Abstract
This study reports a novel ibuprofen (IBU) drug delivery system using a chromium–trithiocyanuric acid metal–organic framework (Cr-MOF) encapsulated with a biodegradable, nontoxic carboxymethyl cellulose (CMC) for sustained release of ibuprofen (IBU) drug. The chromium metal–organic framework (MOF) was synthesized via the solvothermal method in a mixture of solvents in acidic conditions, followed by loading with the ibuprofen drug (Cr-MOF@IBU). Cr-MOF@IBU was further encapsulated with the CMC polymer and cross-linked with ferric chloride to form CMC/Cr-MOF@IBU hydrogel beads. Different characterization techniques were used, such as FT-IR, field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), BET, and UV–vis spectroscopy, to confirm the successful synthesis and drug loading. pH responsiveness of CMC/Cr-MOF@IBU hydrogel beads demonstrated by the swelling studies confirmed the optimal swelling in a mimicked gastrointestinal environment. The BET analysis further confirmed a significant decrease in surface area after drug loading. An in vitro drug delivery study indicated that controlled and sustained drug delivery was important for better efficacy and reducing the side effects of the drug. The cytotoxicity studies of A549 cell lines revealed the improved biocompatibility and lower toxicity of encapsulated CMC/Cr-MOF@IBU compared to Cr-MOF. This study highlights the potential of CMC/Cr-MOF@IBU as an efficient and effective drug delivery vehicle for the sustained and controlled release of ibuprofen.
1. Introduction
One of the most interesting nanotechnology advancements in recent decades has been metal–organic frameworks (MOFs). One, two, or three-dimensional networks of metal ions or clusters with organic ligands form metal–organic frameworks.1 However, metal–organic framework architectures use organic supplementary building units (SBUs) to connect metal cores and form a network.2 The metal–organic frameworks are characterized by large surface areas, variable pore sizes, and flexible surface characteristics.3 These properties have fascinated researchers to explore possibilities for the applications of MOFs in diverse areas. Research on drug delivery systems might improve treatment outcomes by precise dosing, focused, sustained, and controlled release, and decreased side effects.4 Using metal–organic frameworks as carriers or vehicles in drug delivery systems is appealing, and various researchers have documented various studies on metal–organic frameworks for drug loading and delivery.5 Researchers have done extensive studies on chromium-based metal–organic frameworks (Cr-MOFs) from the perspective of their wide variety of applications such as food packaging, adsorption,6 supercapacitors,7 metal removal,8,9 gas adsorption,10 and catalysis.11 The studies on the drug delivery applications of chromium-based metal–organic frameworks (Cr-MOFs) are scarce despite several reports on different applications of chromium MOFs. The importance of chromium metal as a trace element and the great stability of Cr(III) ions are the factors that can contribute toward drug delivery applications.12 Comparing Cr(VI) and Cr(III) ions, Cr(III) ions have much less toxicity. Trivalent chromium is found to be used in nutritional supplements and is reported to keep the blood glucose level normal.13 Recent reports have raised concern over the genotoxicity of Cr(III); however, more studies are still needed to authenticate the data. As per reports, binding of Cr(III) to picolinic acid leads to genotoxicity, while binding with ligands such as arginine, aspartic acid, glycine, and lysine does not result in genotoxicity.14
In anticancer studies, inflammation is linked with various stages of tumor growth and is linked with the pathogenesis of various types of tumors or cancers, including lung cancer. Cyclooxygenase-2 enzyme is overexpressed in different types of cancers, including lung cancer. Ibuprofen (IBU) is a type of nonsteroidal anti-inflammatory drug (NSAID) reported to impact cancer progression. Ibuprofen is known for its anti-inflammatory properties and inhibition of cyclooxygenase-2 overexpression. This way, IBU interferes with the environment and growth of tumors. Despite the fact that IBU is not an anticancer/antitumor drug, its effect on inflammation and cyclooxygenase-2 overexpression presents an opportunity to explore the adjunctive benefits of IBU in cancer therapy. In line with the previous reports in the literature to reduce the cytotoxicity of MOFs, surface modifications through coating have been done. There are many reports on this aspect, and recent research based on the modification of MOFs using coatings with polydopamine for improved bioavailability demonstrated that modifications of MOFs using coatings greatly reduced their cytotoxicity, making them biocompatible even for liver cells.15
In this regard, a possible approach to deal with this issue is to encapsulate MOFs in polymers having biocompatibility and nontoxicity. Different natural polymers or derivatives of such polymers that have these properties can be utilized. Another aspect is related to the stability of the drug delivery vehicle during its passage through the gastrointestinal (GI) tract. To address this gap, a novel drug delivery vehicle has been developed by integrating Cr-MOF with carboxymethyl cellulose (CMC). This encapsulation reduces potential toxicity and ensures a controlled and sustained release of IBU, resulting in improved therapeutic efficacy. The carboxymethyl cellulose polymer was chosen for this study to prevent direct exposure of Cr-MOF.
This study introduces a novel approach for drug delivery through the development of a chromium-based metal–organic framework (Cr-MOF). This study comprises a chromium-based metal–organic framework (Cr-MOF) derived from trithiocyanuric acid. After cross-linking with ferric chloride, the encapsulation with carboxymethyl cellulose results in a drug delivery system that is both stable and pH-sensitive. The innovative aspect of this research lies in the synthesis of Cr-MOF and its integration into the CMC matrix to create hydrogel beads. This combination leverages the advantages of MOFs, such as their extensive surface area, adjustable pore size, and controlled release properties while also enhancing biocompatibility and preventing chromium leaching, a common issue in MOF-based systems. CMC/Cr-MOF@IBU hydrogel beads exhibit notable pH sensitivity, which is crucial for targeted and controlled drug release. The synthesized MOF was characterized using techniques such as FT-IR, field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and BET analysis. Swelling studies demonstrated the pH-responsive behavior of the hydrogel beads, while in vitro drug release experiments showed a sustained release of ibuprofen. This research presents an innovative drug delivery system that combines the strengths of metal–organic frameworks and biodegradable polymers, resulting in a stable, pH-sensitive, and sustained release vehicle, thus opening new avenues for biomedical applications. Cytotoxicity data of CMC/Cr-MOF@IBU indicated the least cytotoxicity among the three samples due to CMC encapsulation. This study addresses the critical gap that exists in the chemistry of the Cr-MOF-based drug delivery vehicle, and cytotoxic analysis and the anti-inflammatory properties of the ibuprofen drug were utilized to develop a safer, biocompatible drug delivery vehicle targeting A549 lung cancer cell lines.
