Targeted nanoparticle for head and neck cancers - Wiley Online Library

Overview

Targeted nanoparticle for head and neck cancers: overview and perspectives Yuying Zhao,1,2† Haolin Chen,1,2† Xing Chen,2† Geoffrey Hollett,3 Zhipeng Gu,2* Jun Wu2,4* and Xiqiang Liu1* Head and neck cancer (HNC) is common in several regions and is associated with high morbidity and mortality worldwide. This review summarizes the recent progress in the development of targeted nanoparticle systems for HNC therapy. © 2017 Wiley Periodicals, Inc. How to cite this article:

WIREs Nanomed Nanobiotechnol 2017, e1469. doi: 10.1002/wnan.1469

INTRODUCTION

H

ead and neck cancer (HNC) refers to malignant neoplasms that develop in the oral cavity, larynx, pharynx and thyroid. As shown in Figure 1, an estimated 842,000 new cases of HNC arose in 2012, accounting for 11.9% of cancers worldwide. In the same year, there were 319,300 deaths due to HNC, accounting for 4.5% of all cancers.1,2 HNC patients regularly have been reported to have dysphagia, respiratory disorders, xerostomia and other symptoms, which will be worse due to the lack of appetite, weight loss, and nutritional deficiency.3 Tobacco and alcohol consumption were found to be the biggest culprit of squamous cell carcinoma of the head and neck (HNSCC) by numerous epidemiologic studies, along with areca chewing, mate drinking and so †

These authors contribute equally to this work.

*Correspondence to: [email protected], wujun29@mail. sysu.edu.cn, [email protected] 1

Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR China

2

Key Laboratory of Sensing Technology and Biomedical Instrument of Guangdong Province, School of Engineering, Sun Yat-sen University, Guangzhou, PR China

3

Materials Science and Engineering Program, University of California San Diego, La Jolla, CA, USA

4

Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou, PR China Conflict of interest: The authors have declared no conflicts of interest for this article.

on.4,5 In the past few decades, human papillomavirus (HPV) (particularly HPV16 and HPV18) infection has led to a new type of HNC patient who is young and does not drink nor smoke.6,7 HPV infection is common in cervical carcinoma via sexual contact. As a result of changes in sexual intercourse, it is predicted that by 2020, more than half of HPV associated patients are HNC sufferers, significantly surpassing the number of cervical carcinoma.6,8,9 Compared with HPV-negative patients, HPV-positive patients have improved treatment outcomes. For example, two-year survival rates of oropharynx cancer for HPV-positive and HPV-negative patients are 95% and 62%, respectively, and 79% and 46%, respectively after five years.7,10,11 The accurate diagnosis and standardized classification of the extent of a cancer is significantly important to plan viable therapeutic regimens by referring to prior cases with a similar prognosis. The tumor node metastasis (TNM) cancer staging system is the most commonly used classification that considers the local tumor growth degree, the spread to regional lymph nodes and the other organ metastases. HNC can take place in a number of regions including the lip and oral cavity, nasopharynx, oropharynx, hypopharynx, supraglottis, glottis, subglottis, maxillary sinus, nasal cavity and ethmoid sinus and thyroid (Figure 2). They all have unique cancer grading standards according to the 8th Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual which is published in cooperation with the International Union for Cancer Control. Herein we summarize the classification of HNC from

© 2017 Wiley Periodicals, Inc.

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Overview

wires.wiley.com/nanomed

The incidence is higher in male

842,000 New cases of head and neck cancer

319,300 Death toll of head and neck cancer

Tobacco

Alcohol OLD

11.9%

CAUSING CULPRITS

4.5%

NEW

Incidence rate of all cancers

It is predicted that by 2020, more than half of HPV associated patients are HNC, surpassing the cervical cancer patients.

Death rate of all cancers

HPV infection

FI GU RE 1 | Head and neck cancer statistics worldwide. stage 0 to stage IV.12 Stage 0, tumors have definite shapes and clearly separate from the surrounding normal tissues, no invasion or metastasis. Stage I, tumors retain its shape with less than 2 cm in diameter, have not push through the submucosa. Stage II, cancer cells push through or between adjacent normal cells and the diameter of tumor is between 2 cm and 4 cm. Stage III, cancer cells rapidly divide and multiply, extend to the local lymph nodes, the size of the tumor is more than 4 cm. Stage IV, cancer cells get into the bloodstream to other regions, results in metastases. As mentioned above, HNC is a complex and difficult disease that can easily infiltrate surrounding systems and induce metastasis. In the clinic, they are usually treated by surgery, radiotherapy and chemotherapy. The intractable threats to HNC patients are cancer recurrence and metastasis. Scattered

Oral cavity Tonsil Posterior pharynx Base of tongue

F I G U R E 2 | Anatomic subsites of some common primary sites of HNC.

