Investigating the potential application of organic and inorganic nanoparticles for gastric cancer treatment: an evidence-based review

1. Introduction

Gastric cancer, which is considered a major health concern, is the sixth most common cancer and the second leading cause of cancer-related mortality across the globe [1]. From a histological point of view, this cancer is divided into two categories: diffuse and intestinal. It is categorized as a multifactorial disease, whereas infectious, environmental, and genetic factors have been introduced as risk factors for this disease [2]. The diagnosis of gastric cancer at an early stage increases the chance of a complete cure for the patient. Considering that the symptoms of gastric cancer appear very late, it is crucial to control and measure patients' risk based on their main predisposing components [3, 4]. Although several risk factors, such as age, male gender, cigarette smoking, and race, are described, Helicobacter pylori infection and family history are the two main risk factors for gastric cancer [5].

A range of various therapeutic strategies, such as chemotherapy, radiotherapy, surgery, or combinations of these methods, are currently applied for the treatment of cancers [6]. As the favorite surgical resection management for cancer treatment, chemotherapy is recognized as the most reliable therapy for recurring and developed cancer for patients who cannot undergo surgical intervention since they lack the required conditions [6]. Nonetheless, studies have demonstrated that chemotherapy is associated with some side effects, which are generally linked to nonspecific medicine spreading to healthy organs, unselective failure of normal cells, toxicity, and the competency of cancerous cells to produce resistance mechanisms [7]. Recently, the increasing prevalence of cancer deaths, as well as the serious defect of chemotherapy and radiotherapy methods in advanced forms of cancer, has highlighted the necessity of discovering new strategies to control cancer [8]. Targeting anticancer drugs in a way that only affects cancer cells and uses the minimum concentration of drugs seems necessary to reduce the toxic effects of the drug on normal cells [9]. Therefore, to specifically deliver the drug to the cancerous tissue and reduce its side effects, new drug delivery methods to the tissue can be used by nanoparticles (NPs) as a carrier [9]. Nowadays, we are witnessing a widespread use of NPs with a size of 100 nm or less for delivering and targeting diagnostic and pharmacological agents in cancer medical projects [10]. Recently, many NPs have been utilized in targeted drug delivery to malignant tumor cells, including gastric cancer cells, by dropping the systemic toxicity of anticancer drugs [11]. Nanoparticles can be used to improve drug delivery by increasing the drug's solubility, bioavailability, and stability. This allows for lower doses of drugs to be used, reducing the risk of toxicity and side effects [11]. This survey aimed to systematically review the anti-gastric cancer effect of all organic and inorganic NPs in in vitro, in vivo, and clinical trials.