2. Experimental Section
2.1. Materials and Methods
The synthesis of the Cr-MOF involved the use of chromium chloride hexahydrate (Loba Chemie Pvt Ltd.) and trithiocyanuric acid (Sigma) as the precursor and ligand, respectively. In addition, DMSO (dimethyl sulfoxide, Sigma), DMF (dimethylformamide, Sigma), sodium carboxymethyl cellulose (Sigma), ibuprofen (IBU), and n-hexane (Sigma) were also used in the synthesis. The solvents were subjected to drying procedures reported in the literature. Double-distilled water was used in this study wherever mentioned. Solid-state (powdered form) IR spectra (4000–400 cm–1 region) were obtained using a PerkinElmer Bruker Avance Neo 500 MHz instrument. FE-SEM analysis was conducted utilizing a HITACHI SU8010 series instrument (Bruker). XRD data were obtained with a Siemens diffractometer at room temperature using Cu Kα radiation at 35 kV. UV–vis absorption spectra were obtained using a Shimadzu Model spectrophotometer. The specific surface area and pore size distribution were measured. The specific surface area and the pore size distribution were measured by a Quantachrome Novae 2200.
2.2. Synthesis of Cr-MOF
CrCl3·6H2O (1 g) and trithiocyanuric acid (0.665 g) were weighed and dissolved in the mixture of solvents containing dimethylformamide (1 mL) and dimethyl sulfoxide (5 mL). The solution was then sonicated for 10 min to get a homogeneous solution. To maintain the pH of the reaction mixture between 2 and 4, a drop of hydrochloric acid was added. Thereafter, the solution was transferred to a Teflon-coated stainless steel autoclave and heated to 180 °C temperature for 15 h in a muffle furnace. After completion of the reaction, the autoclave was allowed to cool to room temperature. The resulting green solution was subjected to centrifugation for a duration of 15 min at a speed of 1500 rpm (RPM) to separate the solid. This step was followed by washing of the green-colored solid using DMF and DMSO. The solid was then dried for 24 h in a vacuum oven at 100 °C temperature. The process of synthesis of a chromium metal–organic framework is shown in Figure 1.
Figure 1.
Different steps involved in the synthesis of Cr-MOF.
2.3. Loading of the Ibuprofen Drug in Cr-MOF (Cr-MOF@IBU)
The loading of the ibuprofen drug in Cr-MOF was done in the n-hexane solvent. For this, 0.03 g of Cr-MOF was dispersed in a hexane solution (10 mL), and 0.003 g of ibuprofen was dispersed in 5–6 mL of n-hexane at room temperature. The IBU–hexane solution was added dropwise to the Cr-MOF solution (18 °C) over a period of 5 min, followed by stirring at a speed of 150 rpm for 72 h. The resulting IBU-loaded Cr-MOF (Cr-MOF@IBU) was then subjected to centrifugation, and the solvent was removed by decantation. After centrifugation, Cr-MOF@IBU was dried in a vacuum oven for 3–4 h to eliminate any remaining traces of n-hexane. The loading procedure for ibuprofen (IBU) in Cr-MOF is illustrated in Figures 2 and 3.
Figure 2.
Loading of the ibuprofen (IBU) drug in a metal–organic framework.
Figure 3.
Mechanism of drug loading of Cr-MOF and interaction of Cr-MOF with the drug.
2.4. Synthesis of the Carboxymethyl Cellulose-Encapsulated Drug Delivery Vehicle (CMC/Cr-MOF@IBU)
The first step in this synthesis was the dispersion of Cr-MOF@IBU (0.013 g) in water in a beaker by sonication in distilled water (10 mL). The Cr-MOF@IBU suspension in water was then mixed with 10 mL of carboxymethyl cellulose solution prepared by dissolving 0.13 g of carboxymethyl cellulose in double-distilled water. The resulting solution thus obtained was stirred at room temperature (18 °C) to ensure complete dispersion of Cr-MOF@IBU across the carboxymethyl cellulose polymeric chains. In the last step, the resulting mixture was poured dropwise to form beads in 50 mL of FeCl·H2O (0.675 g of ferric chloride) for cross-linking. A similar process was used for the synthesis of CMC@IBU for comparison. Figures 4–7 illustrate the loading of IBU in Cr-MOF, conversion of Cr-MOF@IBU to CMC/Cr-MOF@IBU, the cross-linking process of FeCl3·6H2O with CMC/Cr-MOF@IBU, and mechanisms before and after the modification of Cr-MOF, respectively.
Figure 4.
Synthesis of Cr-MOF@IBU.
Figure 7.
Mechanisms before and after modification of Cr-MOF.
Figure 5.
Modification of Cr-MOF to CMC/Cr-MOF@IBU.
Figure 6.
Cross-linking process of FeCl3·6H2O with CMC/Cr-MOF@IBU.
2.5. Swelling Studies
For swelling studies, pure CMC/IBU and CMC/Cr-MOF@IBU were kept in buffer solutions with pH values of 1.2, 6.8, and 7.4 at room temperature for different intervals of time mimicking the environment of the gastrointestinal (GI) track. CMC/Cr-MOF@IBU beads were taken out from the buffer solutions at predetermined time intervals, and their weights were determined after removing the excess buffer solution sticking with beads using filter paper. Using eq 1, the percentage of swelling was computed.
 |
1 |
2.6. In Vitro Drug Release Studies
CMC/Cr-MOF@IBU and CMC@IBU beads were suspended in buffer solutions (pH 1.2, 6.8, and 7.4) in order to provide gastrointestinal conditions for the in vitro drug release investigations. The different beads were immersed in 10 mL of buffer solutions of various pH levels at varied times. After adding the beads to pH 1.2 buffer for 1 h in test tube 1, 5 mL was withdrawn for UV spectroscopy, and fresh 5 mL of buffer was added to maintain 10 mL. After 2 h, the beads were withdrawn from pH 1.2 and then placed in a pH 6.8 buffer (10 mL) in test tube 2. The 10 mL buffer solution in test tube 1 was for UV spectroscopy. Test tube 2 was treated for 2 h as test tube 1. Finally, beads were transferred to pH 7.4 buffer in test tube 3 for 4 h using a similar procedure. After incubation for 8 h at different pH values, 5 mL aliquots of buffer solution were withdrawn and stored separately for the subsequent UV spectroscopic analysis. An equivalent volume of fresh buffer (5 mL) was added after each withdrawal to maintain the total volume. A similar procedure was used for CMC@IBU drug delivery studies. The percentage of drug loading and drug released was determined using eq 2
 |
2 |
where MI, MUI, and MM are the total amount of Ibuprofen, the unloaded amount of ibuprofen in the supernatant, and the amount of MOF, respectively. The drug released percentage was calculated using eq 3.