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distribution of chemotherapeutic drugs in the body greatly restricts the application of chemotherapy. The arising applications of nanotechnologies in biomedicine provide new opportunities for dealing with the problems of drugs used in cancer treatments.13–17 Nanoparticle (NP) drug carriers can be composed of polymers, liposomes, dendrimers, carbon, and other metal or metal oxides.18–26 The size of the NPs used in chemotherapy is typically between 1 nm and 200 nm to ensure that they can be took by tumor cells effectively.27,28 The preferential uptake of drug-containing NPs into tumor cells is highly desirable for suppressing systemic side effects, but only if it can be controlled.29–33 Targeted NP delivery systems can be divided into two mechanisms: passive and active targeting. Passive targeting is based on the enhanced permeability and retention (EPR) effect, in which the poorly formed, leaky vasculature of the tumor site causes drug-loaded NPs to accumulate locally. However, the main limitation of passive targeting is insufficient drug concentration at the tumor site. In contrast, NPs decorated with tumor specific targeting moieties participate in active targeting. Specific ligands allow for the particle to interact more strongly with specific cell types, thus allowing for NPs to deliver a payload directly to a tumor cell with minimal drug leeching into general circulation. This carrier strategy maximizes the drug concentration inside the tumor, meaning that a lower overall dose can be administered to the patient while maintaining therapeutic efficacy.19,34–36 Active targeting NPs have shown tremendous promise as drug delivery systems and are presently being pursued as chemotherapy carriers in all types of cancers.26,37 The successfully design and widely use of targeted NPs are usually governed by the selected coupling reaction.38–40 Herein we describe the current status of targeted NPs applied to chemotherapy of


WIREs Nanomedicine and Nanobiotechnology

Targeted nanoparticle for head and neck cancers

HNC and discuss their potential future clinical application.

CURRENT ADJUVANT CHEMOTHERAPY AGAINST HNC For early stage HNC patients, surgical resection is the ideal treatment option. But for the patients in terminal stages, a combined comprehensive, multimodality of treatment is advocated instead of surgical resection. The use of chemotherapy can be divided into three techniques: induction chemotherapy, synchronous chemotherapy and adjuvant chemotherapy. Induction chemotherapy, also called neoadjuvant chemotherapy is used before surgery to reduce the volume of tumors to improve surgical outcomes. Synchronous chemotherapy is aimed to enhance the efficiency of radiotherapy, while simultaneously reducing the risk of lymph node metastasis. The purpose of adjuvant chemotherapy is to kill the small lesions that cannot be removed by surgery or reduce recurrence and improve survival rate. In recent years, the drugs fluorouracil (5-FU), methotrexate (MTX), bleomycin, mitomycin C, hydroxyurea, cisplatin and carboplatin were employed in the research of HNC therapeutic treatment.17,41 From the current literature, platinum-5-FU chemotherapy is regarded as the backbone of the current standard treatment. The platinum-5-FU chemotherapy system was first utilized by the Southwest

Oncology Group (SWOG) who compared the efficacy of cisplatin with 5-FU, caboplatin with 5-FU, and single-agent MTX in HNC patients who were suffering the recurrence and metastasis. The study reported complete and partial response rates is 32% for cisplatin/5-FU, 21% for carboplatin/5-FU, and 10% for MTX, although the median survival rate in those three treatment plans are the same. It should be noted that despite the highest response rate, the cisplatin/5FU group reported higher incidences of systemic side effects.42 At the same time in 2004, European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) published its trails about the treatment of HNC patients. RTOG 9501 conducted a random experiment of HNC patients treat after surgery resection. The group treated with radiotherapy plus cisplatin [100 mg per square meter of body-surface area intravenously (I.V.) on day 1, 22, and 43] gained high two-year survival rate and disease-free survival rate than the group received radiotherapy alone.43 EORTC 22931 conducted almost the same trails except some parameter differences, also showed a significant benefit of overall survival for radiotherapy plus cisplatin group.44 These two landmark trails established the role of chemotherapy. Currently, the molecularly targeted agent, cetuximab, is also expected to play a significant role in the future treatment of HNC (Figure 3). The emerging of new therapeutic drugs and developing of chemotherapy pave the way to improve the treatment effect of HNC.

