Nanotechnology-based inhalation treatments for lung cancer: state of the art

Figures & data

Table 1 Examples of different nanoparticles investigated as targeted anticancer therapeutic carrier for inhalation treatment in lung cancer

Nanomedicines	Chemotherapeutics	In vitro/in vivo model	Remarks	References
Polymeric micelles	Paclitaxel	Male Sprague Dawley rats	Prolonged activity in the lungs and reduced systemic toxicity. AUC0–12 in lungs was 45 times greater than iv-administered formulation. The targeting efficiency to lungs through the pulmonary route was 132-fold higher than the iv route	^Citation27
Liposomes	Paclitaxel and cyclosporine A	Female BALB/c mice; Renca lung metastases mouse model	Targeted combinational drug delivery through liposomes showed excellent antitumor effect	77
Dendrimers	Doxorubicin	Male Sprague Dawley rats, female F344 rats, MAT 13762 IIIB rat model	Pulmonary administration of drug reduced the lung tumor burden by 95% as compared to control. The number of metastatic foci in the lungs was also reduced significantly	^Citation42
Polymer-drug conjugates	Cisplatin	Female Sprague Dawley rats, A549 cell line	Compared to conventional iv infusion, inhalational administration of the hyaluronan–cisplatin conjugate showed higher drug accumulations in the lung tissues	^Citation33
Magnetic nanoparticles	Quercetin	Female BALB/c mice, A549 cell line	Actively targeted to specific lung cancerous cells, the drug-loaded PLGA-MNPs considerably decreased the number of viable A549 cells	^Citation45
NLC	Cxb	BALB/c mice; A549 orthotopic lung cancer model	Cxb-NLC nebulization showed ~4 times greater AUC of Cxb in lung tissues as compared to the drug solution. Lung residence time also improved significantly	^Citation40
Solid lipid nanoparticles	Paclitaxel	B6D2F1 female mice, MXT-B2 cell model	Sustained drug release. Inhalational treatment was more efficient in reducing the number and size of lung metastases when compared to iv delivery of same drug	^Citation35
	Epirubicin	Male Sprague Dawley rats, A549 cell line	Higher cytotoxicity was observed with SLN as compared to that of drug solution. The respirable fraction of SLNs could reach 78.46% and remained stable during nebulization	^Citation37
	Doxorubicin	BALB/c mouse model, NCL-H460 cell line	Inhalable doxorubicin nanoparticle powders increased the survival time of cancer bearing mice compared to iv administration of the same drug dose with lesser cardiotoxicity	^Citation9
Polymeric nanoparticles	Telmisartan and losartan	Nu/nu mice, A549 orthotopic and metastatic tumor models, A549 and H1650 cell line	Increased penetration and uniform intratumoral distribution of fluorescent polystyrene nanoparticles. Inhalation delivery (alternative days) of formulation shows significant reduction in the lung tumor weights compared to vehicle-treated control groups. Significant reduction in the VEGF levels in tumor homogenates was observed	^Citation30
	Doxorubicin and Cisplatin	NCR nude mice, orthotopic model, A549 cell line	Drugs are actively targeted to specific moiety of lung cancerous cells. Approximately 73% of mesoporous nanoparticles was retained in the lungs after inhalation administration, which was 14.6 times higher when compared to iv injection	^Citation49
	NeutrAvidin^FITC	SCID mice model, A549 cell line	The entrance efficiency of nanoparticles in lung adenocarcinoma cells (A549) was increased as compared to that in the normal fibroblast cells (HFL1) and lung squamous cells (H520). The formulation shows dose-dependent cytotoxicity	^Citation51
	NeutrAvidin^FITC	BALB/cAnN.Cg-Foxn1^nu/CrlNarl mice model; A549 cell line	Gelatin nanoparticles modified with EGF (GP–Av–bEGF) could trap by EGFR-overexpression cancer cells, resulting in a greater degree of accumulation in the cancerous lung tissue. Nanoparticles delivered by inhalation do not cause lung inflammation and are thus safe for use	^Citation12
	Cisplatin	SCID mice in subcutaneous cancer model, metastatic lung cancer model, A549 cell line	Inhalational treatment with GP–Pt–bEGF showed that the Pt concentration was twofold higher in A549 tumor cells than in the HFL1 cells. The IC50 values for GP–Pt–bEGF were twofold lower than CDDP for the A549 cells. Moreover, GP–Pt–bEGF had stronger antitumor activity and was less nephrotoxic than free CDDP and GP–Pt in a subcutaneous model	^Citation52

