PLA-HA/Fe3O4 magnetic nanoparticles loaded with Curcumin: Physicochemical characterization and toxicity evaluation in HCT116 Colorectal cancer cells

doi:10.21203/rs.3.rs-3745071/v1

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PLA-HA/Fe3O4 magnetic nanoparticles loaded with Curcumin: Physicochemical characterization and toxicity evaluation in HCT116 Colorectal cancer cells

https://doi.org/10.21203/rs.3.rs-3745071/v1

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Colorectal cancer (CRC) is the third most common, harmful, and universal cancer and the second lethal type. This paper discusses the therapeutic potential of curcumin, a major curcuminoid found in the substructure of plant Curcuma longa (turmeric), against CRC. Curcumin has the ability to disrupt a variety of cellular signaling pathways and has been validated in several preclinical and clinical studies, but suffers from low solubility and bioavailability. To address these issues, PLA-HA/Fe₃O4 magnetic nanoparticles were synthesized and loaded with curcumin. The average size and zeta potential of the nanoparticles and the magnetic properties were measured. The drug encapsulation efficiency and cumulative release of curcumin from the nanoparticles under acidic and neutral pH values were evaluated, as well as the cytotoxic effect of the nanoparticles on HCT116 colorectal cancer cells. The results demonstrated that nanoparticles have a high degree of biocompatibility and the ability to carry Curcumin medications. HCT116 cells with 200 µg/ml PLA-HA/Fe₃O₄/Curcumin nanoparticles have 58.63 ± 3.7% percent cell viability. Ultimately, PLA-HA, Fe₃O₄, and Curcumin's physicochemical characteristics and impact on cell viability render them valuable instruments for precisely delivering drugs to colorectal cancer cells. The PLA-HA/Fe₃O₄-curcumin nanoparticles demonstrated a well-targeted drug delivery system for upcoming colorectal cancer treatments, as evidenced by their overall strong cytotoxic effects on colorectal cancer cells and negligible toxicity towards non-cancerous cells.

Curcumin

targeted drug delivery

nanoparticles

green synthesis

metastatic disease

CD44

What is the current knowledge?

Investigating the characteristics of loading, release, drug transfer efficiency and toxicity of PLA-HA/Fe₃O₄ nanoparticles loaded with curcumin.
Determining the characteristics of a drug delivery system for effective cancer treatment without side effects on healthy tissues.

What is new here?

Using curcumin as drug to treat HCT116 colorectal cancer cells.
Investigating the toxicity of PLA-HA/Fe₃O₄ nanoparticles.
Comparing the efficiency of nanocarrier in drug delivery to cancer tissue compared to free drug.
PLA-HA/Fe₃O₄/curcumin nanoparticles can be a potential approach for targeted drug delivery due to the presence of physicochemical properties and release profile, appropriate toxicity and efficiency in the transfer of curcumin drug to colorectal cancer cells.

Colorectal cancer (CRC) is the third most common, harmful, and universal cancer and the second lethal type. In 2020, an estimated 1,880,725 people were diagnosed with colon cancer. By 2035, there may be nearly 2.5 million new cases. [1] According to the pathological characteristics of the tumor, there are various therapeutic options for CRC. The principal therapeutic strategy for mCRC (Metastatic colorectal cancer) patients is palliative chemotherapy, while non-systematic therapy (such as surgery and optional radiation and ablative techniques) is optional for patients with respectable metastatic lesions to improve survival. The early-stage primary disease typically requires laparoscopic surgery; cases involving metastases necessitate open surgery for tumor resection, and nonresectable cases typically require adjuvant radiotherapy. Neoadjuvant and palliative chemotherapies, [2] immunotherapy, [3] and tyrosine kinase inhibitor (TKI) [4] therapy are additional CRC treatments. Currently, targeted drug delivery through nanoparticles has been an emerging approach for addressing various problems associated with chemotherapeutic agents. [5–7]