 |
3 |
2.7. Cytotoxicity Studies
The cytotoxic effects of the samples on the A549 cell line, obtained from NCCS Pune, were assessed using the MTT assay. The cells (10,000 cells/well) were cultured in a 96-well plate over 24 h in a medium containing DMEM (Dulbecco’s modified Eagle medium—AT149–1L-HIMEDIA) enriched with 10% FBS (fetal bovine serum—HIMEDIA-RM 10432) and 1% antibiotics solution (penicillin–streptomycin—Sigma-Aldrich P0781) at 37 °C using five percent carbon dioxide (CO2). On the following day, the cells were subjected to various concentrations of samples. The stock solution for each sample was made in DMSO and subsequently diluted to achieve various concentrations in an incomplete cell culture medium (excluding FBS). Following a 24 h incubation period, MTT solution (5 mg/mL) was introduced to the cell culture and incubated for an additional 2 h. The untreated cells were designated as the control, while the cells lacking MTT were classified as blank. Upon completion of the experiment, the culture supernatant was discarded, and the cell layer matrix was dissolved in 100 μL of dimethyl sulfoxide. The solution was then analyzed using an ELISA plate reader (iMark, Biorad) at a wavelength of 540 nm. The percentage of viable cells was determined using eq 4
 |
4 |
where Atest is the absorbance of the test sample and Acontrol is the absorbance of the control.The cytotoxicity tests were conducted in quadruplicates to ensure reproducibility.
3. Results and Discussion
Chromium-based metal–organic frameworks were synthesized and characterized by various techniques. Cr-MOF (green solid) exhibited a high melting point and was found to be insoluble in almost all commonly used solvents. FT-IR spectroscopy was employed to confirm the synthesis of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU. UV–vis spectroscopy was utilized to assess the concentration of the released ibuprofen by Cr-MOF by measuring the absorbance using the calibration curve of standard IBU via UV spectroscopy at a wavelength of 265.5 nm. Cr-MOF@IBU encapsulated with carboxymethyl cellulose was formed by the dropwise addition of a solution of Cr-MOF@IBU and carboxymethyl cellulose to a solution of ferric chloride hexahydrate. Instant gel sphere formation was observed due to rapid physical cross-linking when solutions reached FeCl3. The interaction of Fe3+ ions with multiple carboxylate groups on CMC potentially facilitated the formation of a cross-linked network through van der Waals interactions and metal coordination. The MOF–IBU-encapsulated hydrogel was collected as beads in FeCl3 solution during this process. The gradual and controlled release of ibuprofen ensured proper anion diffusion into the carboxymethyl cellulose network, releasing the drug from Cr-MOF@IBU into the carboxymethyl cellulose matrix via an ion exchange mechanism. Consequently, the drug diffused from the beads into the surrounding aqueous media.
3.1. FTIR Studies
FTIR spectral studies of the thiocyanuric acid ligand revealed distinctive peaks ranging from 2906 to 3135 cm–1 attributed to N–H stretching vibrations (triazine), while the peak at 1524 cm–1 likely originated from nonaromatic thione triazine stretching. Additionally, a peak at 1356 cm–1 indicated the presence of C–N stretching. Furthermore, the peak associated with the C=S stretching vibration appears in the region of 1114 cm–1. However, the absence of N–H stretching peaks in the IR spectrum of synthesized MOF suggested that deprotonation in the MOF had occurred. The appearance of a weak broad peak at 3095 cm–1 suggested the presence of moisture trapped within the MOF pores. Moreover, the peak at 1522 cm–1, attributed to nonaromatic thione triazine stretching, shifted to a higher frequency of 1554 cm–1. The C–N stretching frequency shifted from 1356 to 1350 cm–1 in the MOF, which is indicative of bond formation. The C–S peak at 1114 cm–1 shifted to 1125 cm–1, and a sharp peak at 479 cm–1 was attributed to the stretching vibration of the Cr–Cl bond.16 Cr-MOF and trithiocyanuric acid ligand IR spectra are depicted in Figure 8.
Figure 8.
IR spectra of the trithiocyanuric acid ligand and Cr-MOF.
A comparison of the IR spectra of Cr-MOF@IBU with those of Cr-MOF and IBU confirmed the synthesis of the desired product. The stretching vibrations of the carbonyl group and C–H bonds caused peaks at 1713 and 2900 cm–1 in ibuprofen’s FT-IR spectra, respectively. The peak at 1230 cm–1 was attributed to C–O bond stretching.17 The characteristic carbonyl stretching peak observed at 1713 cm–1 in IBU shifted to 1716 cm–1 in Cr-MOF@IBU. This shift indicated a change in the chemical environment upon interaction. Additionally, the C–O stretching peak in the spectrum of the MOF@IBU complex shifted from 1230 to 1209 cm–1, providing further evidence of the complex formation. Notably, the characteristic peaks corresponding to the C–H groups of ibuprofen suggested the successful formation of the Cr-MOF@IBU complex.18 The peak at 518 cm–1 in the spectrum of MOF@IBU also indicated the interaction between oxygen and chromium. The hydrogen bonding between the carboxylic group of ibuprofen and the C–S group of Cr-MOF resulted in the formation of a complex. Figure 9 shows the IR spectrum of Cr-MOF@IBU.
Figure 9.
Comparison of the IR spectra of Cr-MOF, IBU, and Cr-MOF@IBU.
IR spectra of CMC showed peaks at 3254 cm–1 due to OH stretching, at 2930 cm–1 due to CH2 stretching, and at 1052 and 1587 cm–1 due to COO– vibrations. The CMC/Cr-MOF–IBU spectra showed Cr-MOF, CMC, and CMC/Cr-MOF@IBU peaks. Figure 10 shows the IR spectra of CMC and CMC/Cr-MOF@IBU.