Cetuximab or lapatinib

Radiotherapy alone Original ajuvant therapy

He

ad

Induction chemotherapy

er

Antibody against EGFR

a n d n eck ca

nc

Docetaxel, cisplatin plus 5-fluorouracil

Chemoradiotherapy

Cisplatin plus radiotherapy

FI GU RE 3 | Illustration of adjuvant therapy of HNC. Radiotherapy was the standard treatment care for resectable HNC. While now cisplatin plus radiotherapy is the mainstay of HNC. Docetaxel, cisplatin plus 5-fluorouracil (TPF) is the standard regimen for induction chemotherapy. Cetuximab/lapatinib is the monoclonal antibody against the ligand binding domain of EGFR.


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Overview


NANOPARTICLES IN HNC THERAPY Materials Requirements for HNC Therapy

C

O

NH

O

C

H

O

O

NH

CO

C

C

HOOC

NH

NH

HOOC

O

H N

Emerging nanotechnologies offer new pathways of biomedical applications for cancer diagnosis and therapy.45–49 NP-based delivery vehicles with precise control of size, shape, and surface functionalization are providing new avenues to carry multiple diagnostic and/or therapeutic agents for better outcomes and fewer side effects. Taking advantage of the unique properties of materials at the nanoscale, such as large surface area to volume ratio, novel optical and magnetic properties, facile modification, nanomaterials have been explored to overcome a lot of biological barriers to cancer treatment (Figure 4).20,28,50,51 However, before employed in the cancer therapy, nanomaterials are required to have excellent biocompatibility, well biodegradation and low toxicity. Furthermore, nanomaterials must have the ability to load sufficient drugs and accurately deliver to the tumor sites. For these application qualifications, various materials are exploited including polymers, liposomes, dendrimers, carbon, and other metal or metal oxides. Herein we choose some representative examples to have an overview of nanomaterials used in HNC therapy.

O

C

C

O CO

HOOC

H N

O

C

H

O

H

C

N

O

O

N

C

H

C

HN

O

HN OC

HO

PEG

Amphiphilic block polymer

EGFR vIIIAb

F I G U R E 4 | Illustration of nanoparticles modified with targeted groups. EGFR vIIIAb was attached on surface of Amphiphilic block polymer nanoparticles for specific targeting to the tumor site.

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In the area of HNC research, the novel physiochemical properties of gold NPs, such as localized surface plasmon resonance (LSPR), enhanced light scattering, and photo-thermal and photo-acoustic properties52,53 have generated significant attention for developing diagnostic platforms and effective treatments in HNC.54–57 Similarly, carbon-based nanovectors were used to load paclitaxel, which was selected as a classic example of a water insoluble drug with high therapeutic efficacy and severe off-target toxicity. At the same time, the molecularly targeted agent cetuximab combined has yielded synergistic effects, deserving of further preclinical development for HNC therapy.58,59 Bhirde reported that carbon nanotubebased drug delivery system holds great promise for cancer therapy. They reported in vivo targeted cancer treatment by attaching the anticancer agent cisplatin along with epidermal growth factor (EGF) to a single wall carbon nanotube (SWNT) (Figure 5).60 Induced hyperthermia via magnetic iron oxide (IO) NP (~15 nm in diameter) was explored for treatment of HNC using a mouse xenograft model of HNSCC cell line (Tu212). IO NPs generate hyperthermia using alternating magnetic fields for cell killing, providing a new option to the existing HNC treatment approaches.61 Xie et al. developed a folateconjugated cisplatin-loaded magnetic nanomedicine (CDDP-FA-ASA-MNP) and used it as a magnetic resonance imaging (MRI) contrast agent while simultaneously delivering a chemotherapeutic drug, providing an alternative platform for drug delivery in HNSCC patients and lays the foundation for molecular targeted treatment of cancer.62 Carboxyl functionalized IO NPs conjugated with a fibronectin-mimetic peptide (Fmp) were combined with a second-generation photodynamic therapy (PDT) drug (Pc), showing obviously inhibition of tumor growth at lower dose, which showed great potential to serve as both MRI agent and PDT drug in the clinic (Figure 6).63 Polymeric NPs were also used for delivering medicinal drugs and bioactive molecules showing significant therapeutic value. Matthew S. Brown used sub–50-nm tenfibgen nanocapsules to deliver antiCK2α/α0 oligodeoxynucleotide, showing significant suppression of tumor growth, CK2 effects on NFκB–mediated and TP53-mediated signal activation with corresponding gene and protein expression in vivo.64 Diblock copolymers were used to effectively deliver small interfering RNAs (siRNA) targeting a proapoptotic gene and proved to be effective in conferring radioprotection to the salivary glands.65 Colley proved the ability of pH-sensitive poly 2-




