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Abstract

Background

Oral cancer remains 1 of the biggest health care challenges; it has a poor response to treatment, and treatment often results in severe side effects. Nano-targeted drug carrier-assisted drug delivery systems can improve the benefits of targeted drug delivery and treatment efficacy. A systematic review and meta-analysis was conducted to investigate the effect of targeted nano carrier drug delivery systems on the management of oral cancer.

Methods

A comprehensive literature search was performed using PubMed, ScienceDirect, the Cochrane Library, Google Scholar, and Scopus using PRISMA guidelines, to identify relevant in vitro and in vivo (human) studies. Studies evaluating the impact of nanocarrier-based delivery systems on oral cancer cells or human models were selected. Pooled effect sizes were calculated using random-effects models via RevMan 5.4, and heterogeneity among studies was assessed.

Results

After full-text assessment, 15 research articles were included [14 in vitro studies and 1 randomized controlled trial (RCT)]. In the meta-analysis, the pooled data (IC₅₀) for the impact of the nanocarrier delivery system vs control on oral cancer was −7.67 (95% CI: −41.77, 26.43), with a high heterogeneity (I² = 92%, P < 0.00001). Moreover, in vitro studies had a medium risk of bias, while the RCT had some concerns in the randomization domain.

Conclusion

Nanocarrier-based drug delivery has been found to be a superior approach compared to drug delivery in free form, increasing the efficacy and safety of oral cancer treatment.

Graphical Abstract

Keywords

nano-particles drug delivery system targeted delivery system treatment therapeutic efficacy OSCC oral cancer

Introduction

Cancer is the leading cause of death and a major health concern worldwide and is the leading cause of death globally. Among head and neck cancers, oral cancer is the most commonly found 1, contributing 40% of all cases.^1,2 Meanwhile, increasing trend (2%–3%) was observed annually in oral cancer cases.³ Oral cancer refers to tumors that occur in various parts of the mouth, including the hard plates, lips, anterior two-thirds of the tongue, buccal mucosa, and other tissues of the oral cavity.⁴ In addition, craniofacial tumors are characterized by the presence of many cystic and neoplastic pathoses and are considered unique due to functional impairment and aesthetic defects.⁵ As such, the survival rate of oral cancer has plateaued at approximately 50% over the past 30 years, despite great advancements in knowledge and treatment opportunities.⁶ Likewise, in a study, 5-year overall survival in oral cancer patients was significantly lower than control (53.7% vs 55.8%).⁷ Given that there are no specific symptoms for oral cancer, the majority of patients are diagnosed at an advanced stage, and only one-third of patients are diagnosed at an early stage.⁸

The oral cancer therapy for the early stage is usually surgical recession, and the advanced stage can be treated with radiotherapy or chemotherapy combined with surgery.⁹ Moreover, utilization of diode laser ablation also has promising functional and aesthetic outcomes.¹⁰ Nevertheless, these modalities do have significant side and antagonistic effects: radiotherapy causes permanent tissue damage to the organs and pathways around the tumor, while chemotherapy leads to vomiting, nausea, hair loss, diarrhea and infections in the patient, causing declining QoL and wellbeing.¹¹ Another barrier is the development of multidrug resistance.¹² In addition to these problems, the poor solubility of chemotherapeutic agents, low-solubility drugs administered intravenously plug off the blood vessels, a high hydrostatic pressure within the tumor interstitial fluids induces an outward convective interstitial flow, sets up a barrier for the effective transport of drugs, and aggressively drains out the therapeutic agents from the tumor cells.¹³ Similarly, acidic microenvironments in tumors can also cause the deterioration of acid-sensitive drugs.¹⁴

Because of the enormous impact of this deadly disease, investigators worldwide are progressively discovering nanotechnology to create advanced drug delivery systems. Which has the potential to revolutionize oral cancer treatment by improving drug targeting, tumbling toxicity, and enhancing therapeutic outcomes.¹⁵ In addition, various advantages of nanocarriers have been investigated compared with conventional delivery systems, such as enhanced and precise biodistribution, prolonged plasma half-life, and targeted delivery of anticancer agents.¹⁶ Nanocarriers expect constant, direct, and controlled drug release to malicious cells as they are programmed to identify malicious cells and provide specific drug release to them without any interference over normal healthy cells. Additionally, many disadvantages have been overcome with the evolution of nano-carrier-based drug delivery systems.¹⁷