2. Context

The investigation followed the PRISMA guidelines, and the findings were recorded in the CAMARADES-NC3Rs Preclinical Systematic Review and Meta-Analysis Facility database. We searched the publications in various English databases, such as Scopus, Web of Science, EMBASE, PubMed, and Google Scholar, with no specified publication time frame to obtain papers regarding the anti-gastric cancer properties of nanoparticles. The search process was performed using the following terms: "Nanoparticles," "Gastric cancer," "Anti-gastric cancer," "Metal nanoparticles," "Organic nanoparticles," "Inorganic nanoparticles, "in vitro," "Clinical," and "in vivo," (Figure 1). All duplicate papers were removed after importing the selected papers into EndNote X9 software (Thomson Reuters, New York, NY, USA). Independent authors evaluated the titles and abstracts of the papers, and the relevant articles were involved in advanced analysis. After careful reading of the articles, the eligible papers with acceptable inclusion criteria were nominated. In the case of any disagreement between authors, the corresponding author would resolve the problem.The inclusion criteria in this investigation entailed in vitro, in vivo, and clinical studies assessing the effects of NPs on gastric cancer treatment. On the other hand, the papers with insufficient data, studies with no full text, inconformity between methods and findings, and incorrect descriptions of the results were excluded from this study. The extracted data from the selected papers included the name of nanoparticles, in combination/loaded with, preparation methods, type of study, and outcome. Out of 11,189 articles, 31 papers, including 19 in vitro (45.5%), 3 in vivo (13.6%), 3 clinical trials (13.6%), and 6 in vitro/in vivo (27.3%), up to 2023, met the inclusion criteria for discussion in this systematic review with the data extracted (Table 1). The most widely used NPs were organic nanoparticles, such as polylactic acid and poly lactic-co-glycolic acid (PLGA) (16, 80.0%), followed by inorganic nanoparticles, such as silver NPs (13, 41.9.0%). Nowadays, it has been established that effective anticancer drugs must be capable of eliminating cancer cells while causing minimal toxicity to normal cells [10]. Consequently, the development of new drugs with minimal side effects on the immune system has emerged as a significant field in advanced biomedicine research. In recent decades, with progress in nanotechnology, the discovery of proper and effective drugs to treat a broad spectrum of high-impact diseases, such as gastric cancer, is considered one of the primary goals of this medical science. Given the possible anticancer mechanisms of nanoparticles, the induction of apoptosis demonstrated a critical role in determining cellular cytotoxicity subsequent to drug therapy [25, 32]. Recently, Xu et al. (2019) revealed that polyethylene glycol-poly (ε-caprolactone) NPs through inducing cell apoptosis and increasing G2-M arrest in cancer cells, demonstrating the suppression of microtubule synthesis so that the biological and clinical uses of DOC-PEG-PCL-mAb NPs were shown by PD-L1 mAbs for gastric cancer treatment [17]. In another study, Mousavi et al. (2018) demonstrated that silver NPs green synthesized by Artemisia turcomanica had a marked effect on gastric cancer cell lines in a dose- and time-dependent response through the induction of apoptosis in treated cells [25]. Tang et al. (2020) pointed out that green synthesized zinc oxide NPs by Morus nigra extract through the induction of apoptosis in gastric carcinoma cells acted as a substitute for cell death via reducing matrix metalloproteinase, as well as increasing the level of reactive oxygen species and cytotoxicity in adenocarcinoma gastric cancer cells [33]. Another anticancer mechanism of NPs is gene therapy, which suppresses some key molecules involved in gastric cancer [11]. In this regard, Wu et al. (2010) demonstrated that PEG-modified polyethyleneimine copolymer NPs overwhelmed the activity of CDD4 cells through siRNA delivery, a molecule that is comprised in the development

Fig 1. Flowchart describing the study design process

of gastric cancer [32]. In the same vein, Xiao et al. (2016) indicated that cerium oxide NPs (CNPs) improved the expression of DEAH box helicase 15 (DHX15) and its downstream signaling pathways, representing that CNPs could be a promising strategy to inhibit the malignant activity of gastric cancer by enhancing the expression of DHX15 [12]. In another investigation, Mohammadian et al. (2016) exhibited that chrysin-PLGA-PEG NPs inhibited the human gastric cell line by increasing the expression of miR-22, miR-34a, and miR-126 [31]. Currently, the intracellular release of some drugs utilizing NPs is one of the main mechanisms of the anticancer effects of NPs [11]. The results of a study conducted by Bonelli (2012) revealed that ibuprofen-loaded PLGA NPs had an antiproliferative activity against MKN-45 human gastric adenocarcinoma cells through the intracellular release of ibuprofen from the NPs, indicating that ibuprofen more rapidly encouraged the expression of transcripts complicated in multiplying and invasiveness manners [27].

3. Conclusion

The results of this review study highlighted the high anti-gastric cancer potential of a wide range of organic and non-organic NPs. Therefore, after conducting additional studies, especially on human models, and clarifying all aspects of their effectiveness and toxicity, they can be

Table 1. List of organic and inorganic nanoparticles to treat gastric cancer.

used to cure cancer. Although the possible mechanisms of these anti-gastric cancers are not clearly understood, studies have illustrated that NPs exert their activity through some mechanisms, such as induction of apoptosis, gene therapy, and drug delivery. Nevertheless, further studies are needed to confirm their anti-gastric effects and precise mechanisms, especially in clinical settings.