Figure 10.
Comparison of the IR spectra of CMC and CMC/Cr-MOF@IBU.
3.2. FE-SEM Analysis
The pores and surface morphology of Cr-MOF were studied using FE-SEM. Cr-MOF SEM images showed spherical particles arranged irregularly in the assemblies. The images also suggested the presence of pores in the assemblies of the spherical structures. The FE-SEM images captured at different magnifications (10, 5, 1, and 500 nm) revealed a porous structure. This porous morphology is indicative of the potential of Cr-MOF for effective drug loading and encapsulation of drug molecules. Images at higher magnifications (500 nm) further supported the presence of pores available for drug delivery applications. Figure 11 displays the FE-SEM images of the chromium metal-based MOF.
Figure 11.
FE-SEM images of Cr-MOF at (a) 30 μm, (b) 10 μm, (c) 500 nm, (d) 400 nm, (e) 5 μm, (f) 1 μm, (g) 1 μm, and (h) 500 nm.
3.3. EDX Analysis
The elemental makeup of Cr-MOF was studied by using energy-dispersive X-ray spectroscopy (EDX). Chromium (Cr), sulfur (S), nitrogen (N), oxygen (O), chlorine (Cl), and carbon (C) were detected in the EDX spectra of the synthesized Cr-MOFs (Figure 12). The elements found in the EDX spectrum suggested the successful synthesis of the Cr-based MOF. EDX spectra also confirmed the purity of the metal–organic framework. The EDX data of Cr-MOF showed 11.71 weight and 24.54 atomic percentage of carbon, 27.89 weight and 43.88 atomic percentage of oxygen, 6.38 weight and 4.53 atomic percentage of chlorine, 2.95 weight and 2.32 atomic percentage of sulfur, and 51.07% weight and 24.73 atomic percentage of chromium. On the basis of above data, formula Cr3(C3N3S3)Cl0.55(H2O)5.18 can be assigned the Cr-MOF.
Figure 12.
EDX spectra of Cr-MOF.
3.4. XRD Analysis
Powder XRD analysis of Cr-MOF revealed its crystalline nature and purity. The peaks at 2θ of 11.2, 14.4, 16.0, 30.4, 31.7, 36.4, 36.6, 38.0, 40.8, and 42.4 corresponding to the (010), (110), (121), (220), (132), (342), (343), (323), (106), and (315) planes, respectively, were obtained in the powder XRD spectra of Cr-MOF, suggestive of a triclinic crystal structure in line with earlier reports in the literature.8,19 XRD data indicated 80.7% crystallinity and 19.3% amorphous index of the synthesized Cr-MOF. These sharp peaks indicated the crystalline nature and ordered structure of MOF, reflecting the periodic arrangement of the chromium ions and trithiocyanuric acid in the framework. The XRD pattern of IBU showed distinct peaks at 2θ values of 6.1, 16.4, 17.7, 20.2, 19.8, 22.4, and 27.7. There was a shift in the XRD peaks of IBU on loading in Cr-MOF. This shift suggested an interaction between the Cr-MOF framework and IBU drug molecules. Such changes in the XRD pattern are critical for understanding how the drug is accommodated within the MOF structure. The introduction of CMC to Cr-MOF@IBU led to a significantly different XRD pattern. The characteristic peaks of Cr-MOF@IBU were retained, suggesting that the fundamental structure of MOF and its interaction with the drug were maintained. However, a broad band at a 2θ of 20° highlighted the amorphous nature of CMC.20 This amorphous character of CMC in the composite suggested that a matrix formed around Cr-MOF@IBU, which influenced the release profile and stability of the drug. Figure 13 shows the powder XRD patterns of Cr-MOF and the simulated patterns of Cr-MOF, IBU, Cr-MOF@IBU, and CMC/Cr-MOF@IBU. The observed changes/shifts in the peaks in powder XRD data before and after drug loading supported the fact that the drug was encapsulated in MOF pores. After encapsulation, the appearance of new peaks as well as broadening of the peaks suggested that drug molecules interacted with MOF. The characteristic peaks of Cr-MOF were present but slightly shifted in Cr-MOF@IBU. This subtle shift in peak positions indicates the fact that MOF undergoes desorption on drug encapsulation, which is a common result of successful drug loading.
Figure 13.
XRD patterns of (a) Cr-MOF (as-synthesized and simulated), (b) IBU, (c) Cr-MOF@IBU, and (d) CMC/Cr-MOF@IBU.
3.5. BET Analysis
BET analysis was performed to evaluate the surface area and porosity of the material. Figure 14 shows a type IV isotherm with an H3 hysteresis loop, characteristics of mesoporous materials. A higher gas uptake at comparatively higher pressure indicated higher pore volume in the case of Cr-MOF before loading. The surface area of the MOF before drug loading was 127 m2/g with a pore diameter of 3.8 nm. After drug loading, as shown in Figure 14b, the surface area decreased significantly to 5 m2/g, indicating that the pores were effectively occupied by the drug molecules. A smaller hysteresis loop in the case of Cr-MOF after drug loading indicated reduced pore accessibility. After drug loading, a noticeable reduction in adsorption–desorption volumes is observed, signifying that the drug molecules have successfully occupied the MOF’s pores. This is further evidenced by a slight narrowing and shift in the hysteresis loop, which indicates reduced pore accessibility and structural changes due to drug incorporation. From the results, it was clear that mesoporosity was retained, indicating that the Cr-MOF was maintained even after drug loading, crucial for drug delivery applications. Figure 14 displays the BET analysis of Cr-MOF before and after drug loading.
Figure 14.
(a) Cr-MOF before drug loading and (b) Cr-MOF@IBU after drug loading.
3.6. Swelling Studies
Swelling studies provide insights into swelling behavior in various pH environments, mimicking conditions of the gastrointestinal (GI) tract. The swelling studies of prepared CMC/MOF@IBU hydrogel beads were studied in buffer solutions of different pH (1.2, 6.8, and 7.4) at room temperature (Figure 15).
Figure 15.
Digital images of the CMC/Cr-MOF@IBU beads before and after drying.
