Nanomedicine, an emerging therapeutic strategy for oral cancer therapy

Highlights

• Nanomedicine-based therapies in OSCC have been evaluated in in vitro settings.

• Subcutaneous xenograft models do not accurately reproduce human oral cancer.

• Nanomedicine-based therapies have been proven effective in chemoresistant cells.

• No nanomedicine-based therapy has been clinically approved for oral cancer.

• New nanomedicine-based approaches for metastatic OSCC therapy remain an unmet need.

Abstract

Oral cavity and oropharyngeal carcinomas (oral cancer) represents a significant cause of morbidity and mortality. Despite efforts in improving early diagnosis and treatment, the 5-year survival rate of advanced stage of the disease is less than 63%. The field of nanomedicine has offered promising diagnostic and therapeutic advances in cancer. Indeed, several platforms have been clinically approved for cancer therapy, while other promising systems are undergoing exploration in clinical trials. With its ability to deliver drugs, nucleic acids, and MRI contrast agents with high efficiency, nanomedicine platforms offer the potential to improve drug efficacy and tolerability. The aim of the present mini-review is to summarize the current preclinical status of nanotechnology systems for oral cancer therapy. The nanoplatforms for delivery of chemopreventive agents presented herein resulted in significantly higher anti-tumor activity than free forms of the drug, even against a chemo-resistant cell line. Impressive results have also been obtained using nanoparticles to deliver chemotherapeutics, resulting in reduced toxicity both in vitro and in vivo. Nanoparticles have also led to improvements in efficacy of photodynamic therapies through the development of targeted magnetic nanoparticles. Finally, gene therapy using nanoparticles demonstrated promising results specifically with regards to inhibition of gene expression. Of the few in vivo studies that have been reported, many of these used animal models with several limitations, which will be discussed herein. Lastly, we will discuss several future perspectives in oral cancer nanoparticle-based therapy and the development of appropriate animal models, distinguishing between oral cavity and oropharyngeal carcinoma.

Introduction

Squamous Cell Carcinoma (SCC) is the most frequently diagnosed oral cancer. It is important to note that while this term is oftentimes used to include both oral cavity and oropharyngeal SCC tumors, these are both separate entities [1], [2]. Both are included within the larger group of Head and Neck Squamous Carcinoma (HNSCC), which is the sixth most common form of cancer worldwide [3]. Herein, the term oral SCC (OSCC) is used in reference to both SCC of the oral cavity and oropharynx. OSCC represents ∼2 to 3% of all human cancers [4]. In 2012, more than 300,000 and 140,000 new cases of lip/oral cavity-SCC and oropharyngeal SCC were diagnosed worldwide [2]. In Western Countries, the most frequent primary sites of oral cavity SCC are the tongue and the floor of the mouth [2].

The major risk factors of OSCC include tobacco and alcohol consumption [2], [5]. Human papillomavirus (HPV) is emerging as an additional important risk factor, particularly associated with oropharyngeal SCC [2]. Oral cancerogenesis is a multistep process, in which multiple genetic and cellular alterations are involved [5]. In the oral cavity, the most common potentially malignant disorder is oral leukoplakia [6], [7]. Imbalance of growth factors such as EGF, VEGF, PDGF, and TGF-β1, caused by gene mutations associated with tobacco use and/or HPV 16 and 18 infection, may also contribute [2], [8], [9], [10], [11], [12].

Regional lymphatic metastasis and distant metastasis (DM) occurs especially in advanced stages of OSCC and correlates with a poor prognosis [8], [13], [14]. Indeed, the 5-year survival rate of OSCC in the US is 63%. The survival rate has been reported to be less in the presence of lung and bone metastases [2], [14]. DM was reported in 6.6% of upper gingiva and 4.1% of tongue carcinomas [15]. However, another study reported that the majority of patients with neck lymph node metastasis had tongue cancer (69.6%) [13]. In a larger study consisting of 502 patients affected by oral cavity SCC, only 54 patients (10.8%) presented DMs, especially in lung, bone, and the mediastinum [14].