Interestingly, drug delivery systems are being used in many ways to transplant therapeutic agents at targeted sites using nanocarriers. Major nano-carriers include drug delivery systems like liposomes, carbon nano-tubes, polymeric, polymeric micelles, solid lipids, quantum dots and magnetic nanoparticles.¹³ Both natural and synthetic polymers have been used for the preparation of nanocarriers. In this technique, active therapeutic agents are trapped with polymers by covalent bonds or materially embedded in a polymeric matrix. Polymeric nano-agents can be used for early diagnosis of oral cancer.^18,19 Polymer-based drug delivery systems consist of either amphiphilic or branched capsules. Moreover, lipid-based nanocarriers were the earliest carriers to be used in nano-medicine and are considered good delivery systems as they can easily degrade inside the body and their unique property to capture the lipophilic agent outside the lipid layer and hydrophilic agents inside the aqueous environment.²⁰ Lipid-based drug delivery systems have been approved for the treatment of Acquired Immunodeficiency Syndrome (AIDS)-linked cancers and mammary gland tumors.²¹ Similarly, magnetic particles are nanostructures with sizes of 1-100 nm and are divided into a magnetic core and a coating on the surface, that is, the coating of the functional layer. Metal Nanoparticles (MNPs) are composed of pure metals (cobalt, nickel, and iron) and oxide particles based on iron oxide, which are predominantly used in biomedical studies.¹³ This formulation of IGF1-IONPDOX (a magnetic nanocarrier) was able to penetrate the barrier erected by the tumor’s stromal membrane, which inhibits the dispersion of the drug in the tumor; therefore, it not only reduced the tumor mass, but also slowed down its proliferation in pancreatic tumors in humans.²² Similarly, the drug delivery efficiency of the carbon nanotube-based drug delivery system reached 80% in breast cancer cells.²³

Although these approaches have several advantages, some nanomaterials used in nanocarrier drug delivery systems might have some toxic issues, and their clearance from the body might be a challenge. Similarly, oral cancer treatment is a positive approach, and treatment with nanocarriers effectively reduces cancer tumor/cells. However, their clinical benefits in the treatment of oral cancer are still limited, and only a few studies have evaluated the role of nano-carrier-based drug delivery systems in the treatment of oral cancer in humans. The main objective of this cumulative analysis was to gauge the efficacy and impact of a nano-carrier-based drug delivery system vs a conventional drug delivery system and to provide rationale and a compilation of all evidence and complication rates with nanocarrier drug delivery systems, which could aid professionals and investigators as guidance expertise to update the development of novel, safe, and effective nano drug delivery systems or treatment modalities to restore patient outcomes.

Materials and Methods

The protocol for the current systematic review and meta-analysis was adopted according to the Preferred Reporting for Systematic Reviews and Meta-analysis (PRISMA) guidelines for the purposes of reproduction and transparency of the studies. A predefined search process was followed from the beginning to the end of the selection of relevant literature.²⁴ The PRISMA statement is very useful for transparent and thorough reporting in the literature.²⁵ The protocol for this systematic review was registered on the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) (registration number: (2024100110).

Literature Search

The studies were identified from a systematic analysis of the listed online databases, including PubMed, ScienceDirect, the Cochrane Library, Google Scholar, and Scopus, during the search without any date restrictions. Different keywords such as “nano-particles” OR “nano-carriers” OR “liposomes” OR carbon nano-tubes” “polymeric nano-particles” OR “quantum dots” OR “magnetic nano-particles” OR “dendrimer” AND “drug delivery” OR “drug carrier” AND “oral cancer” OR “oral squamous carcinoma” OR “mouth neoplasm” OR “oral health” were used (see Supplementary Table 1).