The weight of the swollen hydrogel beads was checked every hour (up to 8 h) in different pH conditions in different time intervals, as mentioned in the Experimental Section. After the analysis of different weights of CMC/MOF@IBU in different pH conditions, it was observed that the maximum swelling was at pH 6.8, followed by 7.4, and at pH 1.2, swelling was least. Under highly acidic conditions (pH 1.2), the chances of protonation of the carboxyl groups of CMC were high (RCOOH). The carboxyl groups in their protonated state possess an oxygen–hydrogen bond (O–H) capable of establishing hydrogen bonds. As a result of hydrogen bonding, swelling decreased.
Thus, at a low pH of 1.2, similar to the stomach’s acidic environment, the swelling of CMC/Cr-MOF@IBU beads was minimal. This occurred because the carboxyl groups became protonated, leading to hydrogen bonding and reduced swelling. In contrast, at a higher pH of 7.4, similar to the intestinal environment, the carboxyl groups deprotonate, resulting in electrostatic repulsion and increased swelling. This increased swelling facilitates a greater drug release, making the material more effective in neutral or basic environments. At pH 7.4, carboxyl groups of the CMC were likely predominantly deprotonated (RCOO). Deprotonation of the polymer chains resulted in an augmented (increased) negative charge, which, in turn, caused electrostatic repulsion between carboxylate groups. This repulsion enhanced the elongation of the polymer structure, leading to better water absorption and swelling than at pH 1.2. The swelling of the CMC-encapsulated beads in buffer solutions of different pH values indicated that pH sensitivity and the optimal pH for the swelling were between 6 and 8. In this pH range, some changes in the structure of the cellulose beads were found. The penetration of the acidic fluids into hydrogel beads at pH 6.8 increased owing to MOF disintegration, and the swelling ratio increased. According to the swelling data of pure CMC, the maximum swelling occurred at pH 7.4 > 6.8 > 1.2. At pH 7.4, the swelling increased after every hour, and at pH 6.8, the swelling increased, but the increase was less than that at pH 7.4. According to the swelling data of CMC/MOF@IBU, the maximum swelling occurred at 6.8 > 7.4 > 1.2 because of the pH sensitivity of the hydrogel. In the case of CMC@IBU, the maximum swelling occurred at pH 7.4 > 6.8 > 1.2. Swelling behavior is a key factor influencing the ibuprofen release rate. In vitro studies demonstrate that at pH 7.4, CMC/MOF@IBU beads provide a slow and sustained drug release, while at pH 1.2, the release is faster but less prolonged. This controlled release mechanism is vital for maintaining therapeutic drug levels over extended periods, reducing the frequency of dosing and potential side effects. Swelling studies of pure CMC, CMC@IBU, and CMC/Cr-MOF@IBU are shown in Figure 16. The swelling of hydrogel beads is shown in Figure 17.
Figure 16.
Swelling studies of pure CMC, CMC@IBU, and CMC/Cr-MOF@IBU.
Figure 17.
Swelling of hydrogel beads.
3.7. In Vitro Drug Release Studies
Ibuprofen is a painkiller drug that has side effects including irritation of the gastrointestinal tract. Encapsulation of IBU in a biocompatible, biodegradable polymer may reduce the negative effects of this drug, and loading the drug into a porous metal–organic framework can lead to sustained and controlled release. The biocompatible and biodegradable carboxymethyl cellulose (CMC) hydrogels that absorb water and are pH-sensitive allow slow drug release. Drug release was sustained in a metal–organic framework. This steady release is essential for long-term therapeutic drug levels. Since MOFs have large surface area and porosity also, these are suitable for drug loading. Hydrogel beads were tested as an oral medication delivery method in vitro to imitate the digestive tract pH. The slow and prolonged release of the drug from hydrogel beads maintained the drug concentration, potentially minimizing unwanted effects. On comparing release profiles, CMC@IBU exhibited rapid drug release at pH 1.2 (45% release at 120 min), whereas CMC/MOF@IBU demonstrated slower release (26% release at 120 min at pH 1.2). At pH 7.4, CMC/MOF@IBU displayed gradual and prolonged drug release (83% release at 480 min), while CMC@IBU exhibited greater release (90% release at 480 min). At pH 6.8, CMC/MOF@IBU exhibited slower drug release (30% release at 180 min) than CMC@IBU, which exhibited rapid release (65% release at 180 min). Figure 18 shows the drug release profiles of CMC@IBU and CMC/MOF@IBU over time and at different pH values.
Figure 18.
Drug release behavior of CMC@IBU and CMC/Cr-MOF@IBU with respect to pH and time.
3.7.1. Mechanism of Drug Release
The drug release mechanism at pH 1.2, 6.8, and 7.4 is illustrated as follows.
-
(a)
Drug release at pH 1.2 (simulated gastric fluid)
-
CMC@IBU
CMC@IBUsolid + H2O → CMCswollen + IBUreleased (45% release at 120 min, rapid release due to quick swelling and dissolution of CMC)
CMC/MOF@IBU
CMC/MOF@IBUsolid + H2O → CMCswollen + MOFstabilized + IBUreleased (26% release at 120 min, slow release due to additional stability of the MOF structure)
-
(b)
Drug release at pH 6.8 (simulated intestinal fluid)
-
CMC@IBU
CMC@IBUsolid + H2O → CMCmoderately swollen + IBUrapidly released (65% release at 180 min, rapid release due to moderate swelling)
CMC/MOF@IBU
CMC/MOF@IBUsolid + H2O → CMCmoderately swollen + MOFstabilized + IBUslowly released (30% release at 180 min, slow release due to additional stability provided by the MOF structure)
-
(c)
Drug release at pH 7.4 (simulated intestinal fluid)
-
CMC@IBU
CMC@IBUsolid + H2O → CMCmoderately swollen + IBUapidly released (90% release at 480 min, greater release due to moderate swelling)
-
CMC/MOF@IBU
CMC/MOF@IBUsolid + H2O → CMCmoderately swollen + MOFstabilized + IBUgradually released (83% release at 480 min)
3.8. FE-SEM Analysis of CMC/Cr-MOF@IBU
FE-SEM studies provided a comprehensive understanding of the use of CMC/Cr MOFs as effective vehicles for ibuprofen delivery. The images before and after the drug delivery confirmed the successful loading and release of the drug and underlined the structural robustness and functional dynamics of this novel drug delivery system (Figure 19). These data are essential for further optimization and the potential clinical application of such MOF-based drug delivery systems.
