Original Article SYNERGISTIC EFFECT LUNG CANCER THERAPY: CO-DELIVERY OF QUERCETIN AND CISPLATIN VIA EUDRAGIT L-100 NANOPARTICLES IN VITRO FIRAS F. AL-MAMOORI 1,2* , HABIBAH A. WAHAB 1 , WAQAS AHMAD 1 1 School of Pharmaceutical Science, Universiti Sains Malaysia. 2 School of Pharmaceutical Science, University of Babylon, Iraq * Corresponding author: Firas F. AL-Mamoori; * Email: ferasfalih2@gmail.com Received: 02 May 2024, Revised and Accepted: 25 Sep 2024 ABSTRACT Objective: This study aims to investigate the potential of Eudragit L-100 nanoparticles for the co-delivery of quercetin and cisplatin to lung cancer cells, seeking to exploit the synergistic effects of the two drugs while overcoming their individual limitations. Methods: We investigate the synergistic effect of co-delivering quercetin and cisplatin using Eudragit L-100 nanoparticles for lung cancer therapy. The nanoparticles were synthesized using the nanoprecipitation method, where Eudragit L-100 was dissolved in an organic solvent, followed by the incorporation of quercetin and cisplatin. The resultant nanoparticles were characterized for size, zeta potential, drug loading efficiency, and morphology using techniques such as Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). Results: The co-loaded Quercetin-Cisplatin Nanoparticles (Qu-Cis)-NPs formulation had a mean particle size of 475±4.77 nm. Polydispersion index of 0.266±0.093 and zeta potential was-24.03±0.89 mV. The in vitro cytotoxicity was assessed using normal cell and lung cancer cell lines in vitro studies showed that the developed nanoparticles significantly increased cancer cell mortality compared to individual drug treatments. The combination (Qu-Cis)-NPs showed more cytotoxicity on the Non-Small Lung Cancer Cell Line (NCI-H460) cancer cell line after 48 h of incubation compared to Qu loaded-NPs and Cis loaded-NPs, particularly at a concentration of 1 mg/ml. The combination showed no cytotoxicity effect on normal Human Lung fibroblast cell Lines (CCD-19 lu) cells at all concentrations after 24 h, but showed cytotoxicity effects at concentrations (0.125, 0.25, 0.5, and 1.0) mg/ml after 48 h. Conclusion: The Eudragit L-100 nanoparticle system for co-delivering quercetin and cisplatin showed a promising synergistic effect in lung cancer treatment. It effectively addresses the solubility and toxicity issues of both drugs, offering a potentially more effective treatment option that merits further clinical investigation. Keywords: Quercetin, Cisplatin nanoparticles, Lung cancer, Eudragit®L-100, Cytotoxic test, pH-sensitive polymer, Synergistic effect © 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2024v16i6.52449 Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Cancer remains a leading cause of death worldwide. According to the World Health Organisation, cancer is projected to become the top cause of death globally by 2025, resulting in approximately 12.7 million deaths. This staggering number accounts for nearly one in six deaths [1, 2]. The most common types of cancer include breast, lung, colon, rectum, and prostate cancer [3]. The main factors contributing to about one-third of cancer-related deaths are tobacco use, alcohol consumption, a diet lacking in fruits and vegetables, and insufficient physical activity [4]. Non-non-small lung cancer is the most common form of lung cancer, impacting both smokers and non-smokers, including individuals under the age of 45 y. In male smokers, large lung carcinoma accounts for roughly 30% of primary lung tumors, while in female smokers, it accounts for 40%. Among non-smokers, these rates are approximately 60% in males and 80% in females [5]. The most common cancer treatment approaches include chemotherapy, radiation, and surgery. These approaches can be used individually or in combination. The major challenges associated with these treatment approaches include unwanted side effects, tumor recurrence, and resistance to chemotherapy or radiation therapy [6]. The low water solubility of most chemotherapeutic agent could also pose significant therapeutic challenges. Drug candidates such as quercetin and cisplatin are poorly water-soluble, meaning that intravenous administration could cause complications like embolism and respiratory system failure due to drug precipitation, while extravascular administration could lead to poor absorption [7, 8]. Since chemotherapeutic drugs given intravenously are distributed to all tissues, including healthy ones, severe systemic side effects are possible with intravenous administration of adjuvant chemotherapy [9]. Pharmaceutical industries frequently use Eudragit® polymer, a family of commercially available acrylic acid and its derivatives, and film coating to slow the rate of drug release from tablets and capsules. Eudragit® L-100, the most popular form of this polymer, was developed as an enteric coating. It is a Food and Drug Administration (FDA)-approved cationic polymer with a high solubility above pH 5 (pH 5.5-6.7). It is a synthetic polymer for film coating that outperforms natural products such as sugar and shellac. It has higher contents of methyl methacrylate and methacrylic acid in comparison to other Eudragit® polymers (e. g. Evonik and Eudragit® polymer). Carboxyl groups attached to the side chains of polymers are susceptible to protonation in an acidic environment, and polymers do not dissolve in acids (such as stomach acid). Nevertheless, carboxyl groups undergo ionization at neutral or basic pH [9]. It has been found that the polymer's payload is released when it becomes more soluble in water and when the negative charges between the carboxylate groups make them repel each other. The amount of carboxyl or other substituent groups on the polymer can be varied to fine-tune the pH value that governs their water solubility. The ratio of carboxyl groups to ester groups in poly- methacrylic acid-co-methyl methacrylate can be varied to modify the polymer [8]. Quercetin (Qu) is a well-known flavonoid that has been shown to have antiproliferative activity against several types of cancer, such as gastrointestinal, brain, skin and ovarian cancer, through multiple mechanisms involving free radical scavenging and chelation of transition metal ions [10]. However, quercetin has a very low water solubility (log P = 0.35) compared to the majority of other flavonoids in its category [11]. As a result of its potential activity against lung cancer, cisplatin is a chemotherapy medication used to treat various types of cancer, including lung cancer. It works by damaging the DNA of cancer cells, thereby inhibiting their ability to divide and grow. Despite its effectiveness, cisplatin has significant limitations, such as poor solubility and high toxicity, which can lead to severe side effects. This is possible due to the variation in the solubility of Eudragit® L-100 at different pH along the gastrointestinal tract (GIT). It was hypothesised that the pH sensitivity of the polymer would protect the drug as it passes International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 16, Issue 6, 2024