Inclusion Criteria

Studies were included on the basis of PICO guidelines: P = Participants/Patients with any type of oral cancer, I = Intervention based on nanoparticle delivery system, C = Control/comparator based on alternative drug delivery system or placebo, O = Outcomes; any outcome regarding survival after treatment. Only randomized controlled trials (RCTs), case-control studies, in vitro studies, and cohort studies published in English were included, without any data restrictions.

Exclusion Criteria

Studies with insufficient data or those that did not focus on oral cancers, case reports, reviews, editorials, commentaries, or published in languages other than English were excluded.

Study Selection and Assessment

Papers were selected based on a review of studies, wherein two reviewers searched, screened, and initially assessed the titles and abstracts for inclusion in the present study, according to their aims. Then, a full-text assessment of all the papers considered eligible was completed. The reviewers’ views were discussed to arrive at a consensus. In case of a contradiction or ambiguity issue, it was forwarded to the third consensual independent reviewer and resolved.

Data Extraction

Data were extracted from the included studies based on the pre-specified data extraction form in an Excel sheet. Each study was independently reviewed by two reviewers for the following characteristics: author ID, country, study design, sample size, participant characteristics (age, gender, cancer type), intervention and control characteristics (type of nanoparticle, drug used, dose delivered, delivery approach), adverse events, key outcomes, and conclusion.

Quality Assessment

To appraise the methodological quality of in vitro studies, the quality index tool (QUIN) was used with 12 items. Each study was assessed for 12 items and scored in the response as “yes” (allocated 1-2 points), “no” (allocated zero points) or “not applicable”.²⁶ The second step was to rank each study by using a point response. The studies scored below 50% were considered to have a high risk of bias (RoB), those between 50%–70% were the medium RoB, >70% were the low RoB.²⁶ For RCTs, we employed the Cochrane collaboration tool to perform quality assessment using the Robvis web-based app.²⁷ Assessment was carried out in the realms of randomization, deviation from the intended intervention, measurement of outcomes, missing outcomes, and reporting.

Data Analysis

A qualitative synthesis combined the outcomes of studies to show the general, intervention characteristics, and key findings. RevMan 5.4 was used to perform meta-analysis that measured the pooled efficacy of intervention on cytotoxicity and test for heterogeneity.²⁸ In addition, statistical heterogeneity was assessed using the chi-square test (P-value) and I² statistics. It is critical in the determination of the variability among the studies which involve I² statistics. Substantial heterogeneity was considered when I² was >50%. In addition, the Cochrane Q test was used for the assessment of heterogeneity. Meanwhile, heterogeneity estimates quantify the variation in effect sizes across studies. This may arise from differences in study design, population, intervention, or outcomes. By marking the degree of difference, investigators can determine whether the effect is different or not. A random-effects model was used (P-value <0.01).

Results

Literature Search

Searches of the literature were performed using PubMed, Scopus, ScienceDirect, the Cochrane Library, and Google Scholar, and 613 primary research papers were identified. In the screening phases of PRISMA, namely, identification and title and abstract screening, 54 duplicated research papers were identified and excluded, which were found in the identification phase of PRISMA. Therefore, 559 research papers were considered for the screening of studies to determine which research papers were eligible for inclusion in our study. After screening, 533 studies were deemed unsuitable for this study and were thus excluded. We assessed only 26 research papers for full screening, and we analyzed only 15 qualitative and quantitative research papers because 11 studies were excluded for some reasons, which are presented in Figure 1.

Figure 1.

PRISMA flow chart and article selection process.

General Characteristics of in Vitro Studies

Table 1 summarizes the general characteristics of the included in vitro studies that investigated various drug interventions in oral cancer cell lines. These studies span multiple countries, with China^29-33 and India^34-38 as the most reported countries. Meanwhile, a single study was reported in Brazil,³⁹ Israel,⁴⁰ Turkey,⁴¹ and Malaysia⁴² and focused primarily on human tongue squamous cell carcinoma (SCC) cell lines such as KB,³⁴ SCC-9,^35,39 SCC090,^36,37 KB-3-1 human oral cell lines,³⁸ and CAL-27.^{29,30,32,33,42} The interventions examined range from natural compounds, such as ellagic acid and curcumin^34,36,37,39 to conventional chemotherapeutic agents, such as cisplatin and doxorubicin.^29,30,32,40 Several studies have also explored combination therapies, including paclitaxel and temozolomide,⁴² and cetuximab with cisplatin,⁴¹ doxorubicin (DOX), trypsin-EDTA, and penicillin-streptomycin³³ as indicated in Table 1.

