Future trends and emerging issues for nanodelivery systems in oral and oropharyngeal cancer

Figures & data

Figure 1 The main mechanisms of internalization in the case of nanoparticles.

Table 1 Characteristics of nanodelivery systems used for drug delivery

Type of nanoparticle	Size	Type of agent used for delivery	Advantages	Disadvantages	Reference(s)
Lipidic nanosystems	~20 nm–1 μm	Amphiphilic drug loading; hydrophilic anticancer drugs and siRNA in the core; hydrophobic cytotoxic agents on membrane surface	Long circulation time in blood; easy modification of surface, size, charge; active targeting carriers; biocompatibility and almost biologically inert; reduced antigenic or toxic reactions	Limited control of drug release; stability and industrial reproducibility issues; difficulties in sterilization; drug-loading capacity low in outer membrane due to limited space; intravenous delivery can lead to complement activation-related pseudoallergy	^Citation33^–^Citation37
Polymeric micelles	20–80 nm	Poorly soluble cytotoxic drugs; hydrophilic drugs	Long circulation times; smallness and uniformity lead to better permeability and distribution	Modification requires additional chemical synthesis steps; insufficient stability in systemic circulation; premature drug leakage	^Citation38,Citation39
Dendrimers	10–100 nm	Different hydrophobic or hydrophilic anticancer drugs	High uniformity; high level of control over their architecture; high drug-loading capacity; multiple functional groups on their surfaces; drug-release profiles customizable by controlled depolymerization processes	Multistep synthesis that increases production costs; higher toxicity rate; uncontrolled drug release with encapsulation	^Citation40
Polymeric nanoparticles	60–300 nm	Cytotoxic drugs can be encapsulated or physically entrapped within a polymeric matrix (nanospheres) or entrapped into a cavity surrounded by a polymeric membrane (nanocapsules)	Controlled and prolonged targeted delivery; high stability; high drug payload; more controlled drug release	Natural polymers like chitosan are too easily biodegradable, not homogeneous, and need purification steps	^Citation16,Citation41,Citation42
Metal	<50–200 nm	Hydrophobic, hydrophilic	Nanoparticles can be readily functionalized with drugs and with probe molecules; unique magnetic properties with the ability for surface functionalization; potential to be produced with near monodispersity; absorbing nanoshells are suitable for hyperthermia-based therapeutics; pure; gold nanoparticles are relatively easy to synthesize and manipulate	Not biodegradable or small enough to be cleared easily; potential accumulation in the body, which may cause long-term toxicity	^Citation43

Figure 2 The main imaging techniques used for the characterizing of nanoparticles: when they are in suspension, following their internalization in cells in vitro imaging, or inside an organism in vivo imaging.

Abbreviations: SPECT, single-photon-emission computed tomography; DLS, dynamic light scattering; PET, positron-emission tomography; MR, magnetic resonance.

