkable potential activity against cancerous cells, its clinical use is bound due to its physicochemical properties³. Since this drug belongs to the biopharmaceutical classification system II (BCS II) its higher lipophilic nature solubility, and dissolution rate are low, which further affects drug absorption and bioavailability⁴⁻⁵. Attributing to its potential and promising therapeutic targets in cancer, there is an urge for researchers to develop different types of nanomedicine for the refurbished delivery of celecoxib⁶.

A mesoporous delivery of celecoxib is proposed here for the solubility and dissolution enhancement of the drug⁷. Mesoporous silica drug carriers are amongst the most effective novel carriers for drugs⁸. The excellent physicochemical characteristics of the carriers include their pore size, pore volume, and surface characteristics in an ordered or disordered porous network⁹. Mesoporous silica represents one of the promising novel vehicles for drugs, because of its unique properties of chemical stability, and surface functionality. It protects the loaded molecules from heat, mechanical stress, pH, and hydrolysis¹⁰. The availability of large surface area and pore volume in mesoporous silica makes the active drugs easily rest in the microporous silica pores and helps to formulate a monodisperse system¹¹. It is highly effective in the amorphization of the drug by entrapping them in their nano-sized pores. It offers alteration of the surface chemistry, which impacts drug loading and drug release¹².

The dispersion of drugs in an amorphous matrix has been considered as an efficient method for improving the drug solubility and dissolution rate. This is the most adoptive method because it is easy to produce, and reproducible. In this process, the drug molecules are actively dispersed in a carrier, and the crystallinity of the drug changes to an amorphous state by interacting with the carrier, which leads to the enhancement of solubility and dissolution. In addition to amorphization particle size also plays an important role This can be easily employed in the present study by the fabrication of mesoporous silica.

Mesoporous silica nanoparticles have been reported to have potential chemotherapeutic effects due to their structural features which offer targeting through surface functionalization.

The present study explores the use of Syloid 244 FP, a versatile mesoporous carrier, and compares the anticancer activity of mesoporous delivery of celecoxib carriers in HCT-116 cancer cell lines with pure celecoxib and a standard drug. The outcome of the research provides effective, and potentially safer delivery of celecoxib with fewer side effects and will assist in the processing pace of drug development.

Material and Methods

Material

Celecoxib was obtained as a gift sample from Prudence Pharma Chem (Ankaleshwer, Bharuch, Gujrat) Syloid 244 FP was obtained as a free sample from Grace Pharmaceuticals, Mumbai. The rest of the chemicals used were of analytical grade and procured from local suppliers.

Preparation of mesoporous celecoxib

A solvent evaporation method was used to load celecoxib in Syloid 244FP. An extensive preformulation study was carried out to optimize the solvent system and time of incubation

From the initial observations, the formulation was carried out by dissolving celecoxib in the optimized solvent mixture of methanol and water (3:1) to obtain a concentrated solution. Syloid 244FP was added to the drug solution. The above solution was mechanically stirred at room temperature for 24 h to attain adsorption equilibrium³. Three such formulations (F1, F2, and F3) were prepared varying the drug/silica weight ratio (1:1, 2:1, and 2.5:1 respectively). Later, the dispersion was filtered and the residual solvent was evaporated using a rotary evaporator at 50 °C, and 100 rpm¹³. The solid dispersion thus obtained was collected and evaluated for further studies.

Evaluation of mesoporous nanoparticles of celecoxib

Drug Loading Estimation

A specific amount (10 mg) of drug-loaded mesoporous formulations was dispersed in a suitable volume (25 ml) of methanol and water mixture. The dispersion was centrifuged at 10000 rpm for 30 min to separate the residue silica, if any. An aliquot was taken from the supernatant, diluted in methanol, and analyzed spectrophotometrically for the amount of drug in formulation. The UV spectrophotometric method was developed using methanol at 252 nm and the calculation was carried out using a linearity equation of Y= 0.0546X - 0.0096, where Y = absorbance, and X = concentrations in µg/ml.¹⁴. The percentage of drug loading was calculated by the following formula.