Table 1.

General characteristics of the included in vitro studies.

Study ID	Country	Study design	Cancer type	Type of drug
³⁴	India	In vitro	Human oral cancer cell line (KB)	EA
³⁹	Brazil	In vitro	Human oral cancer cell line SCC-9	Cu
³⁶	India	In vitro	Human tongue SCC cells (SCC090)	Cu and Fu
³⁷	India	In vitro	Human tongue SCC cells (SCC090)	Cu and Fu
³²	China	In vitro	OCSCC cell lines (HSC3, SCC4, and CAL-27)	Cisplatin
⁴⁰	Israel	In vitro	Human tongue SCC cells	DOX
³⁵	India	In vitro	Human tongue carcinoma cell line SCC-9	Docetaxel
³⁰	China	In vitro	Human tongue SCC cells (CAL-27)	DOX
⁴¹	Turkey	In vitro	Oral cavity cancer cell line (UPCISCC-131)	Cetuximab and Cisplatin
³¹	China	In vitro	Human tongue SCC cells (SCC15)	Plasmid
²⁹	China	In vitro	Human tongue SCC cell line (CAL-27) and Human oral keratinocyte cell line (HOK)	DOX
⁴²	Malaysia	In vitro	Human tongue SCC cells (CAL-27)	Paclitaxel and Temozolomide
³⁸	India	In vitro	KB-3-1 human oral cell lines	Erlotinib
³³	China	In vitro	Human tongue SCC cells (CAL-27) and Human oral keratinocyte cell line (HOK)	DOX, trypsin-EDTA, and penicillin-streptomycin

Abbreviations: EA = Ellagic Acid, Fu = Fluorouracil, Cu = Curcumin, DOX = Doxorubicin, OCSCC = Oral Cancer Squamous Cell Carcinoma, SCC = Squamous Cell Carcinoma.

General characteristics of RCTs

Table 2 summarizes the general characteristics of only 1 available RCTs performed on humans that study was conducted in the USA, with 10 subjects (5:5 ratio of women and men and aged 64.3 years on average), studying the impact of cisplatin in patients with OCSCC grade T1-T2,Nx, M0.⁴³

Table 2.

Summary of the General Characteristics of the Included RCTs.

Study ID	Country	Study design	Sample size	Gender (M: F)	Age (years)	Cancer type	Cancer stage	Type of drug
⁴³	USA	RCT	10	5:.5	64.3	OCSCC	T1-T2, Nx, M0	Cisplatin

Abbreviations: RCT = Randomized Controlled Trail, OCSCC = Oral Cancer Squamous Cell Carcinoma, Cu = Curcumin.

Outcomes of in Vitro Studies

Different types of nanoparticles have been used, such as chitosan,^34,39 gold nanoparticles,^30,41 PGLA,³⁵ liposomes,^38,40 and Carboxylated GO with HA and HN-1 peptide,³³ with particle sizes ranging from 5 nm³² to 400 nm.⁴⁰ The dosage and delivery approaches for these nanoparticles are primarily localized, with a few cases involving intracellular⁴¹ or systemic delivery.³¹ Key outcomes from these studies indicate that these nanoparticles, when loaded with therapeutic agents such as curcumin (Cu), 5-fluorouracil (Fu), or DOX, often exhibit enhanced cytotoxic effects, reduced drug resistance, or improved cancer cell targeting. For instance, chitosan-based nano-particles demonstrated improved efficacy in delivering ellagic acid (EA) with IC₅₀ (0.95 g/mL) compared to the drug only (3.12 g/mL)³⁴ and Cu (IC₅₀ = 47.89 μg/ml),³⁶ while gold nanoparticles conjugated with cetuximab showed potential in overcoming radiotherapy resistance.^30,41 The conclusions generally suggest that these novel nanoparticle formulations hold promise for enhancing oral cancer treatment by increasing drug efficacy, reducing toxicity, and overcoming treatment resistance^{31,33,34,36-39,41} (Table 3).

