Biogenic synthesized CuO nanoparticles and 5-fluorouracil loaded anticancer gel for HeLa cervical cancer cells

Discover Nano Research Biogenic synthesized CuO nanoparticles and 5‑fluorouracil loaded anticancer gel for HeLa cervical cancer cells Gouranga Dutta1 · Santhosh Kumar Chinnaiyan2 · Thirunavukkarasu Palaniyandi3 · Abimanyu Sugumaran4 · Damodharan Narayanasamy1 Received: 11 August 2024 / Accepted: 4 December 2024 © The Author(s) 2024  OPEN Abstract Cervical cancer remains a significant health challenge in developing countries are high due to low HPV vaccination rates, delayed diagnosis, and restricted healthcare access. Metal nanomaterials, such as copper oxide (CuO) nanoparticles (NPs), have shown significant promise in cancer therapy due to their ability to induce apoptosis. 5-Fluorouracil (5-Fu) enhances the cytotoxic effect against cervical cancer, working synergistically with CuO NPs to maximize the therapeutic impact while potentially reducing the 5-Fu’s systemic side effects. This study explores the synergistic therapeutic potential of green-synthesized CuO NPs combined with 5-Fu in a gel formulation for targeted anticancer activity against HeLa cervical cancer cells. CuO NPs were synthesized using Trichosanthes dioica dried seeds extract and incorporated into a pectin-xanthan gum-based gel. The green-synthesized CuO NPs exhibited a zeta potential of −23.7 mV, a particle size of approximately 26 nm, and spherical morphology. Characterization studies, including FTIR, viscosity, spreadability, pH, and stability assessments, confirmed the gel’s suitability for vaginal delivery. In-vitro drug release showed xanthan gum extended the release up to 8 h. The MTT assay revealed PXFCu6 gel’s I C50 at 11.82 ± 0.22 μg/mL, significantly more cytotoxic to HeLa cells, being 3.62 times potent than CuO NPs ( IC50: 42.8 ± 0.24 μg/mL) and 1.63 times potent than 5-Fu alone (IC50: 19.3 ± 0.49 μg/mL). The antibacterial assay showed no inhibition for the plain gel, but T. dioica-mediated CuO NPs exhibited inhibition of 22.35 ± 4.9 mm. PXFCu6 gel had the more potent inhibition at 52.05 ± 1.37 mm against Escherichia coli growth. The PXFCu6 gel showed better stability at 4 °C, maintaining viscosity, pH, and drug release, unlike 25 °C where a mild degradation occurred. This research highlights the potential of the CuO NPs-5-Fu gel as a novel, effective therapeutic strategy for cervical cancer treatment. Keywords CuO NPs · Cervical cancer · 5-fluorouracil · Hela cells · Pectin · Vaginal gel * Abimanyu Sugumaran, ; * Damodharan Narayanasamy, | 1Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India. 2Department of Pharmaceutics, Rajiv Gandhi Institute of Pharmaceutical Sciences and Research (RPISAR), Trikaripur, Kasargod, Kerala 671310, India. 3Department of Biotechnology, Dr. M.G.R Educational and Research Institute, Chennai, Tamil Nadu 600095, India. 4Department of Pharmaceutical Sciences, Assam University, Silchar, Assam 788011, India. Discover Nano (2024) 19:217 | https://doi.org/10.1186/s11671-024-04166-7 Vol.:(0123456789) Research Discover Nano (2024) 19:217 | https://doi.org/10.1186/s11671-024-04166-7 1 Introduction Cancer continues to grow globally, with rising mortality rates due to various factors. Recent studies show that in 2024, the United States alone registered over 2,000000 new cases, with 611,720 deaths [1]. Among all cancer types, cervical cancer is one of the most prevalent in women worldwide, with over 600,000 new cases reported in 2022 and 13,820 new cases in the U.S. in 2024 [1–3]. The primary cause of cervical cancer is chronic Human Papilloma Virus (HPV) infection, which affects the squamous cells in the cervix. Cervical dysplasia induced by HPV can result in malignancy if kept untreated. Some of the symptoms are aberrant vaginal bleeding, pelvic discomfort, and weight loss. The disease is prevalent in developing countries with limited access to healthcare services, examinations, and vaccines, making early detection challenging due to the asymptomatic stages [4–6]. The malignancy stage influences the treatment options available, including surgical procedures, radiation therapy, and chemotherapy. Early diagnosis of cervical cancer may lead to more favorable treatment outcomes [4, 6, 7]. Traditional cancer treatments are often unable to hinder spreading and reduce mortality. Nanomaterials have shown promise as cancer treatment agents. Drug loading and targeted distribution are more straightforward by nanoparticles with a high surface area-to-volume ratio, typically 1 to 100 nm. Metal NPs, including gold, silver, iron, zinc oxide, and copper oxide, show promise for cancer therapy, including cervical cancer [8, 9]. Pandurangan et al. studied ZnO NPs [10], and Ke et al. used gold NPs [11] on cervical cancer cell lines to demonstrate anticancer efficacy. Those nanomaterials can produce reactive oxygen species (ROS), induce apoptosis, and enhance the effectiveness of traditional treatments. The therapeutic benefits of metal NPs are maintained, while toxicity and environmental impact are reduced using green synthesis methods [12, 13]. Among all the metal NPs, the therapeutic potential and unique properties of copper oxide (CuO) NPs have attracted substantial attention in cancer therapy [14, 15]. Since pre-Vedic times, copper has been essential to human society, supporting conventional medical procedures and daily activities [16, 17]. Co-administering chemotherapeutic drugs with CuO NPs enhances anticancer activity through a synergistic effect. 5-fluorouracil is a common, affordable anticancer agent with various applications, including antibacterial effects. 5-Fu acts as a pyrimidine analog, inhibiting thymidylate synthase, a key enzyme in DNA synthesis. This causes the depletion of thymidine triphosphate (dTTP), leading to DNA damage and stopping the cell cycle in the S-phase. 5-Fu integrates into RNA, disrupting RNA processing and function, leading to cell death by apoptosis [18, 19]. Combining 5-Fu with CuO NPs is a strategic method to enhance therapeutic efficacy, allowing for lower dosages of the anticancer drug, minimizing adverse effects, and improving treatment outcomes. A localized therapeutic gel delivering CuO NPs and 5-Fu using pectin and xanthan gum may effectively treat cervical cancer. Pectin and xanthan gum have strong mucoadhesive properties, making them suitable for vaginal gel formulations that ensure long-lasting retention and contact with vaginal tissues [20, 21]. Their hydrophilicity helps maintain moisture balance, while their biocompatibility and biodegradability make them non-toxic and suitable for sensitive vaginal environments. The ability to form gels of appropriate viscosity, pectin, and xanthan gum ensures sustained drug release at the target site. This makes the pectin-xanthan gum gel an ideal carrier for localized cervical cancer treatment, enhancing the delivery of CuO NPs and 5-Fu while minimizing side effects [21, 22]. In this work, we synthesized CuO (...truncated)