Nanoparticle-Based Chemotherapy Formulations for Head and Neck Cancer: A Systematic Review and Perspectives

Abstract

Head and neck cancer (HNC) is a complex and heterogeneous disease associated with high mortality and morbidity worldwide. Standard therapeutic management of advanced HNC, which is based on radiotherapy often combined with chemotherapy, has been hampered by severe long-term side effects. To overcome these side effects, tumor-selective nanoparticles have been exploited as a potential drug delivery system to improve HNC therapy. A combination of MEDLINE, EMBASE, Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception up to June 2020 was used for this systematic review. A total of 1747 published manuscripts were reviewed and nine relevant references were retrieved for analysis, while eight of them were eligible for meta-analysis. Based on these studies, the level of evidence about the efficacy of nanoformulation for HNC therapy on tumor response and adverse side effects (SAE) was low. Even though basic research studies have revealed a greater promise of nanomaterial to improve the outcome of cancer therapy, none of them were translated into clinical benefits for HNC patients. This systematic review summarized and discussed the recent progress in the development of targeted nanoparticle approaches for HNC management, and open-up new avenues for future perspectives.

Keywords: head and neck cancer; nanoparticles; selective drug delivery; targeted therapeutics.

Figure 1

Study flow diagram. Following the guidelines of the Cochrane Handbook for Systematic Reviews of Intervention [25], it was performed a sensitive search in the online databases to identify the studies that examined associations between different nanoformulation and head and neck cancer (HNC) treatment. This systematic review searched for relevant studies considering publications up to June 2020. The chart diagram was reproduced from Moher, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement; published by PLoS Med., 2009 [26].

Figure 2

Forest plots showing the proportions of overall severe adverse events (SAE—grade 3 or 4). The graphs display the reference of the study with the name of the author and year of publication, the prevalence (Prev) and the 95% confidence interval (95% CI) for each of the three nanoparticles carrier chemotherapy (NCC) identified on the search. The overall rates of adverse events per 100 patients were calculated with random-effects models due to limited sample size.

Figure 3

Timeline of development of nanoformulations identified in this study [15,17,18,19,20,21,22,23,24,33,34,35,36,37,38,39,40]. The scheme compiles the main chemotherapeutic agents and nanostructures for cancer treatment over the last 7 decades. The year listed in the blue line shows the moment that FDA approved the nanoformulation to the clinical practice and the intersection of the nine clinical studies analyzed in this research. NSLC: Non-Small Cell Lung Cancer; HNC: Head and Neck Cancer.

Figure 4

Representation of the most common types of nanoformulations identified in clinical studies of HNC. The nanoformulations carrying chemotherapeutics are expected perform transcytosis throughout the endothelium barrier and accumulate in tumor sites due the EPR effect and release the drug inside the cancer cells. This ideal pharmacokinetic depends on the nanotechnology engineering (chemical composition, physical properties and targeting ligand) and how this variables interacts with the biological events, e.g., plasmatic concentration depending on the administration mode (A), plasmatic proteins interaction (B), particle stability and drug release (C and H), biodistribution (D), transcytosis rate (E), stromal cells interaction (F) and tumor cell internalization (G).