In vitro dissolution studies

Dissolution of the mesoporous nanoparticles of celecoxib was conducted in USP type II dissolution apparatus, containing phosphate buffer pH 12 as dissolution medium¹⁵. The study was carried out in 900 ml medium at 37℃ at 50 rpm. The formulation equivalent to 50 mg celecoxib was directly introduced in the dissolution medium in a normal capsule shell. An aliquot of the sample was collected at a fixed interval of time, diluted, and analyzed by UV–vis spectrophotometer at 252 nm wavelength. Experimentations were performed in triplicates.

A confirmatory dissolution was carried out by the same process in phosphate buffer pH 6.8 for the selected formulation and pure drug to calculate the dissolution efficiency¹⁶.

Dissolution efficiency (Deff) was estimated for all the release data using the following formula.

Where AUC0− 60min - area under the curve for 1 h period, t - the total time of drug release and Q100 indicates 100% drug release.

The kinetics of drug release from the mesopores was also studied from the in vitro dissolution data.

Statistical analysis

Pareto analysis of all the formulations was carried out on an 80/20 scale, considering the highest drug loading and drug release to select the best formulation for further studies. The parameters were evaluated using a random scaling between 1 and 6, with 6 being the highest and 1 being the lowest. The highest drug loading and drug release from the formulations were considered for the highest scaling.

Material structure characteristics

The Malvern particle size analyzer, (Model: Zetasizer Nano S-90) was used to determine the particle size¹⁷ using the dynamic light scattering (DLS) technique. The samples were dispersed suitably in Millipore water and analysis was carried out at 250C. The particle size of each trial formulation was recorded as an average of three trials ± SD.

A Hitachi SU 3500 electron microscope was used to observe the surface morphology of plain drug, Syloid 244FP, and formulation prepared at different incubation periods.

The FTIR spectra of pure drug and the selected formulation were examined and illustrated by the Attenuated Total Reflectance (ATR) technique (Bruker, Germany).

DSC (Shimazu 60 Japan) experiments were carried out to characterize the physical state of the pure drug and the best formulation.

PXRD was performed using a Bruker D8 Advance (Bruker, Germany) diffractometer at room temperature in the range between 4°to 60° at a rate of 0.02 °/min 2Ɵ¹⁸.

The adsorption isotherms of plain Syloid 244FP and formulation were generated using NOVA 2200E (Quanta chrome, USA). The samples were degassed for 6 h at bath temp 77.3 K prior to experimentation. The adsorption and desorption isotherms are generated at the same temperature of cross-sectional area 16.2 Å, for 65.58 min¹⁹.

Molecular docking study

The mesoporous celecoxib F3 was used for molecular docking study with the proteins MCL1 – 604U and Survivin – 1F3H²⁰. Chem Draw V26 was used to draw the structure of mesoporous celecoxib. The crystal structure of the protein was derived from www/rscb.org/pdb by eliminating the enzyme structure and docking was performed using Autodock v 4.2. software. Binding energies of the ligand-receptor interactions were recorded²¹.

Cytotoxicity Studies on Cancer Cell

Human colorectal carcinoma cell lines (HCT-116) were used to assess the anticancer activity of the formulations. The cells were procured from the American Type Cell Culture Collection (ATCC), USA. Cells were grown in a fortified medium composed of Dulbecco Modified Eagle Medium (DMEM) with 10% Foetal Bovine Serum (FBS) in a CO2 incubator at 98% humidity, 5 % CO2 at 37 ℃ [10].

MTT Assay

MTT assay was conducted to compare the anticancer activity between pure drug and the mesoporous nanoparticles of celecoxib. Cell wells were prepared to contain 100µL of the media where 3-5X103 cells were seeded and incubated for 48 h at 37 ℃. The cells were treated with 25, 50, and 75 µM concentrations of pure drug and the best formulation. After incubation for 48 h,100 µL reagents were added to the cell and further incubated for 4 h at 37 ℃. The formazan crystals thus formed were dissolved in DMSO solution and quantified spectrophotometrically at 570 nm²².

Acridine Orange/ Ethidium Bromide (AO/EB) Staining

A quantity of 25 μl culture containing approximately 1x105 cells was placed in micro centrifuge tubes, and stained with 5 μl of AO-EtBr for 2 minutes with gentle stirring. A quantity of 10 μl of cell suspension was placed on a slide, a coverslip was placed over it and viewed using a fluorescence microscope at 200x magnification¹⁰. A comparative study on apoptosis was carried out among the formulation F3, pure celecoxib, and standard drug doxorubicin.