Table 3.

Summary of Nanoparticle Characteristics and Key Outcomes of the in vitro Studies.

Study ID	Type of nano-particle	Size of nano-particle (nm)	Dosage	Delivery approach	Key outcomes (Toxicity)	Conclusion
³⁴	Chitosan	30-120	25-100 mg	Local	IC₅₀: EA = 3.125 g/mLl	The present drawbacks of EA might be solved by this creative formulation.
³⁴	Chitosan	30-120	25-100 mg	Local	EA-CS-NP = 0.953 g/mLl
³⁹	Chitosan	104-127	Chitosan = 60 mg Cu = 5 mg	Local	Cu-loaded NPs showed reduced cytotoxicity than free drug	For the treatment of oral cancer, chitosan-coated PCL NPs may be a potential way to transport Cu directly into the mouth.
³⁶	NPs	200	NA	Local	IC₅₀: Cu-NP = 47.89 μg/mLl	Cu-NPs provide chemo-protective nature towards 5-FU induced-toxicity
³⁶	NPs	200	NA	Local	FU-NP = 26.19 μg/mLl
³⁷	NPs	150-200	1 x 10⁴ cells/well in 96 well plates	Local	IC₅₀: 5 FU-NE = 51.79 μug/mLl Cur-NE = 79.16 μug/mLl	The ability of the combined loaded Cu and 5-FU in nano-formulation system to provide enhanced anticancer activity against oral cancer has been demonstrated.
³⁷	NPs	150-200	1 x 10⁴ cells/well in 96 well plates	Local	5-FU-Cur-NE = 31.05 μug/mLl
³²	Polyethylene glycol-modified graphene quantum dots	5	The concentration of Pt was 5 mg/kg, and the volume was 100 μL.	Local	IC₅₀: CAL-27 = 6.42 ± 1.16 μM SCC4 = 2.77 ± 0.84 μM	GPt exhibits superiority in addressing hypoxia-induced chemoresistance.
⁴⁰	Liposomes	200-400	NA	Local (Paste)	Highly effective in promoting cancer cell death	This technique facilitates the prolonged release of anti-cancer medication.
³⁵	PLGA	120	75 μL	Local	Higher cytotoxic effect was observed in PLGA DTX NPs formulation group	Enhanced anti-proliferative efficacy of PLGA DTX nanoparticles relative to free DTX
³⁰	AuNPs	NA	5 mLl, 0.1 mg/mLl	Local	The synthesised (PDPN Ab)-AuNP-DOX system exhibits little toxicity, substantial drug loading capacity, and efficient cellular absorption.	This device can serve as a multifunctional drug-delivery nanoplatform for targeted and combination chemotherapy and photothermal therapy.
⁴¹	AuNPs	15	10, 20, 25, 50, and 100 μg/mL	Intracellular	A significant reduction (p = 0.03) of UPCI-SCC-131 colony numbers was observed in GNP and GNP–CTX combined with radiotherapy group than radiation alone and radiation with free CTX	The cetuximab and cisplatin-conjugated gold nano-drug complex possesses significant potential to enhance cytotoxicity.
⁴¹	AuNPs	15	10, 20, 25, 50, and 100 μg/mL	Intracellular	DMP/phBimS group exhibited a 57.9% cell survival rate.
³¹	DOTAP-mPEG-PCL (DMP) micelles	28.32 ± 3.56	DMP and plasmid at a ratio of 20:1 (w:w)	Local and systemic	The DMP group exhibited a survival rate of 84.3% (P < 0.05), indicating the anti-proliferative impact of the DMP/phBimS complex.	The DMP/phBimS complex is an alternative effective strategy for suicide gene therapy in OSCC.
²⁹	PEGylated nano-graphene oxide (NGO)	NA	1 mL of 1 mg/mL DOX aqueous solution was mixed with 1.0 mg of NPF	Local	Improved cytotoxicity in the intervention group	NPF-DOX can accurately target OSCC, and the combination of chemical and photothermal therapy can enhance the total therapeutic efficacy for OSCC.
⁴²	HA/chitosancoated PLGA	159.46 ± 14.50	1 mL of PLGA NPs suspension into 2 mL of the HA/CS complex	Local	Paclitaxel, Temozolomide, and their combination induced more cytotoxicity compared to free drugs	The developed nanoparticles may serve as a viable option for oral cancer treatment.
³⁸	Liposomal gel	<200	0.73% w/w	Local	ERB (558.94 ng/mLl), ERB Lipo (163.89 ng/mLl) and CS ERB Lipo (279.80 ng/mLl)	The topical treatment of ERB lipo gel and CS-ERB lipo gel shows promising results in resolving early-stage oral cancer.
³³	Carboxylated GO with HA and HN-1 peptide	197	Combine GO or GHA with HN-1 at a mass ratio of 10:1	Local	GHHD reduced the growth rate with the lowest cell viability of 38%	DOX@GO-HA-HN-1 combined with photothermal therapy has a potential for the treatment of OSCC.