Abbreviations: AUC_0–12, area under the plasma concentration–time curve from 0 to 12 hours; CDDP, cis-diamminedichloroplatinum; Cxb, Celecoxib; GP–Pt–bEGF, CDDP integrated with gelatin nanoparticles were combined with biotinylated epidermal growth factor; GP–Pt–bEGF, gelatin nanoparticles implanted with NeutrAvidin^FITC and bEGF; IC₅₀, half maximal inhibitory concentration; iv, intravenous; NLC, nanostructured lipid carriers; PLGA-MNP, poly(lactic-co-glycolic acid) coated magnetic nanoparticles; SCID, severe combined immunodeficiency; SLN, solid lipid nanoparticles; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; HFL, human lung fibroblasts.

Figure 1 Organs exposure and toxicity associated with inhalational NPs.

Note: The figure indicates that such NPs can accumulate into the lungs for a very long time and may also enter into the systemic circulation and subsequently reach the other vital organs through blood flow.
Abbreviation: NP, nanoparticle.

GillKKNazzalSKaddoumiAPaclitaxel loaded PEG5000–DSPE micelles as pulmonary delivery platform: formulation characterization, tissue distribution, plasma pharmacokinetics, and toxicological evaluationEur J Pharm Biopharm20117927628421575719

 PubMed Web of Science ®Google Scholar

KaminskasLMMcLeodVMRyanGMPulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapyJ Control Release2014183182624637466

 PubMed Web of Science ®Google Scholar

XieYAillonKLCaiSPulmonary delivery of cisplatin–hyaluronan conjugates via endotracheal instillation for the treatment of lung cancerInt J Pharm201039215616320363303

 PubMed Web of Science ®Google Scholar

VermaNKStauntonKCSattiAMagnetic core-shell nanoparticles for drug delivery by nebulizationJ Nanobiotechnology201311123343139

 PubMed Web of Science ®Google Scholar

PatlollaRRChouguleMPatelARJacksonTTataPNSinghMFormulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriersJ Control Release201014423324120153385

 PubMed Web of Science ®Google Scholar

VideiraMAlmeidaAJFabraAPreclinical evaluation of a pulmonary delivered paclitaxel loaded lipid nanocarrier antitumor effectNanomedicine201281208121522206945

 PubMed Web of Science ®Google Scholar

HuLDJiaYDingWPreparation and characterization of solid lipid nanoparticles loaded with epirubicin for pulmonary deliveryPharmazie20106558558720824958

 PubMed Web of Science ®Google Scholar

RoaWHAzarmiSAl-HallakMHInhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse modelJ Control Release2011150495521059378

 PubMed Web of Science ®Google Scholar

GoduguCPatelARDoddapaneniRMarepallySJacksonTSinghMInhalation delivery of Telmisartan enhances intratumoral distribution of nanoparticles in lung cancer modelsJ Control Release2013172869523838154

 PubMed Web of Science ®Google Scholar

TaratulaOGarbuzenkoOBChenAMMinkoTInnovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNAJ Drug Target2011191090091421981718

 PubMed Web of Science ®Google Scholar

TsengCLWangTWDongGCDevelopment of gelatin nanoparticles with biotinylated EGF conjugation for lung cancer targetingBiomaterials2007283996400517570484

 PubMed Web of Science ®Google Scholar

TsengCLWuSYWangWHTargeting efficiency and biodistribution of biotinylated-EGF-conjugated gelatin nanoparticles administered via aerosol delivery in nude mice with lung cancerBiomaterials2008293014302218436301

 PubMed Web of Science ®Google Scholar

TsengCLSuWYYenKCYangKC,LinFHThe use of biotinylated-EGF-modified gelatin nanoparticle carrier to enhance cisplatin accumulation in cancerous lungs via inhalationBiomaterials2009303476348519345990

 PubMed Web of Science ®Google Scholar