Results and discussion

Evaluation of mesoporous nanoparticles of celecoxib

A robust method of preformulation study was used to support the loading of the drug in Syloid 244FP by the solvent evaporation technique. Optimized processing conditions that maximize pore size and surface area ensure high drug loading efficiency. The solvent system greatly affects the % drug loading and free-flowing characteristics of the product. Methanol and water mixture in 3 different ratios (1:1, 2:1, and 3:1) were used to identify the best solvent system. The effect of the solvent mixture on a drug/silica ratio of 1:1 is presented in Table 1. The preliminary observation revealed that high proportions of methanol in the formulation lead to a free free-flowing powder mixture and high drug loading in the silica. High loading might be due to the high solubility of the drug in methanol. High water content in the solvent system reduced the flowability of the final formulation, aggregated mass was formed and the evaporation took a longer time. Hence from this preliminary study, methanol: water at 3:1 ratio was used as a solvent mixture for the formulation of mesoporous celecoxib.

The incubation time was optimized by formulation of different ratios of drug/silica mix and impregnated in the selected solvent system for 6, 12, and 24 h. Table 2 shows the necessity of longer impregnation time on the loading of the drug onto the pore of silica to attain adsorption equilibrium.

Therefore, for the final formulations solvent evaporation method was successfully employed with methanol and water at a 3:1 ratio as a solvent system for an incubation period of 24 h.

Table 1: Preformulation study on selection of solvent system

Parameters observed	Methanol water (1:1)	Methanol water (2:1)	Methanol water (3:1)
% Drug loading	40±1.44	45.87±0.66	65.87±1.06
Flowability	Aggregated	Segregated discrete	Free-flowing powder

Table 2: Preformulation study on drug loading of formulations at various incubation times

Estimation of drug loading

The drug was loaded into the mesopores of silica by the solvent evaporation method. The drug loading was found to be in the order F1<F2<F3. The drug loading was found to be 89.31±0.89% and 92.03± 1.09% for the formulations F1 and F2 respectively. The maximum drug loading was found to be 96.74 ±1.02 % in formulation F3. Syloid 244FP offers a disordered pore structure with an enormous surface area. Hence as the drug quantity was increased with the drug/silica weight ratios, multilayer adsorption of the drug occurred on the nanopores of silica. As the loading was very high at drug/silica 2.5:1. further increment in drug /silica ratio was not explored in the present study. The high loading of the drug establishes the suitability of the solvent evaporation method.

In vitro dissolution studies

The in vitro release study of the drug from the different formulations was compared with the pure drug. Pure celecoxib showed a release of approximately 52% in 1 h, but the mesoporous silica nanoparticles of celecoxib exhibited a much higher release. Maximum release was observed from formulation F1. This might be due to the high wicking effect observed in the formulation. As the drug loading was less in formulation F1, the unoccupied pores allowed more penetration of the dissolution media and resulted in a burst release. As the loading was increased, the comparatively lower availability of the unoccupied pores slowed down the rate of dissolution as shown in Figure 1A. The pure drug showed comparatively lower release because of its insolubility, low porosity, and low spreading of the dissolution media.

Pareto analysis with a categorical approach revealed that the formulation F3 had the highest score, hence, F3 was taken for further analysis.

The drug release study from formulation F3 in phosphate buffer pH 6.8 (Figure 1B) showed a remarkably high dissolution profile compared to the pure drug at the same equivalent quantity. The dissolution efficiency was calculated to be 67.78 and 38.16 % for F3 and pure celecoxib respectively. An approximately 1.77 times improvement in dissolution efficiency was observed in the drug release from the formulation. The kinetic study of the release data suggested that the release of the drug from the porous matrix of the carrier followed first-order kinetics, and the Korsemeyer Peppas exponent was calculated to be n-=0.36, which supported Fickian release of the drug. The drug was released through the filled pores by the process of diffusion, the unfilled pores might have generated the wicking effect and created the driving force of the drug to pass through the pores.

Hence, the drug release from mesoporous crystalline structures followed a diffusion-controlled mechanism. The well-defined pore channels provided a pathway for the drug molecules to diffuse out of the matrix. The release rate was governed by the pore size and the interactions between the drug and the pore walls.