Figure 19.
FE-SEM images of CMC/Cr-MOF@IBU before and after drug release.
3.9. Cytotoxicity Studies
It was observed from the analysis of the MTT assay that when the A549 cell line was exposed to different concentrations of the sample, cytotoxic activity was estimated for samples and 50% inhibitory concentration, as mentioned in Table 1. Sample C1 (Cr-MOF) was found to be the most cytotoxic among all the samples. IC50 is the concentration of an inhibitor/sample/formulation at which viable cells are reduced by half. The encapsulation of the ibuprofen in the MOF structure (C2) and further modification with carboxymethyl cellulose (C4) appear to slightly mitigate cytotoxicity compared to the plain chromium MOF (C1). The results suggest that carboxymethyl cellulose encapsulation improves the biocompatibility while maintaining a controlled release of the drug. The cytotoxicity studies of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU for 24 h are shown in Figure 20. Figure 21 displays control and treated for Cr-MOF for 24 h. Figure 22 shows cytotoxicity studies of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU for 48 h. Figure 23 entails control and treatment for Cr-MOF for 48 h. The cytotoxicity studies of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU for 72 h are shown in Figure 24, whereas Figure 25 shows control and treated for Cr-MOF for 72 h. Table 1displays IC50 values for cytotoxicity of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU for 24 h.
Table 1. IC50 Values for Cytotoxicity of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU for 24, 48, and 72 h.
| IC50 value (μg/mL) |
|||
|---|---|---|---|
| time | Cr-MOF | Cr-MOF@IBU | CMC/Cr-MOF@IBU |
| 24 h | 98.92 ± 0.09 | 168.3 ± 0.095 | 188.8 ± 0.078 |
| 48 h | 52.22 ± 0.18 | 59.61 ± 0.16 | 66.77 ± 0.15 |
| 72 h | 225.8 ± 0.20 | 258.3 ± 0.12 | 261.9 ± 0.24 |
Figure 20.
Cytotoxicity studies of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU for 24 h.
Figure 21.
Control and treated for Cr-MOF for 24 h.
Figure 22.
Cytotoxicity studies of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU for 48 h.
Figure 23.
Control and treated for Cr-MOF for 48 h.
Figure 24.
Cytotoxicity studies of Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU for 72 h.
Figure 25.
Control and treated for Cr-MOF for 72 h.
At 24 h, Cr-MOF exhibited the highest cytotoxicity indicated by the lowest IC50 value. Loading with ibuprofen and further encapsulation with CMC decreased the cytotoxicity, indicating the protective effect of CMC encapsulation. As compared to 24 h, at 48 h, all samples showed increased cytotoxicity, and Cr-MOF remained the most toxic. At 72 h, IC50 values increased compared to 24 and 48 h, indicating less cytotoxicity. The figures attached indicate cytotoxicity at different concentrations. The control image showed no cytotoxicity, while 1 μg/mL concentration showed minimum cytotoxicity, 50 μg/mL moderate cytotoxicity, and 100 μg/mL highest cytotoxicity, in line with the IC50 values. Cr-MOF showed the highest cytotoxicity across all the concentrations. Cr-MOF@IBU showed reduced cytotoxicity, while CMC/Cr-MOF@IBU showed the least cytotoxicity, improving biocompatibility.
A comparison of control and treated images at different concentrations and times also provided insights into cytotoxicity. The controls showed well-distributed healthy cells with no impact of toxicity. The effect of different concentrations (1 μg/mL, 50 μg/mL, and 100 μg/mL) of Cr-MOF, Cr-MOF@IBU and CMC/Cr-MOF@IBUhas been studied resulting in a decrease in cell density, and number of viable cells. This indicated that an increase in concentration of Cr-MOF. Cr-MOF@IBU and CMC/Cr-MOF@IBU, resulted in higher cell deths or higher cytotoxicity. However, CMC/Cr-MOF@IBU showed a higher number of viable cells compared to Cr-MOF@IBU and Cr-MOF, indicating that CMC/Cr-MOF@IBU was least toxic while Cr-MOF was most toxic. The least cytotoxicity of CMC/Cr-MOF@IBU can be attributed to the presence of CMC coatings which has reduced cytotoxicity and enhanced biocompatibility.
4. Comparative Analysis
There have been past studies on MOF encapsulation with CMC in the past also, but those had certain limitations that have been addressed in the present study, as briefly illustrated in the comparative table (Table 2).
Table 2. Limitations of the Existing Studies and Overcomes in the Present Study.
| limitations of the existing studies | overcome in the present study | references |
|---|---|---|
| limited control over drug release: traditional delivery systems often struggle with precisely controlling the release rate of the drug. This can lead to suboptimal therapeutic effects or increased side effects. | enhanced control over drug release: the Cr-MOF@IBU system encapsulated with CMC offers controlled drug release, which is crucial for drugs like ibuprofen, which can cause gastrointestinal irritation. | (21−23) |
| stability issues: many current drug carriers are not sufficiently stable under physiological conditions, leading to premature release or degradation of the drug. | increased stability: the use of chromium-based MOF potentially offers higher moisture and thermal stability. This means the drug carrier is more likely to remain stable until it reaches the targeted site in the body. | |
| poor targeting efficiency: the conventional systems might not effectively target the specific site within the body, leading to reduced efficacy and potential side effects. | targeted drug delivery: the design of this system allows for more targeted drug release, since CMC has a pH-sensitive nature. This ensures that the drug is released at the desired location in the gastrointestinal tract. | |
| limited loading capacity: some existing carriers have limited capacity for drug loading, which can be a significant drawback for drugs that need to be delivered in larger doses. | improved drug loading capacity: MOFs, due to their porous nature, typically have a high surface area, which can accommodate a larger quantity of the drug. This characteristic is particularly beneficial for drugs that require higher doses. | |
| compatibility and safety concerns: there can be concerns regarding the biocompatibility and safety of the materials used in the current drug delivery systems. | safety and biocompatibility: the use of carboxymethyl cellulose (CMC), a biocompatible and safe material for the medical applications, addresses safety concerns. This makes the system more suitable for pharmaceutical applications. |
In comparison to existing research,21−23 this study is unique due to its innovative integration of the structural advantages of MOFs with the practical benefits of biodegradable polymers. This approach not only paves the way for more efficient drug delivery systems but also contributes to the advancement of MOF research by introducing a new synthesis and application framework. The novel Cr-MOF developed in this study represents a significant advancement in the development of more effective and safe drug delivery systems.