(a) 2N

Pt

NH

Pt

O

NH2

O

NH

O

2

Pt

CI

CI HN 2 Pt NH

O

Pt

NH2

CI

O NH2

O O

2

O O

CI

O

CI

NH2

Pt

CI

NH2

O

O

N

H

2

CI

O

O

OH

O

O

Pt

NH2

N

O

O

O

OH

OH

O

NH2

Pt

O

OH

2N

Pt

Pt

O

H

O

OH

EGF, Qdot

O

Pt

O

NH

EDC

NH2

O

2

CI

H

2N

Pt

O

NH2

CI

O

Pt

NH2

O

NH

O

2

O O

CI

Pt

H

2

O

O

Qdot

NH2

Pt

O NH2

N

DDS: SWNT+Cispiatin+EGF

Cancer cell surface

O

2

CI

2N

CI

O

O

NH

H

CI

H2N

CI

H

O

O

NH2

O

2

DDS

NH2

Pt

O NH2

O

O

Pt

CI

O

Pt

CI

O

NH

NH2

Pt

OH

2N

2N

NH2 O

CI

OH

O

CI

H

O

2

H

O

2

O

Pt

NH

EGF, Cispiatin O

NH

NH2

Pt

O

2

2N

Pt

H

H

O

2

CI

EDC

O

2N

CI

O

H2N

CI

H

Pt

O

(b)

NH2

H2N

CI

H

CI

NH2

Pt

CI

EGF: Epidermal growth factor

EGFR: Epidermal growth factor receptor

FI GU RE 5 | Nanotube-based delivery system. (a) Illustration of modified the carboxylated SWNTs (in green) surface with EGF, cisplatin, and Qdots. (b) Schematic presenting the SWNT bundles bioconjugated with EGF and cisplatin recognized by the receptor EGFR on a HNSCC cell surface. (methacryloyloxy) ethyl phosphorylcholine (PMPC)poly 2-(diisopropyl-amino) ethyl methacrylate (PDPA) polymersomes to encapsulate chemotherapeutic agents (doxorubicin and paclitaxel) for effective combination anticancer therapy. The uptake and ability to deliver encapsulated drugs via polymersomes were measured in two and three- dimensional culture systems (Figure 7).66 Wang evaluated the effectiveness of poly (lactic-co-glycolic acid) (PLGA)

NPs assisted 5-aminolevulinic acid (ALA) delivery for topical PDT of cutaneous SCC.67 Changa et al. conjugated the anticancer drug mitoxantrone (MTO) to palmitoleic acid, generating two types of palmitoleyl MTO (Pal-MTO) lipids: monopalmitoleyl MTO (mono- Pal-MTO) and dipalmitoleyl MTO (di-Pal-MTO) at the molar ratio of 1:1 (md11-Pal-MTO NPs) showed the most efficient cellular delivery of siRNA.68 Yu et al. formulated

NH 2 NH 2

NH 2

O

C

C

OH

O

O

C

C

O

OH

O

C

C

O

C O

NH2

C

O O

C

C

C

C

NH2

NH2

C

O

O

C

O C

O C OH

O

O C O H

O H

OH

H

O

O

NH

2

O

C

O

OH

NH2

Nano core

C

C

FMP-IO

O

O C

O C

O

IO

OH

O C

C

OH

O

FMP-IO-PC4

FMP

PC4

FI GU RE 6 | Schematic illustration of the preparation of water-soluble FMP-IO-PC4 nanoparticles which can serve as both a MRI agent and PDT drug.