Figure 1: In vitro dissolution profile at pH 12(A) and pH 6.8(B).

Material structure characteristics

The particle size of the formulation F3 was measured through the DLS technique, and the particle size was found to be 339.5 nm. The nano size of the particle was found to be beneficial in improving the solubility, thereby dissolution of the drug.

SEM images revealed that the pure celecoxib exists as aggregated needles (Figure 2A).

Solid networks of porous structures of Syloid 244FP are shown in Figure 2B. The drug loading in Syloid 244FP occurs by the adsorption of the drug on its active surface. Adsorption occurs in different layers and is greatly affected by the method of preparation and time of incubation. As the loading of drugs occurs due to capillary action, the time of impregnation to completely occupy the pores of the carriers is a critical factor. The SEM study was used to justify the incubation time used in this preparation method for all the formulations. The surface morphology study of the best formulation F3 is projected for different impregnation periods. Figures 2C and 2D represent formulation F3 at 6 h, and 12 h incubation periods respectively. The recrystallization of the pure drug on the external surface of Syloid 244FP is indicative of improper incubation time (Figure 2C and 2D). This might be due to the disordered pore structure of the carrier which prevented complete adsorption of the drug into its pores and hindered complete loading into the carriers. As the impregnation time was prolonged the loading of the drug was increased and the deposition on the external surface was reduced. Figure 2E represents formulation F3 after 24 h incubation period. The absence of needle-like structures of the pure drug and the formation of nano-sized drug-loaded mesoporous particles were evidenced. Hence it supported the method of preparation to achieve high drug-loading at 24 h incubation period.

Figure 2: SEM photographs of Pure drug (A), Syloid 244FP (B), and F3 at different incubation periods (C-6 h, D-12 h, and E- 24 h)

The FTIR spectrum of the pure drug and formulation F3 is illustrated in Figure 3a. The characteristics peaks of celecoxib for asymmetric stretching at 3340.82 cm−1, -NH bend at1564.32 cm−1, C-F stretching at 1228.70 cm−1, and aromatic C-H bend at 794.70 cm−1 were retained in the formulation F3, indicating the compatibility of the drug with the carrier¹⁴.

An endothermic peak of the pure drug was observed at 167 ℃ as observed in Figure 3b, representing the melting point of the drug, whereas in the thermogram of formulation F3 the peak intensity was minimized to a great extent, indicating the entrapment of the drug into the pores of mesoporous silica. The evidence of a small endothermic peak at the melting point of celecoxib further reveals the presence of a minute quantity of recrystallized drug in the formulation.

The PXRD studies of the pure drug and the formulation F3 (Figure 3c) supported the findings from FTIR and DSC results. The characteristics peak of the pure drug at 2Ɵ values 5, 16.2, 19.8, and 22.3 were reduced significantly in the formulation F3. This is an indication of the amorphization of the drug.

The BET thermogram (Figure 3d) of the carrier revealed the porous characteristics of the material. The absorption and desorption graph of the carrier followed Type -IV isotherm with a specific surface area and pore volume of 11.7815 m2/g and 0.0546652 cc/g respectively while the formulation F3 unveiled the loading of the drug in the pores of silica. The specific area and pore volume of F3 were found to be 2.77114 m2/g and 0.00899108 cc/g respectively. The analysis confirmed the high loading of the drug into the pores, and as the specific area of the formulation was increased that might have promoted high dissolution as reported in the in vitro dissolution study earlier¹⁹,²³.

Hence, attractive crystalline structures of mesoporous syloid 244FP, significantly enhanced the bio properties of celecoxib by improving drug loading efficiency, drug stability, and controlled release. The high surface area and ordered pore architecture might contribute to the stabilization of the amorphous drug form, leading to improved bioavailability. The correlated mechanisms involved the controlled pore architecture of the carrier, drug-carrier interactions, and diffusion-controlled release kinetics. These factors collectively might contribute to the therapeutic efficacy and safety of mesoporous celecoxib formulations.