Abbreviations: EA = Ellagic Acid, IC₅₀ = Inhibitory Concentration, PLGA = Poly (lactic-co-glycolic acid), AuNPs = Gold Nano-particles, Fu = Fluorouracil, Cu = Curcumin, DOX = Doxorubicin, HA = Hyaluronic acid, CS = Chitosancoa, GO = Graphene Oxide, GHHD = DOX@GO-HA-HN-1.

Outcomes of RCTs

Single RCT explored chitosan nanoparticles delivering cisplatin (6 or 12 mg per visit) via patches and reported manageable adverse events, including grade 1/2 oral pain (40%) and glossodynia (30%). This approach led to a 69% reduction in tumor volume within 7 days, indicating that combining PRV111 with standard care could improve outcomes in patients with oral cancer,⁴³ as described in Table 4.

Table 4.

Summary of Nano-Particle Characteristics and Key Outcomes of RCTs.

Study ID	Type of nano-particle	Dosage	Delivery approach	Adverse events	Key outcomes (Toxicity)	Conclusion
⁴³	Chitosan	Each visit dose: 6 mg or 12 mg of cisplatin	Local (Patches)	Grade 1/2 oral pain (40%) and glossodynia (30%)	It resulted in a 69% reduction in tumour volume within 7 days.	The incorporation of PRV111 with the existing standard of therapy may enhance health outcomes for individuals with OCSCC.

Abbreviations: Cu = Curcumin, OCSCC = Oral Cancer Squamous Cell Carcinoma.

Meta-Analysis

In vitro studies

A total of four studies were utilized in the meta-analysis, and the pooled data (IC₅₀) for the impact of nano-particle delivery system vs control on oral cancer was −7.67 (95% CI: −41.77, 26.43), as indicated in Figure 2. High heterogeneity (I² = 92%) was found among the studies, with a statistically significant difference (P < 0.00001).

Figure 2.

Forest plot of IC₅₀ values of experimental and control groups against different cells of OCSCC.

Quality assessment

All in vitro studies resulted in a medium risk of bias, with scores ranging from 50% to 70%. Two domain scores were not calculated for any study (operator details and outcome assessor’s details); the domain scores for randomization and blinding were both zero (Table 5).

Table 5.

Quality Assessment of Included in vitro Studies.

Studies	Questions											Total Points	% Age	Status
Studies	Aims/Objectives	Sample Size Calculation	Comparison Group	Methodology Explanation	Operator Details	Randomization	Method of Measurement of Outcome	Outcome Assessor Details	Blinding	Statistical Analysis	Presentation of Results	Total Points	% Age	Status
³⁴	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³⁹	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³⁶	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³⁷	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³²	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
⁴⁰	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³⁵	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³⁰	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
⁴¹	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³¹	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
²⁹	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
⁴²	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³⁸	2	0	2	2	NA	0	2	NA	0	2	2	12	66.6	M
³³	2	0	2	2	NA	1	2	NA	0	2	2	13	72.22	L

Abbreviations: L = Low, M = Medium, H = High, NA = Not Available.