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F I G U R E 7 | pH-sensitive poly 2-(methacryloyloxy) ethyl phosphorylcholine (PMPC)- poly 2-(diisopropylamino) ethyl methacrylate (PDPA) polymersomes used as drug delivery vehicles for effective combinational anticancer therapy. 1,2-dioleoyl-sn-glycero-3-ethylphos-phocholine-based cationic solid lipid nanoparticles (cSLN) containing paclitaxel and siRNA, which demonstrated the potential of cSLN for the development of co-delivery systems of lipophilic anticancer drugs and therapeutic siRNAs (Figure 8).69 Piao et al. determined the cationic lipid NPs could deliver pre-miR-107 (NP/premiR-107) with excellent efficiency (Table 1).70

Nanostructure Requirements for HNC Therapy A broad spectrum of innovative nanostructure has been developed recently for addressing various challenges in HNC, such as polymers, peptides, liposomes, dendrimers, albumin conjugates and so on.71–74 These materials are obviously vary in

Cationic lipid

PEG-DSPE

morphologies and structures. From two-dimensional nanostructures to three-dimensional nanospheres, from positive charge to negative charge of the surface, materials can present different properties. Ideal materials for HNC cancer therapy are desired to be flexible to change its sizes, morphologies, surface properties and so forth. Rait et al. improved the antisense HER-2 oligonucleotide (AS HER-2 ODN) delivery to tumor cells by complexing the AS HER-2 ODN with their previously established folate-liposome delivery system, which resulting in sensitization of HNC cells to chemotherapeutic agents.75 Matthew S. Gayong Shim et al. synthesized trilysinoyl oleylamide (TLO)-based liposomes (TLOL) for systemic siRNA and drug delivery.76 Zhu et al. chose a polymer family equipped with cationic and hydrophobic characters

siRNA

Paclitaxel

F I G U R E 8 | Illustration of the cSLN nanoparticles loaded with paclitaxel and siRNA. EcSLN (a) and PcSLN (b) were used as co-delivery system of lipophilic anticancer drug and therapeutic siRNAs.

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TABLE 1 | An Overview of Various Nanomaterial-based Platforms in Head and Neck Cancer Treatment Nano-platform

Treatment

Targeting Moiety Application

Ref.

Gold

Diagnosis, Photodynamic therapy, Photothermal therapy

EGFR

Optical imaging, targeted therapy

52–57

Carbon

Drug delivery vehicle

Cetuximab

Targeted drug delivery

58,59

SWNTs

Drug delivery vehicle

EGFR

Targeted drug delivery

60

Magnetic

Hyperthermia therapy, Photodynamic Therapy,

Folate receptors, integrin β1

Magnetic resonance imaging, Targeted therapy

61–63

Polymeric Gene therapy, Photodynamic therapy nanoparticles (NPs)

RNA, Salivary receptors

Targeted delivery, Radioprotection using small-interfering RNA (siRNA)-based gene silencing

64–67

Lipid

RNA

Genetic vector

68–70

Gene delivery

to prepare a novel NP which can decorate with protein ligands outside and carry therapeutic proteins inside the particle.21 Ward et al. used a G5 polyamidoamine dendrimer conjugated to the targeting moiety folic acid (FA) for targeted chemotherapy.77 Dosio et al.78 conjugated the anticancer agent paclitaxel to human serum albumin (HSA) to form drug– albumin conjugate and then decorated with FA, which demonstrated increased selectivity and antitumoral activity.

TARGETED NANOPARTICLES DELIVERY FOR HNC THERAPY Targeted Delivery Strategy for HNC Therapy Passive diffusion is the major internalization mechanism of free drugs into tumor cells, whereas NPs enter cells primarily via endocytosis, avoiding the drug refluxing back out of the cell.79 Controlling the particle–cell interaction is one of the most important reasons for NP modification, allowing for targeting ligands such as antibodies and their fragments, nucleic acid strands, peptides and other small molecules.80,81 Epidermal growth factor receptor (EGFR) is often over-expressed in HNSCC cases.82 High levels of EGFR expression are associated with poor prognosis in a variety of cancers, mostly in HNSCC, indicating that receptor directed therapies may be useful as anticancer strategies. He et al. investigated the intratumoral transfer of cationic liposome-mediated antisense EGFR plasmids into HNSCC subcutaneous xenografts through in situ expression of antisense oligonucleotides, which resulted in increased tumor cell apoptosis and inhibition of tumor growth.83 Cho et al. developed a poly-L-arginine (PLR) and dextran sulfate (DEX) based nano-sized polyelectrolyte