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)- 1,6-heptadiene-3,5-dione), likewise alluded to as diferuloylmethane, comprises one of the major curcuminoids existing in the substructure of plant Curcuma longa (turmeric). [8] Curcumin has been practically studied for the majority of human diseases and is highly adequate in treating a diversity of medical conditions, including, but not limited to, cancer, arthritis, major depression, liver disease, dyslipidemia, and chronic obstructive pulmonary disease. [8–12] Curcumin has the ability to encourage a wide range of chemical reactions in living things, such as hydrolysis, enzymatic reactions, reversible and irreversible nucleophilic addition (Michael reaction), and hydrogen donation leading to oxidation. [13] Evidence demonstrates that curcumin disrupts a variety of cellular signaling pathways by directly targeting bioactive proteins or epigenetically regulating gene expression in key disease-associated signaling pathways, according to mounting evidence. [14, 15] Curcumin's therapeutic potential against CRC has been validated in a number of preclinical and clinical studies, and its effectiveness in suppressing various stages of CRC development is noteworthy. [16, 17] In spite of these advantages, curcumin suffers from some limitations in drug administration. Low solubility and bioavailability are major problems of this drug. Also, the passive distribution of curcumin, as to other chemical entities, is another important obstacle to the effective anticancer properties of this drug. The incorporation of curcumin into nanocarriers is a promising strategy to solve the mentioned problems. Nanoparticles have many important potentials to overcome these obstacles. They could increase the solubility and dissolution profile of less soluble drugs. Also, the absorption pathway of drugs may be improved using nanocarriers. However, the most attractive capability of nanocarriers is the ability to modify drug distribution in the body. [18] Since the drug is entrapped inside the nanoparticles, they can release the drug actively, and also through interaction with different organs, and biological or cell components, the fate of the drug could be changed according to treatment goals. Numerous nanocarriers were used for this strategy and among them, the conjugation of polymeric nanoparticles with magnetic cores is very advantageous.

Bioanalytical methods and biomedical applications completely rely on magnetic nanoparticles. With bio-type specimens, they encounter less background interference, making bio-type samples' magnetic susceptibilities nearly nonexistent. [19] As a result of this benefit, and biological samples can be easily accessed in the direction of the external magnetic field. Analytical tools, bioimaging, biosensors, contrast agents (CAs), hyperthermia, photoablation therapy, physical therapy applications, separation, signal markers, and targeted drug delivery (TDD) are just a few of the many biomedical applications that can now be designed into magnetic nanoparticles. [20] Iron oxide nanoparticles (IONPs) are used in most studies because of their biocompatibility, high saturation magnetization, high magnetic susceptibility, chemical stability, and innocuousness. Nickel and cobalt, two examples of IONPs with high magnetic properties, are toxic and easily oxidized. Magnetite (Fe₃O₄) nanoparticles (MNPs) are by far the most commonly used IONPs in biomedical applications. [21] As a result of ion transfer from Fe2 + ions to Fe³⁺ ions, magnetite nanoparticles have unique electrical and magnetic properties.[22] Most biomedical MNPs have superparamagnetism properties because they are smaller than 20 nm. [22] They are also widely used in this field due to their biocompatible surface chemistry, high magnetization saturation value, narrow particle size distribution (100 nm), and superparamagnetism property compared to other magnetic IONPs (M-IONPs). [19–21] In addition to targeting tumors using an external magnetic field, magnetite nanoparticles can also cause hyperthermia-induced apoptosis of cancer cells. [23] One of the most employed polymers for coating Fe₃O₄ is PLA which is readily oxidized and agglomerated, they are often coated with natural or synthetic polymers. [24]

Polylactic acid (PLA) is a flexible polymer that is fermented into a carboxylic acid from sustainable agricultural waste. [25–27] The lactic acid is then polymerized using a cyclic dilactone, lactide, and ring for product modification. [28] PLA and its copolymers have been utilized to encapsulate many classes of drugs, such as hormones, proteins, and chemotherapeutic agents. [29–31] Slow degradation rate and high hydrophobicity are some of the disadvantages that restrict the biomedical application of PLA. [32] On the other hand, nanoparticles can actively target tumor cells by recruiting targeting moieties that bind specifically to over-expressed receptors on cancerous cells. CD44, a transmembrane glycoprotein receptor, is abundantly expressed in tumor cells and plays an important role in tumor progression and metastasis. [33] Hyaluronic acid, a natural mucopolysaccharide found in the extracellular matrix, is a CD44 ligand that has been recently used in tumor-targeting nanoparticle formulations. The great biocompatibility, biodegradability, and hydrophilicity of hyaluronic acid make it a proper candidate for the targeted delivery of drugs and genes to tumor cells. [34]

Literature Review

Curcumin, a polyphenol derived from the turmeric plant, has shown potential in cancer treatment. It reduces inflammation, encourages cell apoptosis, and inhibits cell proliferation to demonstrate anticancer effects.[35] Nevertheless, curcumin's low bioavailability and poor water solubility restrict its efficacy. Curcumin's stability and cellular bioavailability have been enhanced through the use of nanotechnologies in order to overcome these obstacles.[36] To improve curcumin's absorption and delivery, nano-based formulations like cubosomes and nanocarriers have been created.[37] Curcumin's bioavailability, retention in target tissues, and cytotoxic effects against cancer cells have all improved with these formulations, which have demonstrated encouraging outcomes. Curcumin's anticancer properties have also been shown in clinical trials for a variety of cancers, including brain tumors, lung, breast, prostate, pancreatic, gastric, leukemia, and colorectal cancers.[38] It's common knowledge that curcumin inhibits the cell cycle and speeds up cell death in relation to colorectal cancer, two factors that can help prevent the disease from spreading. According to in vitro studies done on different cancer cell lines, curcumin stopped the growth of the cells by molecularly interacting with several targets, which in turn regulated a number of distinct signaling cascade series.[39] In line with He et al., curcumin stopped the cell cycle that was partially in the G1 phase and present in the cells, which inhibited their growth.[40]