Table 2 Use of nanomaterial-based drug-delivery systems in oral cancer

Type of study	Type of nanocarrier	Drug-delivery system	Study model	Reference(s)
In vitro	Polymer-based nanocarriers	PMPC-PDPA polymersomes loaded with doxorubicin and paclitaxel	Normal oral cells and HNSCC cells	^Citation76
		Polymeric nanomicelles to deliver an association of doxorubicin and LY294002 (LY), an autophagy inhibitor	Oral cancer cells	^Citation77
		Cisplatin-loaded polymeric nanomicelles	Four OSCC cell lines	^Citation78
		Polyamidoamine (PMAM) dendrimer mediated short hairpin RNA (shRNA)	Oral cancer cell line	^Citation81
		Ellagic acid-encapsulated chitosan NPs	Human oral cancer cell line (KB)	^Citation51
		CDDP-loaded PLGA-PEG NPs conjugated with NR7 peptide	HN6 cell line	^Citation47
		Chitosan NPs loaded with cupreous complexes	KB cells	^Citation91
		PEG-PEI-Ce6 coupled with Wnt1 siRNA, targeting EMT, invasion, and metastasis	KB cells	^Citation32
		Chitosan-coated PCL NPs loaded with curcumin	SCC9 human OSC cells	^Citation46
	Lipid-based nanocarriers	Curcumin–lipid microemulsions	OSCC cell lines (OSCC4 and OSCC25)	^Citation82
		Transfection with HIF1 decoy ODNs, using the HVJ-liposome method	Oral cancer cell lines	^Citation84
		Solid lipid NPs for delivering unstable and poorly water soluble chemopreventive agents	Oral cancer cell lines	^Citation85
		Nanoemulsion loaded with the proapoptotic lipophilic agent genistein	Human cancer cell lines SCC4 and FaDu	^Citation83
		Lipid–calcium–phosphate NPs loaded with HIF1α siRNA	SCC4 or SAS cells	^Citation100
	Metal-based nanocarriers	XAV939 conjugated with gold NPs	Human OSCC cell line (HSC3)	^Citation86
		Anti-HER2 nanobodies conjugated to gold–silica nanoshells	KB tumor cells	^Citation87
		TiO2 NPs + high-intensity focused ultrasound	Human oral squamous cell line HSC-2	^Citation61
		Dox-loaded silica-coated gold nanoflowers and PTT	Cal27 cells	^Citation88
In vivo	Polymer-based nanocarriers	Naringenin-loaded polymeric NPs	Hamster buccal pouch model of OSCC	^Citation63,Citation89
		Dox-Mtx NPs	Rat OSCC model	^Citation90
		Chitosan NPs loaded with cupreous complexes	BALB/c nude mice with KB tumors	^Citation91
	Lipid-based nanocarriers	^64Cu liposomes	Hamster buccal pouch model of oral dysplasia and SCC	^Citation67
		Boron delivery with liposomes for BNCT	Mouse model of OSCC Hamster cheek-pouch model	^Citation92,Citation97
		Gene delivery in tumor tissue with Bubble liposomes	Mouse model	^Citation98
		^188Re liposomes	Orthotopic human HNSCC tumor-bearing mice (FaDu3R cells)	^Citation62
		Lipid–calcium–phosphate NPs with siVEGFA	Human OSCC, SCC4, and SAS xenograft	^Citation99
		Lipid–calcium–phosphate NPs loaded with HIF1α siRNA	Xenograft mouse	^Citation100
	Metal-based nanocarriers	Combined PDT and PTT with rose Bengal-conjugated gold nanorods	Hamster cheek pouch model of OSCC	^Citation101
		TiO2 NPs + high = intensity focused ultrasound	HSC2 tumor mouse	^Citation61
		Cetuximab gold NPs	A431 mouse cells	^Citation102

Abbreviations: NPs, nanoparticles; PMPC, poly(2-[methacryloyloxy]ethyl phosphorylcholine); PDPA, poly(2-[diisopropylamino]ethyl methacrylate); HNSCC, head and neck squamous cell carcinoma; OSCC, oral squamous cell carcinoma; CDDP, cis-diamminedichloridoplatinum; PLGA, poly(lactic-co-glycolic acid); PEG, polyethylene glycol; PEI, polyethylenimine; EMT, epithelial–mesenchymal transition; PCL, polycaprolactone; ODNs, oligodeoxynucleotides; PTT, photothermal therapy; Dox, doxorubicin; Mtx, methotrexate; BNCT, boron neutron-capture therapy; PDT, photodynamic therapy.

Figure 3 Localization and types of cargo in a liposome.

Notes: Hydrophylic cargo is carried inside the core and the hydrophobic cargo within the membrane. The membrane can be conjugated with molecules for functionalization.

Figure 4 Nanodelivery systems used in oral cancer.

Abbreviation: CuCC, cupreous complex-loaded chitosan.