Unfortunately, only 1 RCT compared nanoparticle delivery systems with a control and found some concerns in the randomization domain.⁴³

Discussion

Oral cancer remains a major global health concern, as it presents with high incidence and mortality rates, especially in the developing world.⁴⁴ Mainstream treatment modalities, such as surgery, chemotherapy, and radiotherapy, are often hindered by systemic toxicity, drug resistance, and poor targeting of tumor cells.⁴⁵ One of the most promising approaches to improve the efficacy and specificity of oral cancer therapy is the use of drug delivery systems based on nanocarriers.⁴⁵ These delivery systems include nanoparticles, liposomes, and micelles, which can provide advantages, such as improved bioavailability, targeted drug release, and reduced toxicity. This systematic review and meta-analysis aimed to evaluate the efficacy of nano-carrier-based drug delivery systems for the treatment of oral cancer with respect to therapeutic outcomes.

In the meta-analysis of the in vitro studies of the present study, a significant difference (P < 0.01) was observed in the reduction of oral cancer cell viability between nanoparticle delivery systems and in the absence of oral cancer drug delivery systems. Similar findings were also reported by another review and highlighted nanotech, including nanovesicles, and proved to be effective against cancer.⁴⁶ Furthermore, recent evidence suggests that nanoparticles synthesized with anticancer drugs, such as chemotherapeutic agents, radiotherapy, and immuno-targeting antibodies, can significantly enhance drug release and locally increase drug concentrations in the tumor to improve treatment. This suggests that nano-particles may reduce OSCC and hold promise as an effective drug delivery system.⁴⁷ Furthermore, in vitro results showed that dual-receptor targeting nanoparticles were internalized significantly faster in CAL-27 cells by receptor-mediated end cytology, indicating superior antitumor activity compared to single-receptor nanoparticles. These experimental findings on drug delivery for treating oral cancer highlight CMCS-hyd-CUR-EGFR mAb as a promising alternative.⁴⁸ Similarly, another in vitro study also demonstrated that both intravenous and oral doses of DOX-MTX nanoparticles led to a significant reduction in MMP-2 mRNA levels compared to the untreated group (P < 0.003).⁴⁹ Moreover, nano-particles encapsulating rosemary extract were synthesized and subsequently characterized using electron microscopy. Their effects on the OSCC cell line (Hep-2) were evaluated in terms of cytotoxicity, cell cycle disruption, apoptosis induction, and intracellular reactive oxygen species (ROS) levels. RE nanoparticles showed dose-dependent cytotoxicity against Hep-2 cells (causing apoptosis and arresting the cell cycle at the G2/M phase), increasing the production of ROS in cancer cells, and causing the appearance of autophagosomes in treated cells.⁵⁰ Nanoparticle delivery systems directly improve drug efficacy by enhancing the delivery of targeted anticancer drugs to cancer cells, thereby reducing system consumption and increasing drug levels in the tumor area.⁵¹ This enhances the cellular uptake and makes the therapeutic agent more effective in binding to the targeted organ, helping it to be retained for a prolonged period in the body and enhancing the release, thus helping to improve its solubility and bioavailability and increasing the potency of a drug in comparison with the conventional dosage form. Furthermore, another in vivo study demonstrated that treatment with γ-PGA- gefitinib/Cur NPs significantly reduced tumor size compared to treatment with free Gefitinib/Cur.⁵² The antitumor activity of paclitaxel nanoparticles exhibited significantly higher antitumor efficacy and apoptosis induction, as well as an improved safety profile, compared to free paclitaxel in a mouse xenograft model. A lower expression of Ki-67, EGFR, and markers of angiogenesis (Factor VIII, CD31, and CD34) was observed in the paclitaxel-nanoparticle group compared with the other groups (P < .05), and in the same group, oxidative and nitrosative stress was induced by paclitaxel nanoparticles in the tumor tissue.⁵³ Similarly, nano-particles, especially AuNPs, augment their cytotoxic effects against cancer cells and serve as drug carriers. DOX-loaded pH-resistant AuNPs successfully accumulated more in cancer cell nuclei, which caused prominent apoptosis of the cancer cells. This observation was assessed both in vitro and in vivo, without any effects on the blood cell count.⁵⁴ Meanwhile, these nanoparticles have a promising future due to its safety profile as these are selective towards cancer cells.⁵⁵ Additionally, nanoparticles deliver medication without damaging healthy cells.⁵⁶