Furthermore, the system’s robustness and functionality are confirmed through comprehensive characterization techniques including FT-IR, FE-SEM, EDX, and XRD, alongside detailed swelling and in vitro drug release studies. The pH-responsive behavior and sustained release profile of the CMC/Cr-MOF@IBU hydrogel beads highlight their potential for various biomedical applications. In comparison to existing research, this study is unique due to its innovative integration of the structural advantages of MOFs with the practical benefits of biodegradable polymers. This approach not only paves the way for more efficient drug delivery systems but also contributes to the advancement of MOF research by introducing a new synthesis and application framework. The novel Cr-MOF developed in this study represents a significant advancement in the development of more effective and safe drug delivery systems.
5. Conclusions
Chromium-based metal–organic frameworks (Cr-MOFs) encapsulated with carboxymethyl cellulose (CMC) have shown sustained release for ibuprofen delivery. This unique drug delivery system’s structure and applicability have been revealed by FT-IR, FE-SEM, EDX, XRD, swelling tests, in vitro drug delivery, and cytotoxicity studies. FTIR analysis revealed unique peaks indicating chemical bonds and interactions in the Cr-MOF, Cr-MOF@IBU, and CMC/Cr-MOF@IBU complexes, confirming their synthesis. FE-SEM imaging confirmed the spherical shape of Cr-MOF and the composite structural form, while EDX analysis confirmed the elemental composition. XRD data revealed the crystalline structure and structural changes of Cr-MOF after drug delivery and CMC encapsulation. Studies have shown that most CMC-based hydrogel beads swell at a neutral pH. In vitro drug release investigations revealed controlled and sustained release patterns, which are necessary for therapeutic efficacy and safety. Cytotoxicity studies on A549 lung cancer cell lines revealed lesser cytotoxicity and improved biocompatibility of CMC/Cr-MOF@IBU compared to Cr-MOF@IBU and Cr-MOF. The variations in pH affected drug release, suggesting that this technique may be useful for medication delivery. The BET analysis of Cr-MOF before and after drug loading showed a significant decrease in surface area (96%). The study also showed that the Cr-MOF@IBU and CMC/Cr-MOF@IBU drug delivery systems are stable, efficient, and effective. These findings might advance the understanding of toxic metal-based systems for drug delivery systems through in vivo and toxicity research on controlled drug release and therapy. This study addresses the development of advanced drug delivery vehicles, highlighting their significant contribution to metal–organic framework research.
Acknowledgments
The authors are thankful to Chandigarh University, Mohali, Punjab, India, to provide necessary facilities to carry out this work.
Glossary
Abbreviations
- MOF
metal–organic framework
- XRD
X-ray diffraction
- FE-SEM
field emission scanning electron microscopy
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
The authors declare no competing financial interest.
Special Issue
Published as part of ACS Omegaspecial issue “Celebrating the 25th Anniversary of the Chemical Research Society of India”.
References
- Kitagawa S. Metal–organic frameworks (MOFs). Chem. Soc. Rev. 2014, 43 (16), 5415–5418. 10.1039/C4CS90059F. [DOI] [PubMed] [Google Scholar]
- Kamalzare M.Classification of the MOFs Based on the Secondary Building Units (SBUs). In Physicochemical Aspects of Metal-Organic Frameworks: A New Class of Coordinative Materials; Springer, 2023; pp 15–30. [Google Scholar]
- Zhang J.-P.; Zhou H.-L.; Zhou D.-D.; Liao P.-Q.; Chen X.-M. Controlling flexibility of metal–organic frameworks. Natl. Sci. Rev. 2018, 5 (6), 907–919. 10.1093/nsr/nwx127. [DOI] [Google Scholar]
- Patra J. K.; Das G.; Fraceto L. F.; Campos E. V. R.; Rodriguez-Torres M. D. P.; Acosta-Torres L. S.; Diaz-Torres L. A.; Grillo R.; Swamy M. K.; Sharma S.; et al. Nano based drug delivery systems: recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71 10.1186/s12951-018-0392-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zheng H.; Zhang Y.; Liu L.; Wan W.; Guo P.; Nyström A. M.; Zou X. One-pot synthesis of metal–organic frameworks with encapsulated target molecules and their applications for controlled drug delivery. J. Am. Chem. Soc. 2016, 138 (3), 962–968. 10.1021/jacs.5b11720. [DOI] [PubMed] [Google Scholar]; Taylor-Pashow K. M. L.; Della Rocca J.; Xie Z.; Tran S.; Lin W. Postsynthetic modifications of iron-carboxylate nanoscale metal– organic frameworks for imaging and drug delivery. J. Am. Chem. Soc. 2009, 131 (40), 14261–14263. 10.1021/ja906198y. [DOI] [PMC free article] [PubMed] [Google Scholar]; Wang X. G.; Xu L.; Li M. J.; Zhang X. Z. Construction of flexible-on-rigid hybrid-phase metal–organic frameworks for controllable multi-drug delivery. Angew. Chem., Int. Ed. 2020, 59 (41), 18078–18086. 10.1002/anie.202008858. [DOI] [PubMed] [Google Scholar]
- Khezerlou A.; Tavassoli M.; Alizadeh-Sani M.; Hashemi M.; Ehsani A.; Bangar S. P. Multifunctional food packaging materials: Lactoferrin loaded Cr-MOF in films-based gelatin/κ-carrageenan for food packaging applications. Int. J. Biol. Macromol. 2023, 251, 126334 10.1016/j.ijbiomac.2023.126334. [DOI] [PubMed] [Google Scholar]; Chowdhury P.; Bikkina C.; Gumma S. Gas adsorption properties of the chromium-based metal organic framework MIL-101. J. Phys. Chem. C 2009, 113 (16), 6616–6621. 10.1021/jp811418r. [DOI] [Google Scholar]