Treatment of OSCC is stage-dependent. Early stages treatments involve surgery or radiotherapy (RT) alone. Advanced stages require surgery and/or RT + chemotherapy (CT) as adjuvant treatment [2], [4], [10]. Indeed, the addition of CT significantly improved overall survival (OS) [1]. In contrast, OS was not improved in oral cavity SCC patients undergoing induction CT. However, it may result in a reduction of loco-regional recurrence [16]. The most commonly used chemotherapeutic agents are cisplatin (CDDP) and fluorouracil (5-FU), while other drugs such as carboplatin, paclitaxel, docetaxel (DTX), and methotrexate (MTX) have been reported [1], [12], [17] Molecular-targeted agents (e.g. cetuximab and bevacizumab), gene therapies, photodynamic therapy (PDT), and immunotherapy have also been explored [3], [18], [19]. Indeed, CT results in several adverse side effects and in multi-drug resistance (MDR), which leads to a poor therapeutic response in several cases [4], [19], [20], [21], [22]. Adverse effects of CT stem from non-specific distribution of chemotherapeutics and vary from patient to patient and type of treatment (e.g. agent, duration, dosage) [1], [20], [23]. For instance, important adverse effects of CDDP include nephrotoxicity, neurotoxicity, and gastrointestinal toxicity [23]. Also MDR contributes to CT toxicity, due to exposure of healthy cells to high levels of expelled drug [19], [20]. The MDR mechanisms in oral cancer are still under investigation and contribute to failure of treatment in advanced stages of OSCC [19]. The principal mechanism consists in over-expression of multi-drug transporters, which are responsible for drug efflux from tumor cells, decreasing their efficacy [19], [20]. Indeed, studies have reported an enhanced expression of P-gp, MDR1 and ABCG2 in cell lines resistant to CDDP, 5-FU, and in recurrent OSCC [19], [22].

To overcome the limitations of CT, nanotechnology-based systems are emerging in cancer therapy [17], [20]. In the past decades, the intersection of nanotechnology with medicine, physics, mathematics and biology has given rise to the new field of nanomedicine. Nanoparticle (NP) systems have demonstrated high drug carrier capabilities and site-specific drug accumulation in tumors [20], [24], [25]. Several preclinical studies involving NP-based CT delivery reported higher drug solubility, drug circulation times, and efficacy when compared to conventional free drug formulations [20], [24], [26]. NPs have been reported as suitable carriers of chemopreventive compounds, nucleic acids, and diagnostic agents for both diagnostic and therapeutic (i.e. theranostic) purposes [7], [27], [28], [29], [30]. In light of the many advantages afforded by NPs, several NP systems, such as Doxil/Caelix® and Abraxane®, have been clinically approved for the treatment of certain types of cancer, such as ovarian cancer and metastatic breast cancer. Several other systems, such as gold nanoshells, are currently undergoing clinical trials [31], [32]. However, to date, no NP-based treatment has been approved for HNSCC [31], [32]. Clinical trials have been performed and other trials are currently underway to treat advanced HNSCC [31], [33], [34]. As an example, a liposomal Dox (Doxil/Caelix®) was explored in certain instances of HNSCC [33], [35], [36].

An additional advantage of nanomedicine platforms is their versatility, and the ability to rationally design NPs to overcome sequential biological barriers (e.g. sequestration by the mononuclear phagocytic system, MDR), which have been shown to limit the efficacy of NP-based drug delivery [20], [24], [26], [31]. Indeed, the first NPs developed were able to accumulate in tumors passively through the enhanced permeability and retention effect (EPR, Fig. 1) [37]. This is owed to the fact that tumor vasculature is characterized by the presence of larger endothelial fenestrations than normal endothelium, allowing for passive extravasation of NPs. However, the difference of EPR between different types of cancer may affect NP delivery to the tumor and consequently their efficacy [20], [37]. Enhanced tumor targeting was obtained in second-generation NPs with the addition of components for active targeting (e.g. monoclonal antibodies) and stimulus-responsive release (e.g. pH-or hypoxia sensitive) (Fig. 1) [20], [24], [25], [31], [32], [38], [39]. However, none of the NPs are capable of evading the multiple biological barriers to NP drug delivery, and none of these are FDA and/or EMA approved [20], [24], [26], [31], [32]. Third-generation NPs (MSVs) consist of multistage nanovectors (MSVs). MSVs consist of first stage mesoporous silicon particles (S1MPs) and second stage-NPs embedded within nanopores (Fig. 1). Following IV administration, S1MPs are able to interact with the endothelium, allowing for release of second-stage NPs directly into the tumor interstitium [24], [39], [40].

The aim of the present review is to summarize the current preclinical research in the field of NP-based drug delivery for OSCC therapy. Future perspectives and therapeutic strategies are also suggested.