AkbarzadehARezaei-SadabadyRDavaranSLiposome: classification, preparation, and applicationsNanoscale Res Lett20138110223432972

 PubMed Web of Science ®Google Scholar

Perez-HerreroEFernandez-MedardeAAdvanced targeted therapies in cancer: drug nanocarriers, the future of chemotherapyEur J Pharm Biopharm201593527925813885

 PubMed Web of Science ®Google Scholar

TorchilinVPMicellar nanocarriers: pharmaceutical perspectivesPharm Res200724111617109211

 PubMed Web of Science ®Google Scholar

LuYParkKPolymeric micelles and alternative nanonized delivery vehicles for poorly soluble drugsInt J Pharm2013453119821422944304

 PubMed Web of Science ®Google Scholar

WolinskyJBGrinstaffMWTherapeutic and diagnostic applications of dendrimers for cancer treatmentAdv Drug Deliv Rev20086091037105518448187

 PubMed Web of Science ®Google Scholar

MishraBChaurasiaSDesign of novel chemotherapeutic delivery systems for colon cancer therapy based on oral polymeric nanoparticlesTher Deliv201781294727982736

 PubMedGoogle Scholar

WangXWangYChenZGShinDMAdvances of cancer therapy by nanotechnologyCancer Res Treat200941111119688065

 PubMed Web of Science ®Google Scholar

RaoJPGeckelerKEPolymer nanoparticles: preparation techniques and size-control parametersProg Polym Sci2011367887913

 Web of Science ®Google Scholar

PeerDKarpJMHongSFarokhzadOCMargalitRLangerRNanocarriers as an emerging platform for cancer therapyNat Nanotechnol200721275176018654426

 PubMed Web of Science ®Google Scholar

ColleyHEHearndenVAvila-OliasMPolymersome-mediated delivery of combination anticancer therapy to head and neck cancer cells: 2D and 3D in vitro evaluationMol Pharm20141141176118824533501

 PubMed Web of Science ®Google Scholar

SaiyinWWangDLiLSequential release of autophagy inhibitor and chemotherapeutic drug with polymeric delivery system for oral squamous cell carcinoma therapyMol Pharm20141151662167524666011

 PubMed Web of Science ®Google Scholar

EndoKUenoTKondoSTumor-targeted chemotherapy with the nanopolymer-based drug NC-6004 for oral squamous cell carcinomaCancer Sci2013104336937423216802

 PubMed Web of Science ®Google Scholar

LiuXHuangHWangJDendrimers-delivered short hairpin RNA targeting hTERT inhibits oral cancer cell growth in vitro and in vivoBiochem Pharmacol2011821172321453684

 PubMed Web of Science ®Google Scholar

ArulmozhiVPandianKMirunaliniSEllagic acid encapsulated chitosan nanoparticles for drug delivery system in human oral cancer cell line (KB)Colloids Surf B Biointerfaces201311031332023732810

 PubMed Web of Science ®Google Scholar

WangZQLiuKHuoZJA cell-targeted chemotherapeutic nanomedicine strategy for oral squamous cell carcinoma therapyJ Nanobiotechnology2015136326427800

 PubMedGoogle Scholar

LinMWangDLiuSCupreous complex-loaded chitosan nanoparticles for photothermal therapy and chemotherapy of oral epithelial carcinomaACS Appl Mater Interfaces2015737208012081226339804

 PubMedGoogle Scholar

MaCShiLHuangYNanoparticle delivery of Wnt-1 siRNA enhances photodynamic therapy by inhibiting epithelial-mesenchymal transition for oral cancerBiomater Sci20175349450128070573

 PubMedGoogle Scholar

MazzarinoLLoch-NeckelGBubniakLSCurcumin-loaded chitosan-coated nanoparticles as a new approach for the local treatment of oral cavity cancerJ Nanosci Nanotechnol201515178179126328442

 PubMed Web of Science ®Google Scholar

LinHYThomasJLChenHWShenCMYangWJLeeMHIn vitro suppression of oral squamous cell carcinoma growth by ultrasound-mediated delivery of curcumin microemulsionsInt J Nanomedicine2012794195122393291

 PubMed Web of Science ®Google Scholar

ImaiMIshibashiHNariaiYTransfection of hypoxia-inducible factor-1 decoy oligodeoxynucleotides suppresses expression of vascular endothelial growth factor in oral squamous cell carcinoma cellsJ Oral Pathol Med201241967568122582814

 PubMedGoogle Scholar

HolpuchASHummelGJTongMNanoparticles for local drug delivery to the oral mucosa: proof of principle studiesPharm Res20102771224123620354767

 PubMed Web of Science ®Google Scholar

GavinAPhamJTWangDBrownlowBElbayoumiTALayered nanoemulsions as mucoadhesive buccal systems for controlled delivery of oral cancer therapeuticsInt J Nanomedicine2015101569158425759580