One key feature that makes PLA useful for drug carriers is its biodegradability. PLA readily dissolves in extracellular settings.[41] Aside from this capability, the rate of degradation can be changed to accomplish a particular result. Drug carrier systems might be able to sustain a continuous release of therapeutic agents by prolonging the kinetics of this breakdown.[42] This is crucial because metabolic processes could potentially reduce the effectiveness of this therapeutic approach. It also gives the medication enough time to take effect. Through better drug delivery and fewer side effects, PLA-HA has demonstrated promise in the treatment of cancer. They can reduce toxicity and increase the effectiveness of anticancer medications like arenobufagin (ArBu), tamoxifen, docetaxel, daunorubicin, and ibuprofen.[43] Exploring new avenues for targeted treatment and overcoming multidrug resistance, nanotechnology-based chemotherapy employing nanoparticles has opened up new possibilities. In vitro, cytotoxicity against breast cancer cells has been shown for polymeric nanoparticles of polylactic acid-poly (ethylene glycol) (PLA-PEG) copolymers encapsulating a novel biosurfactant. [44]Biosurfactant has been shown to release under controlled conditions via these nanoparticles, and they are capable of actively delivering anticancer cargo to the cancer site. Biological components attached to nanoparticles can also improve their targetability to the cancerous area.

Superparamagnetic Fe₃O₄ NPs have drawn interest due to their versatility in applications such as localized hyperthermia therapy, target-based carriage, stem cell labeling and tracking, and magnetic resonance imaging (MRI) contrast agents. When an external alternating magnetic field is applied, it can produce heat in tumor regions through hyperthermia therapy.[45] The material of choice for generating magnetism in these nanoparticles is iron oxide. The combination of magnetic hyperthermia and chemotherapeutic drug-loaded nanoparticles has shown remarkable antitumor effects. [46]By enhancing drug targeting, solubility, and bioavailability, nanoparticles can also enhance colorectal cancer diagnosis and treatment.[47] Specifically, nanomagnetic iron oxides have demonstrated potential as drug-delivery vehicles in the context of cancer treatment.

Developing an intravenous injectable aqueous formulation of curcumin is an intriguing idea, as curcumin's bioavailability in vivo is significantly reduced when administered orally. Hydrophobic drugs' poor water solubility can be addressed with biodegradable nanodrug carriers, offering promise for future use.[48] There have been a lot of studies done on this subject to deliver curcumin conjugation with micelles, liposomes, polymeric nanoparticles, and lipid based nanoparticles. In a recent study, CUR and doxorubicin (DOX) co-encapsulated in long circulating liposomes (LCL) at a molar ratio of 1:167 significantly reduced C26 cell proliferation when compared to free DOX in vitro. It was also reported that the amount of CUR encapsulated determines the degree of the synergistic cytotoxic effects of DOX and CUR, with higher amounts of CUR resulting in greater cytotoxic effects. [49] Sesarman et al., revealed a similar result when employing the same liposomal formulation as Tefas et al. to co-deliver CUR and DOX. (LCL-CUR-DOX) in cells of C26. The increased cytotoxic activity of LCL-CUR-DOX in comparison to free CUR-DOX prompted the authors to look into the protumor mechanism causing the C26 cell cytotoxicity. In addition to slightly inhibiting NF-κB activation, LCL-CUR-DOX also inhibits most of the proteins involved in the development of tumors. In contrast to free CUR-DOX, it has less of an effect on oxidative stress reduction in vitro. This might be the result of liposomes' distinct uptake mechanism from that of free medications. The process of endocytosis allows liposomes to enter cells, facilitating a higher degree of CUR internalization. On the other hand, transmembrane diffusion is how free CUR enters the cells. [50] In an effort to enhance CUR encapsulation, Dash and Konkimalla have recently loaded CUR into hydroxypropyl-β-cyclodextrin (HP-β-CD) using polyvinyl alcohol (PVA) as a stabilizer. The solubility of CUR in water has been improved by this formulation of nano-curcumin. It was applied in combination therapy to address the issue of drug resistance resulting from overexpression of p-glycoprotein (P-gp) to DOX. Following prescreening, CUR was chosen as combinatorial agents in this study over other P-gp inhibitors because it sensitized DOX-resistant Colo205 cells at the lowest concentration of 40 µM. CUR-loaded HP-β-CD dramatically reversed DOX resistance, which was obtained by administering DOX liposomes at concentrations ranging from 0.1 to 10 µM, once it reached 40 µM.[51]

