Enhancement of gold-curcumin nanoparticle mediated radiation response for improved therapy in cervical cancer: a computational approach and predictive pathway analysis

Discover Nano Research Enhancement of gold‑curcumin nanoparticle mediated radiation response for improved therapy in cervical cancer: a computational approach and predictive pathway analysis Priya Yadav1,2 · Arghya Bandyopadhyay1,3 · Keka Sarkar1 Received: 27 March 2024 / Accepted: 5 September 2024 © The Author(s) 2024  OPEN Abstract Radiotherapy is prevalently applied for highly effective cancer therapy while the low specificity of radiation is deleterious to the nearby healthy cells. High-Z-based nanomaterials offer excellent radio-enhancement properties while natural products provide radioprotection. Modulation of the radiotherapeutic index via applying nanomaterials is feasible for effective treatment however, the scenario changes when simultaneous protection of non-cancerous cells is required. Here, we report the modulatory radiotherapeutic effect of curcumin conjugated gold nanoparticles in a single nanoformulation to pave the long-awaited hope of a single combination-based, cell-selective radio enhancer, and protectant for cancer radiotherapy. We have validated the effective radiation dose along with the combination of the radio-nanomodulator by a reverse experimentation statistical model. The concept was supported by different sets of experiments, like quantification of ROS generation, cell cycle monitoring, mitochondrial membrane potential measurement, etc. along with gene expression study, and predictive modeling of molecular pathways of the killing mechanism. In conclusion, the nanoconjugate showed a promise to become a candidate for the pH-dependent cell-specific radio-modulator. Keywords Gold-curcumin nanoparticles · Metal-phytodrug nanoconjugates · Ionizing radiation · Radiosensitization · Radioprotection · Oxidative stress · Programmed cell death 1 Introduction Radiation therapy is the foremost chosen method for the treatment of locally advanced cancers. While radiation therapy contributes to severe deleterious effects on neighboring non-cancerous cells. Radiation therapy also potentially influences immune suppression, and bone marrow degradation [1]. To minimize the deleterious effects of radiation, radioligand therapy (RLT) or radionuclide therapy is a better choice over conventional radiation treatment [2]. Radionuclide therapy delivers radionuclides close to the site hence significantly lowering the adverse effect of radiation damage to normal local tissues [3]. During RLT, the healthy local tissues around the tumor tend to receive a prolonged radiation Priya Yadav and Arghya Bandyopadhyay contributed equally. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1186/s11671-024- 04104-7. * Arghya Bandyopadhyay, ; * Keka Sarkar, | 1Department of Microbiology, University of Kalyani, Kalyani, West Bengal 741235, India. 2Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, Tamil Nadu 608002, India. 3Department of Nanoscience and Nanotechnology, University of Kalyani, Kalyani, West Bengal 741235, India. Discover Nano (2024) 19:153 | https://doi.org/10.1186/s11671-024-04104-7 Vol.:(0123456789) Research Discover Nano (2024) 19:153 | https://doi.org/10.1186/s11671-024-04104-7 dose due to the presence of radionuclides within the body. Unfortunately, traditional radiation therapy as well as RLT bombards the system with high-energy radiation doses [4, 5]. Alternatively, Auger therapy relies on low-energy electrons for the treatment of cancer where the presence of a metal within the cell is capable of releasing Auger electrons upon being charged by external radiation. The Auger therapy is low low-energy method for damaging cancer cells unlike conventional radiation therapy consequently it can be implied as the next generation of cancer radiation therapy [6–8]. The Auger therapy can be tailored for targeting cancer cells by combining the electron emitter with a homing ligand molecule. Auger therapy is an attractive approach to treating cancer by damaging the DNA and arresting cell division thereby halting tumor growth and metastases [9]. Unlike conventional radiation therapy, during Auger therapy, the applied radiation dose can be minimized due to the presence of ligands. Moreover, the high Z metals are considered a true magic bullet in Auger therapeutics [10]. For instance, the case of cisplatin served as a potential chemotherapeutic for cancer therapy where metallic parts along with organic effectors are responsible for the potency of cisplatin [11]. However, due to the high energy covalent bonds between metal and organic moiety present in the cisplatin tends to be highly toxic for normal cells as they cannot be metabolized easily nor can be cleared from the system [12]. Metallic gold nanomaterials, due to their inherent chemical stability and excellent biocompatibility, have been utilized for various biomedical applications such as tagging cells and proteins, delivering therapeutic agents [13] and/or drugs, ultrasensitive detection of biomolecules [14], radiosensitizer [15] or radio-enhancers [16]. Gold nanomaterials are also employed for photodynamic therapy [17] and the most recent hyperthermic treatment [18]. Gold nanoparticles (AuNPs) act as an excellent radiosensitizing agent and assist in effective radiation therapy due to increased photoelectric absorption of (radiation) cross-sections relative to tissue [19, 20]. AuNPs along with ionizing radiations (IR) contributes to generating enormous reactive oxygen species ( O2−, 1O2, and ·OH) and are eligible to be potent radiosensitizer [19]. The IRs follow either direct or indirect mechanisms for cellular damage. During direct damage, the radiation knocks the DNA molecule directly and disrupts its molecular structure which leads to cellular death while in the course of indirect radiation damage, the radiation ionizes the aqueous environment of cells and generates highly reactive unpaired free hydroxyl (HO·) and alkoxy (RO·) radicals which further interact with macromolecules to disrupt its structure thereby impair its functional efficiency and eventually cell death [21–23]. In radiobiology, it has been well established that the majority of radio-mediated damages occur due to indirect action mechanisms since water comprises about 70% of the cellular composition [22]. Cancer cells develop radioresistance by eloping from the intracellular reactive oxygen species (ROS) generated through IRs via manipulating the redox system of cells [24]. Studies have revealed that AuNPs are identified to inhibit thioredoxin reductase (TrxR) and disrupt the cellular redox state via interacting and binding to its selenocysteine-containing active site of the TrxR enzyme. Reduced thioredoxin regulates the apoptosis and protects against oxidative stress. The AuNPs binding with the enzyme is therefore preventing the reduction of thioredoxin and disrupts the redox balance in cells resulting in increased oxidative stress thereby induci (...truncated)