 PubMed Web of Science ®Google Scholar

ChenWHLecarosRLTsengYCHuangLHsuYCNanoparticle delivery of HIF1α siRNA combined with photodynamic therapy as a potential treatment strategy for head-and-neck cancerCancer Lett20153591657425596376

 PubMed Web of Science ®Google Scholar

AfifiMMAustinLAMackeyMAEl-SayedMAXAV939: from a small inhibitor to a potent drug bioconjugate when delivered by gold nanoparticlesBioconjug Chem201425220721524409808

 PubMed Web of Science ®Google Scholar

FekrazadRHakimihaNFarokhiETreatment of oral squamous cell carcinoma using anti-HER2 immunonanoshellsInt J Nanomedicine201162749275522131825

 PubMed Web of Science ®Google Scholar

NejadSMTakahashiHHosseiniHAcute effects of sono-activated photocatalytic titanium dioxide nanoparticles on oral squamous cell carcinomaUltrason Sonochem2016329510127150750

 PubMedGoogle Scholar

SongWZGongJXWangYQGold nanoflowers with mesoporous silica as “nanocarriers” for drug release and photothermal therapy in the treatment of oral cancer using near-infrared (NIR) laser lightJ Nanopart Res201618101

 Google Scholar

KrishnakumarNSulfikkaraliNKManoharanSVenkatachalamPRaman spectroscopic investigation of the chemopreventive response of naringenin and its nanoparticles in DMBA-induced oral carcinogenesisSpectrochim Acta A Mol Biomol Spectrosc201311564865323880406

 PubMed Web of Science ®Google Scholar

SulfikkaraliNKrishnakumarNManoharanSNirmalRMChemopreventive efficacy of naringenin-loaded nanoparticles in 7,12-dimethylbenz(a)anthracene induced experimental oral carcinogenesisPathol Oncol Res201319228729623233294

 PubMed Web of Science ®Google Scholar

AbbasiMMMonfaredanAHamishehkarHSeidiKJahanban-EsfahlanRNovel DOX-MTX nanoparticles improve oral SCC clinical outcome by down regulation of lymph dissemination factor VEGF-C expression in vivo: oral and IV modalitiesAsian Pac J Cancer Prev201415156227623225124602

 PubMedGoogle Scholar

MahakianLMFarwellDGZhangHComparison of PET imaging with 64Cu-liposomes and 18F-FDG in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch model of oral dysplasia and squamous cell carcinomaMol Imaging Biol201416228429224019092

 PubMedGoogle Scholar

KreimannELItoizMELonghinoJBlaumannHCalzettaOSchwintAEBoron neutron capture therapy for the treatment of oral cancer in the hamster cheek pouch modelCancer Res200161248638864211751376

 PubMedGoogle Scholar

HeberEMHawthorneMFKuefferPJTherapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch modelProc Natl Acad Sci U S A201411145160771608125349432

 PubMedGoogle Scholar

SuganoMNegishiYEndo-TakahashiYGene delivery system involving Bubble liposomes and ultrasound for the efficient in vivo delivery of genes into mouse tongue tissueInt J Pharm20124221–233233722100513

 PubMedGoogle Scholar

LinLTChangCYChangCHInvolvement of Let-7 microRNA for the therapeutic effects of rhenium-188-embedded liposomal nanoparticles on orthotopic human head and neck cancer modelOncotarget2016740657826579627588466

 PubMedGoogle Scholar

LecarosRLHuangLLeeTCHsuYCNanoparticle delivered VEGF-A siRNA enhances photodynamic therapy for head and neck cancer treatmentMol Ther201624110611626373346

 PubMed Web of Science ®Google Scholar

WangBWangJHLiuQRose-Bengal-conjugated gold nanorods for in vivo photodynamic and photothermal oral cancer therapiesBiomaterials20143561954196624331707

 PubMedGoogle Scholar

PopovtzerAMizrachiAMotieiMActively targeted gold nanoparticles as novel radiosensitizer agents: an in vivo head and neck cancer modelNanoscale2016852678268526757746

 PubMedGoogle Scholar