Drug delivery systems containing folate can penetrate cells through receptor-mediated endocytosis, preventing non-specific attacks on healthy tissues. Additionally, the agents can enhance cellular uptake in target cells and deliver the therapeutic agents to tumor cells. [52]According to reports, the lower micelle concentration resulting from folate conjugation can enhance the stability of the FA-copolymer micelle when compared to copolymer (PLAMPEG) alone. [53]Baek and Cho. have demonstrated that Nutlin-3a's therapeutic potential can be enhanced by folate-decorated, curcumin-loaded nanoparticles, which reverse multidrug resistance. [54]As demonstrated by Kazemi et al. (2020) and Zhang et al. (2019), also demonstrated that folate-drug delivery systems can improve drug targeting and uptake to tumor cells while also extending the drug's half-life in the body.[55, 56] Additionally, Phan et al. developed a folate-modified curcumin-loaded micelle delivery system (Cur/PLA-PEG-Fol) using poly(lactic acid)-poly(ethylene glycol) to improve curcumin's solubility in aqueous solution and increase its targeting ability. As per their research, Folate-modified micelles exhibit promise as a nanocarrier to enhance Cur's solubility, anticancer activity, and systemic targeting capabilities.[57] Therefore, we decided to use the nanotechnology-targeted drug delivery method using PLA-HA copolymer with Fe3O4 magnetic core to increase the efficiency of drug transfer and drug solubility to transfer curcumin drug and increase the efficiency of colorectal cancer treatment.

Research gap

Based on the aforementioned information, the prescribed treatment options demonstrate efficacy in the management of cancer. However, in contemporary times, with the advancement of integrated therapeutic sciences, the conventional and conventional approaches used in the past are of minimal utility in addressing critical disease, including cancer. Therefore, contemporary researchers primarily attribute to integrating diverse methodologies in order to enhance effectiveness and overcome the limitations imposed by different techniques. In recent times, several investigations have been conducted, focusing on the utilization of various chemotherapy medications in combination with different copolymers and nanoparticles. Despite the studies conducted, based on the investigations carried out by our team, until today there is no research on the simultaneous use of curcumin, PLA-HA copolymer, and Fe3O4 nanoparticles for colorectal cancer treatment, to enhance drug efficacy, biodegradability, water solubility, release kinetics, and targeted delivery.

Objective and contributions

The purpose of this work is to assess the physicochemical properties of curcumin-loaded PLA-HA/Fe₃O₄ MNPs and determine their level of toxicity in HCT116 colorectal cancer cells. We predict that these nanoparticles will present with the right physicochemical characteristics to facilitate drug delivery and cause cytotoxicity in HCT116 cells.

Materials

Poly Vinyl Alcohol (PVA) were purchased from Merck (Germany). PLA, HA, FeCl₃.6H₂O, FeCl₂.4H₂O, RPMI 1640, penicillin/streptomycin, FBS, and DMSO were obtained from Sigma-Aldrich (USA). The MTT solution was purchased from Atocel (Hungary) and amphotericin B was obtained from Biowest (France). Other solutions, reagents, and solvents were at analytical grade and obtained domestically.

Green synthesis of magnetite (Fe₃O₄) nanoparticles using the hydroalcoholic extract of Silybum marianum

Equal amounts of FeCl₃ and FeCl₂ (3.3 g) were dissolved separately in 50 ml of water. The reaction was initiated by mixing 15 ml of Silybum marianum methanolic extract, FeCl₃, and FeCl₂ solution under nitrogen gas at 80 ° C for 30 minutes using a stirrer. Then, 60 ml of NaOH (1 mM) was added to the above solution and incubated for another 4 hours under similar conditions. The nanoparticles were centrifuged (10000 rpm for 10 minutes) and washed several times with phosphate buffer (PBS). The resulting iron oxide nanoparticles were then freeze-dried.

Synthesis of PLA-HA copolymer

To polymerize poly lactic acid-hyaluronic acid (PLA-HA), the NH₂-Hyaluronic acid and Acrylate-PLA solutions in chloroform were mixed slowly by 24 hours of stirring at 50°C. To remove impurities, the resulting product was centrifuged for half an hour at 4°C (10000 rpm) using equal volumes of water and methanol. The copolymer was further purified using dialysis membranes (10000 MW) and then the PLA-HA polymer was centrifuged again under the above-mentioned conditions and freeze-dried.

Characterization of PLA-HA copolymer

H-NMR spectroscopy was carried out to investigate the structure of PLA-HA copolymer using CDCl₃ as the solvent (Varian Unityinova 500 NMR Spectrometer, USA). Additionally, the FTIR technique (1B-AR-010, Biotec, USA) was used for confirming the synthesis of PLA-HA synthesis. Also, the thermal stability of PLA and PLA-HA copolymer was evaluated by Thermogravimetric analysis (TGA, STA-PT1000, License, Germany) in a thermal range of 40 ºC to 700 ºC with a heating rate of 10 ºC/min.