complex (nanocomplex) for delivery of epidermal EGFR-siRNA in a HNSCC model. Their experiments showed highest EGFR gene silencing efficiency in both Hep-2 and FaDu cell lines and exhibited excellent tumor growth inhibition in a tumor xenografted mouse model.84 As described above, EGFR can also serve as a target for drug delivery. Ashwin et al. demonstrated that EGF-decorated SWNTs specifically target squamous cancer as a delivery system for cisplatin chemotherapy, which resulted in more rapid cell internalization and distinct regression of tumor growth compared to a nontargeted SWNT-cisplatin.60 Berlin et al. combined paclitaxel-loaded poly(ethylene glycol) functionalized hydrophilic carbon clusters (PEG-HCCs) NPs with cetuximab, a targeting monoclonal antibody that exclusively binds to the EGFR. The targeted nanovector systems have shown high therapeutic efficacy to be a new therapy for HNSCC.58,59 Folate acid receptors (FRs) are glycosylphosphatidylinositol-anchored cell surface receptors with a high affinity for FA, which are overexpressed in a wide range of malignant cancers, such as breast, ovarian, lung, kidney, head and neck and so forth.85 Folate acid is a water-soluble B vitamin, critical for DNA synthesis. FA retains its ability to bind with FRs after conjugation with other structures, and often improves endocytosis through the FR-mediated pathway. As such, the FR pathway has been studied extensively as a target for NP therapeutics.86 Wang et al. synthesized targeted polymeric NPs (HFT-T) loaded with additional paclitaxel, to enhance the antitumor efficacy and selectively recognize the FRpositive HNSCC KB-3-1 cell line in vitro and in vivo. The resulting NP, HFT-T, markedly inhibited tumor growth without showing a resurgence of tumor growth after several weeks treatment.75 Ward et al. fabricated acetylated generation 5 dendrimers conjugated to FA and the therapeutic MTX, then


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Overview


administered to SCID CB-17 mice inoculated with UM-SCC-1, UM-SCC-17B, and UM-SCC-22B cancer cells, showing increased treatment efficacy.77

Administration Routes for HNC Therapy It is the most simple and rapid method to administer chemotherapy drugs into systemic circulation by I.V. route. It is compatible with most hydrophilic chemotherapy agents, ensuring the low risk of infection. However, the I.V. route also has its disadvantages, for example, it is inappropriate for patients to selfadminister and not suitable for most of the hydrophobic anticancer drugs.81,87 Nanomaterials are developed to accurately send the drugs to the tumors by passive (EPR effect) and active targeting. It seems to be the best alternative that poor water solubility drugs loaded in nanomaterials to enhance drugs solubility and bioavailability. One example comes from Wang et al., who has developed a targeted NP platform that combines Pc 4, a second-generation PDT drug, with a cancer targeting ligand and IO NPs. Fmp-IO-Pc 4 administrated by I.V. injection had significantly higher tumor retention than free Pc 4, showing great potential in MRI and PDT in the clinic.63 Piao et al. used the cationic lipid NPs to deliver pre-miR-107 (NP/pre-miR107) in HNSCC cells in vitro and in vivo. The results showed that NP/pre-miR-107 could increase the delivery of miR-107 into HNSCC cells by more than 80,000-fold comparing to free pre-miR-107. NP/premiR-107 was injected I.V. through the tail vein. The results suggested that cationic lipid-based NP delivery of pre-miR-107 could suppress the tumorigenesis of HNSCC efficiently.70 Recently, studies have shown that intraperitoneal (IP) administration can be more valid than administered I.V. for some solid tumors therapy.88–90 Here, Zhao et al. reported an efficient drug delivery system based on a monomeric self-assembled nucleoside nanoparticle (SNNP). Comparing with free 5FU, SNNP loaded with 5-fluoro-uracile (5-FU-SNNP) remarkably retarded the tumor growth and SNNP alleviated the toxic side effects of 5-FU. In this experiment, IP injection was used to evaluate the biosafety of SNNP and Antitumor Efficacy Assay in vivo. The findings suggested that 5-FU has better antitumor efficacy and lower side effects when loaded with SNNP, indicating that SNNP can efficiently act as a promising nanomaterial that may witness wide clinical applications in the future.91 Intratumoral Injection is a kind of local injection, which offering some advantages, such as stabilization of drugs at tumor site, preservation of anticancer activity, controlled and prolonged drug 8 of 13