Nanocarrier-based drug delivery systems offer important clinical advantages in the treatment of oral cancer. Because it can increase the efficiency of treatment and reduce toxicity to the system. These advanced systems enable targeted delivery of anticancer agents. Adding a higher concentration of drug to the tumor site ensures that it can be reduced, and it can also improve the absorption and controlled release of drugs, which can lead to a prolonged treatment effect. In addition, it provides a better quality of life for patients, making them a transformative innovation in oral cancer management.

This study has several strengths and weaknesses. This review summarizes data from different studies to provide solid evidence that nanoparticle systems are more effective, targeted, and safer for drug delivery than conventional systems in humans. The aggregation of data from the meta-analysis via pooled data allows the quantification of therapeutic benefits, which contributes to the contemporary evidence base for the use of these advanced delivery systems. Some limitations include variability of the studies in terms of study design, nanoparticle formulations, and outcome measures, which could affect the generalizability of the results across studies. Furthermore, the observed statistical heterogeneity in vitro studies and the use of a very limited number of studies (human-related) with very small sample size could also impede the possibility of definite conclusions that could be a result of the lack of clinical randomized trials due to which meta-analysis was not performed. Lack of long follow-up data is notably another important limitation which prevents the comprehensive assessment of the efficacy and safety profile. Due to limited number of clinical studies (2 RCTs) safety profile was not established well. Recommendations for future research include large-scale, well-designed clinical trials to demonstrate the efficacy and safety of nanoparticle delivery systems, standardization of test protocols to reduce variability, and evaluation of the timing of outcomes and potential adverse consequences to confirm proper interpretation and clinical application. Furthermore, comparative studies explore various types of nanoparticles and their optimization for targeted delivery systems for drugs. Most importantly, it is cost-effective analysis of the utilization of the nanoparticles in clinical settings.

Conclusion

Collectively, the results of this study revealed that these new delivery systems significantly improved therapeutic outcomes over free drug delivery, despite variability across individual studies and statistically insignificant differences in humans on a study-by-study basis, as demonstrated in the human-focused meta-analysis. Overall, nanoparticle systems systematically improve drug efficacy and decrease toxicity, and the reduction in cancer lesions and enhancement of apoptosis with nano-particle systems points to their potential as an adjunct to conventional treatment regimens. However, challenges like, fabrication complexity and outlining potential solution should also be considered. Further validation of these benefits by conducting such studies with larger sample sizes and better-designed methodologies is needed to maximize the clinical usefulness of nanoparticle drug delivery systems in the management of oral cancer.

Supplemental Material

Supplemental Material - Cytotoxicity of Nanocarrier-Based Drug Delivery in Oral Cancer Therapy: A Systematic Review and Meta-Analysis

Supplemental Material for Cytotoxicity of Nanocarrier-Based Drug Delivery in Oral Cancer Therapy: A Systematic Review and Meta-Analysis in China by Mohammad A. Saghiri, Ravinder S. Saini, and Artak Heboyan in Cancer Control.

Footnotes

Acknowledgments

All the authors are thankful to King Khalid University, Saudi Arabia, for the financial Support.

Author Contributions

Conceptualization and Methodology: M.S. Data Curation and Formal Analysis: R.S. Investigation and Resources: R.S. Validation and Visualization: A.H. Original draft preparation: R.S. Writing, Reviewing and Editing: M.S., A.H. Supervision and Project Administration: A.H. Funding Acquisition: R.S.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is supported by The authors extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work through the Review Article Project under grant number RA.KKU/7/45.

ORCID iD

Artak Heboyan

Supplemental Material

Supplemental material for this article is available online.

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