Synthesis of PLA-HA/Fe₃O₄/curcumin and PLA/Fe₃O₄ nanoparticles

A solvent diffusion technique was used to prepare PLA-HA/Fe₃O₄/curcumin and PLA/Fe₃O₄ without drug nanoparticles. 5 mg of Fe₃O₄ nanoparticles coated by Oleic Acid was added to PLA-HA solutions (30 mg in 1 ml chloroform). Then, 4 mg of curcumin and 1 ml of PVA solutions (1% w/v) were added to the mixture and sonicated for another 30 seconds, respectively. The resulting emulsions were then collected using a syringe and slowly injected into 25 ml of PVA solution (0.3% w/v) under stirring. The final emulsion was stirred at room temperature for 24 hours. The yielded nanoparticles were washed 3 times with centrifugation using deionized water (13000 rpm for 1 hour) and freeze-dried.

In order to prepare drug-free nanoparticles (PLA-HA/Fe₃O₄), the aforementioned procedure was used either. With the difference that curcumin was not added in the loading phase.

Characterization of nanoparticles

The average size and zeta potential of PLA-HA/Fe₃O₄/curcumin and PLA/Fe₃O₄ nanoparticles were determined using dynamic light scattering (DLS, SZ100, Horiba, Japan) techniques. The morphology and size distribution of synthesized nanoparticles were investigated by TEM images (LEO906, Zeiss, Germany). The formation of magnetite nanoparticles was confirmed by FTIR and UV-Vis (Thermo Scientific, USA) spectroscopy. VSM (Vibrating Sample Magnetometer, MDKF-Co., Iran) technique was used to measure the magnetic properties of nanoparticles.

Determination of drug encapsulation efficiency of synthesized nanoparticles

To calculate the drug (curcumin) encapsulation efficiency, the supernatant of the nanoparticle’s mixture was centrifuged (13000 rpm for 1 hour) and the amount of free curcumin present in the supernatant was determined using spectrophotometry at 480 nm. The measured amount was then compared with the initial amount of drug used in the loading process (4 mg) and the encapsulation efficiency was calculated by the following equation:

EE%= (W_{initial CU} – W_{free CU} / W_{initial CU})

Release profile of drug from nanoparticles

Since the tumor tissue has a lower pH compared to the normal tissue, the drug release from nanoparticles was evaluated in PBS buffer with acidic (pH = 6) and neutral (pH = 7.4) pH values. 10 mg of the PLA/Fe₃O₄/curcumin and PLA-HA/Fe₃O₄ nanoparticles were added separately to 2 ml of PBS buffer and stored at 37°C. The nanoparticles supernatant was then collected by centrifugation (13,000 rpm for 10 minutes) at predetermined time intervals and nanoparticles were resuspended in 2 ml of PBS until the next collection. The amount of drug present in the supernatant was evaluated using spectrophotometry. The cumulative release percentage was then calculated using the following equation.

Cumulative release percentage =\(\frac{{Dr}^{t}+ {Dr}^{t+1}}{DE}\)

Dr^t= The measured amount of drug in the supernatant at any time (t)

Dr^t+1= The measured amount of drug in the supernatant at time (t + 1)

De = The amount of drug encapsulated in the nanoparticles

In vitro evaluation of cytotoxicity

The HCT116 colorectal cancer cell line was used to evaluate the toxicity and drug delivery efficiency of PLA-HA/Fe₃O₄ nanoparticles. First, Human Colorectal Carcinoma cell line HCT116 cells were grown in 10% fetal bovine serum and RPMI cell media at 37°C in 5% CO₂. The cytotoxic effect of Fucosterol alone or in combination with curcumin in colon cells was evaluated by an MTT reduction assay. For the MTT assay, 100 µl of HCT116 cells at a density of 7 ×10⁴ cells per milliliter were transferred to 96-well plates. Then, the cells were kept in a CO₂ incubator (at 37 ° C, 90% humidity, and 5% CO₂) for 24 hours. The HCT116 cells were then treated with different concentrations of PLA-HA/Fe₃O₄/ curcumin nanoparticle (25، 50، 75، 100، 200 µg/ml), as well as free curcumin. To evaluate the toxicity of nanoparticles, PLA-HA/Fe₃O₄ was used. The cells were exposed to each treatment for 24 hours. Then, the cell viability was assessed using an MTT assay.

1. Characterization of PLA-HA copolymer

The H-NMR spectra of PLA and PLA-HA are presented in Fig. 1. As shown in the H-NMR spectrum of PLA, the peaks observed at 5.75 (b) and 1.72 (a) ppm were assigned to methine and methylene groups in PLA. Whereas in the H-NMR spectrum of PLA-HA, new peaks were observed at 8.19 and 3.97 ppm, which were related to the alcohol (OH) (d) and amide (NH) (c) protons present in the structure of hyaluronic acid, respectively.