release and so on.92 Chang et al. has developed new modality of anticancer therapy that combines treatment of anticancer drugs and siRNAs. The anticancer drug-derived lipids formed cationic NPs for siRNA complexation. For siRNA treatment, siGL2 or siMcl-1 complexed to md11-Pal-MTO NP was injected intratumorally, showing the most efficient cellular delivery of siRNA.93 Intraarterial infusion is particularly compatible for regional chemotherapy, which get high drug accumulation in the tumor site.94 The significant advances in vascular radiology techniques and new devices, such as fluoroscopy units and angiographic catheters, have made it possible that intra-arterial chemotherapy more safe and accurate.95,96 However, there still remains the risk of infection and thrombosis.97 Intra-arterial infusion was conducted to study a novel NP albumin-bound paclitaxel about its efficacy and safety of intra-arterial induction chemotherapy. Two to four cycles of albumin-bound paclitaxel NP were infused into the external carotid artery or one of its branches, then, response was evaluated by physical examination, multi-detector computed tomography and also by positron emission tomography. The response rates and tolerability of intraarterial chemotherapy with NP albumin-bound paclitaxel demonstrated that the feasibility and efficacy alone or in combination with other agents in advanced HNSCC.98 Retroductal injection is used by Szilvia Arany. PH-responsive NPs complexed with siRNAs were introduced into mouse submandibular glands (SMG), which induced siRNA-based gene silencing. In this way, this method protects the SG from radiation-induced apoptosis.65

CONCLUSION Currently, nanotechnologies are widely used in numerous aspects of materials. Especially in nanomedicine, nanomaterials are employed for cancer detection and therapy due to its excellent properties. For HNC therapy, nanomaterials have the potential to enhance the efficiency of chemotherapy without increasing toxicities. As shown in Figure 9, current chemotherapeutic agents for HNC treatment are shown to be effective, but it hides some shortcomings, such as failing to accumulate an efficient dose at the tumor site while accumulating the cytotoxic drug in healthy tissues. The application of targeted NPs as drug carriers in HNC is paving the way for chemotherapy to be employed in the treatment of terminal patients, in order to alleviate their pain and prolong their life. This therapeutic regimen has attracted great attention. In recent years,




Past (a)

Present (a)

Future

Evaluate the situation of the patients, plan the treatment protocols. Surgical removal of the tumor is the preferred treatment.

Check the tumor site Based on TNM staging, identify the mode of operation

(a)

Different kinds of therapy were called

Radiotherapy Chemotherapy Immunotherapy

Cancer cell

(b) Tumor

(b)

Adjuvant therapies after the surgery Radiotherapy

Surgery to remove the tumor

Cisplatin

(c)

Mix of docetaxel, cisplatin and 5-fluorouracil

Radio Radiotherapy used as adjuvant treatment

Cetuximab or lapatinib

(b)

Targeted nanoparticles used in chemotherapy

Targeted nanoparticles Accumulated in the tumor site

Controlled release

High efficiency and low toxicity

FI GU RE 9 | The past, present and future of the treatment of head and neck cancer. Past, work includes (a) examining the tumor site and identifying the mode of operation based on TNM staging; (b) surgery to remove the tumor; and (c) use of radiotherapy as adjuvant treatment. Present, on-going treatment consists of (a) examining the tumor site and establishing the operation plan; (b) combining radiotherapy and chemotherapy as adjuvant therapies. Future, promising strategies include (a) combining more kinds of treating strategies to optimize the efficiency; (b) employing targeted nanoparticles to deliver the drug in order to improve drug efficiency and decrease off-target effects. many kinds of materials with nanoscale dimensions have been exploited to use as a targeted delivery system. Although most of targeted NP-based drug delivery systems have not been translated for clinical use, there remains a great promise to cater to the needs of HNC therapy. Future investigations of targeted NP delivery system are developing to be more effective

against cancer while being milder on other tissues. With the continuous research of nanomaterials and development efforts of HNC therapy, we expect nanomaterial based chemotherapy will improve the diagnosis, treatment, and prevention of HNC. Which will further bring tremendous impact on human health in the near future.

ACKNOWLEDGMENTS This work was supported by the Thousand Talents Plan for Young Professionals, National Natural Science Foundation of China (81372885), Guangdong Innovative and Entrepreneurial Research Team Program (2013S086), Guangdong Natural Science Foundation (2014A030312018), Science and Technology Planning Project of Guangdong Province (No. 2016A010103015), and the Major Special Research Collaborative Innovation of Guangzhou (201604020160).

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