Figure 3: FTIR (a), DSC (b), PXRD (c) of Pure drug (A) and F3(B), BET (d) of Syloid 244FP (A) and F3(B),

Molecular Docking Study

The structure of mesoporous celecoxib with Syloid 244FP is presented in scheme 1. The formation involves physical adsorption, hydrogen bonding, and van der Waals forces, which stabilize the drug within the pores.

Scheme 1: Structure of mesoporous celecoxib

The anticancer activity of the mesoporous celecoxib was investigated through a molecular docking study. The pathway of anticancer activity of celecoxib was targeted with the proteins. The 3D structures of the docking, revealed better docking score/binding energy of the formulation F3 with 604U and 1F3H than pure celecoxib, as shown in Figure 4. Docking with 604U showed the best binding score of -11.1. The number of interactions with the targeted amino acids GLY257, GLY262, VAL258, VAL216, ARG263, etc. were significantly improved with the formulations compared to the pure drug indicating a high degree of anticancer activity.

Figure 4: 3-D Docking results of Celecoxib and Mesoporous celecoxib targeting different proteins

Cytotoxicity study

The cytotoxicity study and MTT assay on cancer cell line - HCT-116 showed a significant effect of formulation F3 on anticancer activity²². The anticancer activity of celecoxib was highly improved after loading into mesoporous silica for all the concentrations compared and studied with the pure drug as shown in Figure 5. The effect of Syloid 244FP in the enhancement of dissolution efficiency of celecoxib might have contributed to the remarkable anticancer activity.

Acridine Orange (AO) is a fluorescent dye that can permeate the intact cell membrane and stain the nuclei of live cells green and can be visible under fluorescence microscopy. Ethidium Bromide (EB) is another fluorescent dye that enters the cells by damaging the membranes. It stains the nucleus of cells that have lost membrane integrity, making them appear red under fluorescence microscopy.

Considering the efficacy of the formulation at the highest concentration (75µM), formulation F3, pure drug, and doxorubicin were taken for the AO/EB staining. The control cells displayed normal morphology and appeared green. This suggested that the control cells were live and had intact cell membranes. When HCT-116 cells were treated with formulation F3, morphological changes were observed, including cell shrinkage, membrane blebbing, chromatin condensation, and apoptotic body formation. These changes are indicative of apoptosis in colon cancer cells. Formulation F3 was found to be more active in the apoptosis of cells compared to the standard drug doxorubicin. A significant anticancer activity was observed with the mesoporous delivery of celecoxib.

Figure 5: Cytotoxicity (A) and Cell apoptosis study – Control cells(B), Administration of celecoxib(C), Formulation F3(D) and Doxorubicin(E)

Conclusion

The research work aimed to study the effect on anticancer activity of celecoxib by solubility enhancement using a mesoporous delivery system. A synthetic mesoporous silica Syloid 244FP was used for this purpose. The solvent evaporation method was found to be effective in loading celecoxib in the pores of silica. The highest loading was observed for formulation F3 at the drug/silica ratio of 2.5:1. The high loading of the drug in the mesoporous silica was confirmed by the SEM and BET studies. An enhancement in the dissolution efficiency of celecoxib was evidenced in the formulation. The molecular docking study predicted the suitability of the formulations for the targeted proteins. The MTT assay and AO/EB staining studies disseminated the efficacy of F3 on HCT-116 cell lines over pure celecoxib and doxorubicin. Hence it can be concluded that mesoporous delivery of celecoxib could be beneficial and effective against colorectal cancer for its new indication.

Conflict of interest

The authors report no conflicts of interest.

Acknowledgement

The authors would like to thank the principal and management of Krupanidhi College of Pharmacy, Bengaluru, India, for providing facilities for the completion of the research work.

List of abbreviations

Acridine Orange/ Ethidium Bromide -AO/EB

American Type Cell Culture Collection - ATCC

Attenuated total reflectance -ATR

Brunauer–Emmett–Teller -BET

Biopharmaceutical Classification System II -BCS II

Differential Scanning Calorimetry - DSC

Dynamic Light Scattering -DLS

Dulbecco Modified Eagle Medium -DMEM

Fourier Transform Infrared Spectroscopy -FTIR

Human colorectal carcinoma cell lines -HCT

Powder Xray Diffraction -PXRD

3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide -MTT

Scanning Electron Microscope- SEM

Data availability statement

Data will be made available on request.

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