The FT-IR spectra of PLA and PLA-HA copolymer shown in Fig. 2, confirms the synthesis of PLA-HA. As shown in the FT-IR spectrum of PLA, the IR bands observed at 1750 cm^− 1 and 2900–3000 cm^− 1 were related to C = O and C-H groups present in PLA. The FT-IR spectrum of PLA-HA revealed new peaks at 1596 and 3532 cm^− 1 which were respectively related to N-H and O-H bonds in hyaluronic acid. These findings can indicate the bonding of HA to PLA.

TGA analysis is mostly performed to study the thermal stability of samples, but this method can also estimate the percentage of constituents present in the sample. The TGA analysis of PLA, shown in Fig. 3, represents a severe weight loss stage which is indicative of the purity of the PLA polymer. On the other hand, several stages of weight loss were observed in the TGA analysis of PLA-HA polymer in the temperature range of 200–250, 300–320, and 350–380 ºC, which indicated the presence of several materials in PLA-HA compared to PLA. Considering that the weight loss of PLA was observed in the temperature range of 200 to 320 ºC, it can be concluded that the weight loss in the temperature range of 350 to 380 ºC is related to the hyaluronic acid present in the structure of PLA-HA copolymer.

2. Characterization of PLA-HA/Fe₃O₄/curcumin nanoparticles

The results of studying the morphological properties and size of PLA-HA/Fe₃O₄/curcumin nanoparticles by transmission electron microscope (TEM) indicated that these nanoparticles had a spherical structure and a size of about 100–200 nm (Fig. 4).

The DLS results shown in Fig. 5 confirm the nanoscale dimensions of the synthesized nanoparticles. PLA/Fe₃O₄/curcumin nanoparticles had an average size of 208 ± 12.8 nm.

3. Drug release pattern

The drug encapsulation efficiency in PLA-HA/Fe₃O₄ nanoparticles was 42/18 ± 2.7 percent. The drug release pattern in acidic and neutral media (shown in Fig. 6) involved two different phases: burst release and sustained release. More than 50% of the drug released within 3 days was released. For example, the amount of released drug of PLA-HA/Fe₃O₄/curcumin within 14 days of incubation with PBS buffer, pH = 7.4 was 43.6 ± 3.1 percent (Fig. 6). Also, it was found that the drug release rate was higher in acidic pH compared to the neutral media. For example, the amount of curcumin drug released from nanoparticles in 14 days at pH = 7.4 was 57.36 ± 2.9%, while this amount increased to more than 85% at pH = 6.

4. In vitro cytotoxicity

MTT assay results, shown in Fig. 7, demonstrated that PLA-HA/Fe₃O₄ nanoparticles are biocompatible on HCT116 cells since the encapsulation of the drug curcumin inside these nanoparticles significantly increased its toxicity on the HCT116 cell line. Although the encapsulation of curcumin drug inside PLA-HA/Fe₃O₄ nanoparticles increased the antitumor properties of these nanoparticles, however, the lowest cell viability of HCT116 cells was observed after its treatment with free curcumin drug. For example, the survival rate of cells after treatment with 200 µg/ml of PLA-HA/Fe₃O₄/curcumin nanoparticles was 58.63 ± 5.1%, while this rate was for an equal amount of curcumin drug encapsulated in 0 µg/mL of PLA-HA/Fe₃O₄/curcumin nanoparticles was 52.26 ± 4.3.