- Al-Thabaiti S. A.; Mostafa M. M. M.; Ahmed A. I.; Salama R. S. Synthesis of copper/chromium metal organic frameworks-Derivatives as an advanced electrode material for high-performance supercapacitors. Ceram. Int. 2023, 49 (3), 5119–5129. 10.1016/j.ceramint.2022.10.029. [DOI] [Google Scholar]
- Jalayeri H.; Aprea P.; Caputo D.; Peluso A.; Pepe F. Synthesis of amino-functionalized MIL-101 (Cr) MOF for hexavalent chromium adsorption from aqueous solutions. Environ. Nanotechnol., Monit. Manage. 2020, 14, 100300 10.1016/j.enmm.2020.100300. [DOI] [Google Scholar]
- Wei F.; Zheng T.; Ren Q.; Chen H.; Peng J.; Ma Y.; Liu Z.; Liang Z.; Chen D. Preparation of metal–organic frameworks by microwave-assisted ball milling for the removal of CR from wastewater. Green Process. Synth. 2022, 11 (1), 595–603. 10.1515/gps-2022-0060. [DOI] [Google Scholar]
- Bloch E. D.; Queen W. L.; Hudson M. R.; Mason J. A.; Xiao D. J.; Murray L. J.; Flacau R.; Brown C. M.; Long J. R. Hydrogen storage and selective, reversible O2 adsorption in a metal–organic framework with open chromium (II) sites. Angew. Chem. 2016, 128 (30), 8747–8751. 10.1002/ange.201602950. [DOI] [PubMed] [Google Scholar]; Surblé S.; Millange F.; Serre C.; Düren T.; Latroche M.; Bourrelly S.; Llewellyn P. L.; Férey G. Synthesis of MIL-102, a chromium carboxylate metal– organic framework, with gas sorption analysis. J. Am. Chem. Soc. 2006, 128 (46), 14889–14896. 10.1021/ja064343u. [DOI] [PubMed] [Google Scholar]; Kayal S.; Sun B.; Chakraborty A. Study of metal-organic framework MIL-101 (Cr) for natural gas (methane) storage and compare with other MOFs (metal-organic frameworks). Energy 2015, 91, 772–781. 10.1016/j.energy.2015.08.096. [DOI] [Google Scholar]
- Bhattacharjee S.; Chen C.; Ahn W.-S. Chromium terephthalate metal–organic framework MIL-101: synthesis, functionalization, and applications for adsorption and catalysis. RSC Adv. 2014, 4 (94), 52500–52525. 10.1039/C4RA11259H. [DOI] [Google Scholar]; Bromberg L.; Diao Y.; Wu H.; Speakman S. A.; Hatton T. A. Chromium (III) terephthalate metal organic framework (MIL-101): HF-free synthesis, structure, polyoxometalate composites, and catalytic properties. Chem. Mater. 2012, 24 (9), 1664–1675. 10.1021/cm2034382. [DOI] [Google Scholar]
- Genchi G.; Lauria G.; Catalano A.; Carocci A.; Sinicropi M. S. The double face of metals: The intriguing case of chromium. Appl. Sci. 2021, 11 (2), 638. 10.3390/app11020638. [DOI] [Google Scholar]
- Khodavirdipour A.; Haddadi F.; Keshavarzi S. Chromium supplementation; negotiation with diabetes mellitus, hyperlipidemia and depression. J. Diabetes Metab. Disord. 2020, 19 (1), 585–595. 10.1007/s40200-020-00501-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Islam S.; Kamila S.; Chattopadhyay A. Toxic and carcinogenic effects of hexavalent chromium in mammalian cells in vivo and in vitro: a recent update. J. Environ. Sci. Health, Part C 2022, 40 (3–4), 282–315. 10.1080/26896583.2022.2158675. [DOI] [PubMed] [Google Scholar]; Sawicka E.; Jurkowska K.; Piwowar A. Chromium (III) and chromium (VI) as important players in the induction of genotoxicity-current view. Ann. Agric. Environ. Med. 2021, 28 (1), 1–10. 10.26444/aaem/118228. [DOI] [PubMed] [Google Scholar]
- Feng J.; Xu L.; Qi L.; Fu Z.; Hu Q. Polydopamine-Mediated Metal–Organic Frameworks Modification for Improved Biocompatibility. Macromol. Biosci. 2024, 24, 2400071 10.1002/mabi.202400071. [DOI] [PubMed] [Google Scholar]
- Huang Z.; Zhao M.; Wang S.; Dai L.; Zhang L.; Wang C. Selective recovery of gold ions in aqueous solutions by a novel trithiocyanuric-Zr based MOFs adsorbent. J. Mol. Liq. 2020, 298, 112090 10.1016/j.molliq.2019.112090. [DOI] [Google Scholar]
- Carreras N.; Acuña V.; Martí M.; Lis M. Drug release system of ibuprofen in PCL-microspheres. Colloid Polym. Sci. 2013, 291 (1), 157–165. 10.1007/s00396-012-2768-x. [DOI] [Google Scholar]
- Horcajada P.; Serre C.; Maurin G.; Ramsahye N. A.; Balas F.; Vallet-Regí M.; Sebban M.; Taulelle F.; Férey G. Flexible porous metal-organic frameworks for a controlled drug delivery. J. Am. Chem. Soc. 2008, 130 (21), 6774–6780. 10.1021/ja710973k. [DOI] [PubMed] [Google Scholar]
- Martí-Rujas J. Structural elucidation of microcrystalline MOFs from powder X-ray diffraction. Dalton Trans. 2020, 49 (40), 13897–13916. 10.1039/D0DT02802A. [DOI] [PubMed] [Google Scholar]
- Zhang Z.; Wang H.; Chen X.; Zhu C.; Wei W.; Sun Y. Chromium-based metal–organic framework/mesoporous carbon composite: Synthesis, characterization and CO 2 adsorption. Adsorption 2015, 21, 77–86. 10.1007/s10450-015-9651-2. [DOI] [Google Scholar]
- Huang X.; Brazel C. S. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J. Controlled Release 2001, 73 (2–3), 121–136. 10.1016/S0168-3659(01)00248-6. [DOI] [PubMed] [Google Scholar]
- Wu L.; Zhang J.; Watanabe W. Physical and chemical stability of drug nanoparticles. Adv. Drug Delivery Rev. 2011, 63 (6), 456–469. 10.1016/j.addr.2011.02.001. [DOI] [PubMed] [Google Scholar]
- Li Y.; Yang L. Driving forces for drug loading in drug carriers. J. Microencapsulation 2015, 32 (3), 255–272. 10.3109/02652048.2015.1010459. [DOI] [PubMed] [Google Scholar]