In this study, PLA-HA/Fe₃O₄/curcumin nanoparticles were synthesized successfully to deliver curcumin as a drug into HCT116 Colorectal cancer cells. First, PLA-HA copolymer synthesized successfully and characterized by H-NMR, FT-IR spectra, and TGA analysis. Second, PLA-HA/Fe₃O₄/curcumin and PLA/Fe₃O₄ nanoparticles synthesized, and TEM and DLS analysis were conducted to investigate the morphological characteristics and size of nanoparticles. According to the TEM results, the synthesized PLA-HA/Fe₃O₄/curcumin nanoparticles were found to have a spherical structure. In agreement with the results obtained from the research of other researchers, it has been determined that the efficiency of drug transfer to target tissues directly depends on the morphology of nanoparticles. For example, among the types of spatial structure, nanoparticles with spherical structure have high transfer efficiency. According to the results obtained in this research, due to the spherical structure, PLA-HA/Fe₃O₄/curcumin nanoparticles will have a high potential in drug delivery to cancer cells and tissues. [58] The size and surface charge of nanoparticles are two other important factors in the successful delivery of the drug encapsulated inside the nanoparticles. In accordance with the results obtained from other research, by decreasing the size of nanoparticles, the possibility of success in transferring them to cancer cells increases, while non-specific absorption by normal cells increases in nanoparticles with a size smaller than 50 nm. In other words, by reducing the size of nanoparticles to less than 50 nm, in addition to increasing the transfer efficiency, the amount of side effects also increases with non-specific absorption by normal cells. [59] Based on the results, nanoparticles with a size of 200 nm are considered a suitable option for targeted drug delivery to cancer tissues. This group of nanoparticles has a higher transfer efficiency due to their size smaller than 200 nm, and the non-specific absorption of these nanoparticles by normal cells is less than nanoparticles with a size smaller than 100 nm. According to the results obtained in this research, the size of PLA-HA/Fe₃O₄/curcumin nanoparticles was in the range of 200 nm, so it is expected that these nanoparticles have a high penetration ability to cancer cells and minimal absorption by normal cells in vivo. In the study conducted by Noor Alaam and colleagues on designing and determining the properties of PLGA-HA nanoparticles loaded with Cisplatin, a slight increase in the size of nanoparticles conjugated with hyaluronic acid was seen compared to PLGA nanoparticles. The possible reason for this increase in size is the presence of hyaluronic acid segments. Nanoparticles containing HA in this study also had more negative zeta potential, which is due to the negative carboxylic groups present in hyaluronic acid. [60]

After that, based on the obtained results of the Drug release pattern, this phenomenon is consistent with the results observed in previous studies which have stated the biochemical mechanisms involved in the separation of drugs from nanoparticles as the probable reason for the different release rates in an acidic and neutral environment. Therefore, due to the lower pH of tumor tissues compared to healthy tissues, encapsulation of curcumin into the synthesized nanoparticles can lead to a lower incidence of side effects. Many researchers are interested in using iron oxide nanoparticles in drug delivery systems because of their biocompatibility and favorable magnetic properties. These nanoparticles provide the possibility of drug accumulation in the tumor site by applying an external magnetic field. Also, these nanoparticles have a high potential in imaging applications as well as hyperthermia. The results of past research have shown that magnetic nanoparticles increase the contrast of images in MRI imaging. Also, these nanoparticles significantly increase the efficiency of drug transfer to the tumor tissue. [61] In previous studies, drug release from polymer nanoparticles with a magnetic core was also examined. Amani et al. conducted a study in which, in terms of the design and evaluation of iron oxide nanoparticles coated with a PLA-PEG-PLA copolymer, the burst and continuous release patterns of drug release were observed in both neutral and acidic environments. In a similar condition, compared to a neutral medium, the rate of drug release from nanoparticles in an acidic medium was significantly higher. The chemical and biochemical processes involved in the separation of drugs from nanoparticles, as well as the reason for the difference in release rate between an acidic and a neutral environment, were discussed in this study. It was likewise expressed that, as a general rule, the course of medication partition from nanoparticles in an impartial climate is slower than in an acidic climate. When compared to healthy cells or tissues, cancer cells or tumor tissues have a lower pH, so a high rate of release in acidic tissue may result fewer side effects than when the free drug is used. [62] In addition, polymer degradation was cited as the cause of the continuous phase release of Berberine from PLGA-HA copolymer nanoparticles in the study by Bhatnagar and colleagues. Additionally, the hydrolysis of PLGA ester bonds in an acidic environment is the cause of the faster release of Berberine than in a neutral environment. Berberine release from PLGA-HA nanoparticles was higher than that of PLGA nanoparticles in this study. Due to the hydrophilic nature of hyaluronic acid, Bhatnagar believes that the increased interaction of nanoparticles with the aqueous environment is to blame for this phenomenon. [63]

In this research, the PLA polymer surface was targeted by using hyaluronic acid in order to increase the efficiency of drug transfer to cancer cells. In addition, the ability to transport curcumin drug through these nanoparticles and its effect on the viability of HCT116 cells was also evaluated through the MTT test. Similar outcomes have been observed in other studies employing hyaluronic acid as a targeted component against cancer cells. Also, the findings of this research are consistent with other studies which have employed Hyaluronic acid as a tumor-targeting moiety in nanoparticles. The reason for this phenomenon could be the increased adsorption of nanoparticles by cells due to the specific interaction between hyaluronic acid present in the nanoparticle’s structure and CD44 receptors which are over-expressed on the surface of the HCT116 cell membrane. Noor Alaam's research found that when PLGA-HA nanoparticles were used instead of hyaluronic acid nanoparticles, the internalization of the nanoparticles improved because hyaluronic acid specifically interacted with CD44 receptors in SKOV-3 cells. It is excessive, and the rally is necessary for the nanoparticles' endocytosis. The cell toxicity of the drug-containing nanoparticles and the free drug was not significantly different, in contrast to the results of the current study. This is due to the ability of post-endocytosis nanoparticles to transmit drugs in greater volumes and the cellular toxicity of the materials used in their preparation, despite the sluggishness of this process in comparison to the release of the free drug. [60]

Chemotherapy drugs are effective at reducing cancer cell survival, although they have many side problems such as their effect on healthy cells and resistance to the drug. In addition, due to the fast catabolism and short half-life of these drugs, continuous intravenous infusion is often used. In order to solve the obstacles mentioned above, it is possible to use drug loading in targeted nanoparticles. Encapsulation of curcumin in the magnetite (Fe₃O₄) nanoparticles prepared by green synthesis method and coated with PLA-HA copolymer could be a proper approach for addressing its non-specific effect on healthy cells. Prepared PLA-HA/Fe₃O₄/curcumin nanoparticles have a spherical shape and a size of about 200–300 nm. According to the results obtained in this research, due to the spherical structure, PLA-HA/Fe₃O₄/curcumin nanoparticles will have a high potential in drug delivery to cancer cells and tissues. The drug encapsulation efficiency in PLA-HA/Fe₃O₄ nanoparticles was 42/18 ± 2.7 percent. The synthesized nanoparticles are able to create a two-phase release pattern explosively and continuously for 14 days. More than 50% of the drug released within 3 days was released. Furthermore, the amount of drug release in acidic pH is significantly higher than in neutral pH. Considering the acidity of the pH of cancer cells and tumor tissue compared to healthy tissue, this capability can lead to a decrease in the release of the drug in the healthy tissue and, as a result, reduce the side effects of the drug. Therefore, PLA-HA/Fe₃O₄/curcumin nanoparticles can be a potential approach for targeted drug delivery due to the presence of physicochemical properties and release profile, appropriate toxicity, and efficiency in the transfer of curcumin drug to colorectal cancer cells.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Author Contribution

S.B. Led the writing of the article and Proofreading of the final version of the manuscript, S.A. conducted the research and investigation process, M.N. analyzed the statistical, mathematical, and computational, and Wrote the original Draft of the article, A.M. Performed the experiments, S.A. Provided the study materials, materials, laboratory samples, H A.E. Supervised: Oversight and leadership responsibility for the research activity planning (Correspondence) and V.AH. Performed the numerical calculations for the suggested experiment.All authors reviewed the manuscript

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No competing interests reported.

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You are reading this latest preprint version

PLA-HA/Fe3O4 magnetic nanoparticles loaded with Curcumin: Physicochemical characterization and toxicity evaluation in HCT116 Colorectal cancer cells

Status:

Version 1

Abstract

Figures

Study Highlights

Introduction

Literature Review

Research gap

Objective and contributions

Materials and methods

Materials

Green synthesis of magnetite (Fe₃O₄) nanoparticles using the hydroalcoholic extract of Silybum marianum

Synthesis of PLA-HA copolymer

Characterization of PLA-HA copolymer

Synthesis of PLA-HA/Fe₃O₄/curcumin and PLA/Fe₃O₄ nanoparticles

Characterization of nanoparticles

Determination of drug encapsulation efficiency of synthesized nanoparticles

Release profile of drug from nanoparticles

Results

1. Characterization of PLA-HA copolymer

2. Characterization of PLA-HA/Fe₃O₄/curcumin nanoparticles

3. Drug release pattern

4. In vitro cytotoxicity

Discussion

Conclusion

Declarations

Data availability

Author Contribution

References

Additional Declarations

Status:

Version 1

PLA-HA/Fe3O4 magnetic nanoparticles loaded with Curcumin: Physicochemical characterization and toxicity evaluation in HCT116 Colorectal cancer cells

Status:

Version 1

Abstract

Figures

Study Highlights

Introduction

Literature Review

Research gap

Objective and contributions

Materials and methods

Materials

Green synthesis of magnetite (Fe3O4) nanoparticles using the hydroalcoholic extract of Silybum marianum

Synthesis of PLA-HA copolymer

Characterization of PLA-HA copolymer

Synthesis of PLA-HA/Fe3O4/curcumin and PLA/Fe3O4 nanoparticles

Characterization of nanoparticles

Determination of drug encapsulation efficiency of synthesized nanoparticles

Release profile of drug from nanoparticles

Results

1. Characterization of PLA-HA copolymer

2. Characterization of PLA-HA/Fe3O4/curcumin nanoparticles

3. Drug release pattern

4. In vitro cytotoxicity

Discussion

Conclusion

Declarations

Data availability

Author Contribution

References

Additional Declarations

Status:

Version 1

Green synthesis of magnetite (Fe₃O₄) nanoparticles using the hydroalcoholic extract of Silybum marianum

Synthesis of PLA-HA/Fe₃O₄/curcumin and PLA/Fe₃O₄ nanoparticles

2. Characterization of PLA-HA/Fe₃O₄/curcumin nanoparticles