Inhaled chemotherapy in lung cancer: future concept of nanomedicine

Figures & data

Table 1 Efficiency enhancement mechanisms

Liposome composition (neutral or anionic lipids)

Phosphatidylcholines (lecithins)

Phosphatidylethanolamines Sphingomyelins

Phosphatidylserines

Phosphatidylglycerols

Phosphatidylinositols

Microparticles

Polylactic acid

Polylactic-co-glycolic acid

Sodium hyaluronate

Calcium phosphate-polyethylene glycol particles

Oligosaccharide derivatives

Oligosaccharide-lipid mix

Lipid-based Pulmosphere

Carbohydrates

Xylitol

Maltitol

Glucose

Sorbitol

Mannitol

Lactose

Cyclodextrins

Pegylation

Biodegradable polymers

Polylactic acid

Oligolactic acid

Mucoadhesive polymer

Bioadhesives

Lectins

Peptides

Antibodies

Heparin

Heparin sulfate

Octa-arginine

Antibodies

Cell-type specific targeting

Alveolar macrophages

Cancer cells

Epidermal growth factor

Folic acid

Low-density lipoprotein

Intracellular targeting

Intracellular trafficking

Endosomal release

Nuclear localization

Figure 1 Encapsulation vehicles.

Figure 2 Transporters and their position where they are most highly expressed.

Abbreviations: P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; MRP, multidrug resistance-associated proteins; PEPT, peptide transporters; OCT, organic cation transporters; OCTN, organic cation transporters electroneutral; OAT, organic anion transporters; OATP, organic anion transporting proteins.

Table 2 Published studies with inhaled chemotherapy regimens and study investigated parameters

Author	Inhaled chemo	Main adverse effects	Synthesis	FEV1	FVC	DLCO	6MIN	TLC	Evaluation	Subjects	Inhalation device	Protection	Reference
Zarogoulidis et al^Citation29	CARBO	Cough	–	√	√	√	√	–	Thorax HRCT, RECIST, Blood samples	Human	Nebulizer	HEPA	^Citation30
Tatsumura et al^Citation31	5-FU	Glottitis	–	–	–	–	–	–	Radiological, blood samples	Human	Supersonic Nebulizer	Protected room	^Citation31
Tatsumura et al^Citation32	5-FU	–	–	–	–	–	–		Bronchoscopy, HPLC, histopathology, blood samples	Human	Nebulizer	Protected room	^Citation32
Wattenberg et al^Citation54	5-FU	Weight loss	–	–	–	–	–	–	Histopathological	Animal	Nebulizer	Hood	^Citation54
Hitzman et al^Citation60	5-FU	–	Lipid-coated nanoparticles	–	–	–	–	–	HPLC, blood samples	Animal	Ultrasonic Atomizer	Plexiglass chamber	^Citation60
Hitzman et al^Citation60	5-FU	–	Lipid-coated nanoparticles	–	–	–	–	–	HPLC, blood samples	In vitro Animal	Ultrasonic Atomizer	Plexiglass chamber	^Citation230
Hitzman et al^Citation60	5-FU	–	Liposomes, microspheres, Lipid-coated nanoparticles	–	–	–	–	–	Microdialysis	–	–	–	^Citation231
Hershey et al^Citation34	PTX DOX	Cough, upper airway toxicity, pneumonitis/fibrosis	PEG	–	–	–	–	–	Chest x-ray V/Q, blood samples	Animal	Nebulizer	Controlled environment	^Citation34
Koshkina et al^Citation35	9-NX PTX	–	Liposome	–	–	–	–	–	HPLC, histopathological, blood samples	Animal	Nebulizer	Plastic cage	^Citation82
Koshkina et al^Citation35	PTX	Neurological toxicity, aggressiveness	Liposome	–	–	–	–	–	HPLC, histopathological	Animal	Nebulizer	Plastic cage	^Citation50
Knight et al^Citation55	PTX CYS A	Weight loss	Liposome	–	–	–	–	–	HPLC, histological	Animal	Nebulizer	Sealed plastic cage	^Citation55
Hureaux et al^Citation48	PTX	–	Lipid nanocapsules	–	–	–	–	–	V/Q, HPLC	In vitro	Mesh nebulizer	Controlled environment	^Citation48
El-Gendy et al^Citation58	PTX CIS	–	Nanoparticle loaded	–	–	–	–	–	HPLC, TEM DSC, TGA	In vitro	Manually	–	^Citation58
Anderson et al^Citation49	CIS	–	a-TEA, Liposome	–	–	–	–	–	Histological, HPLC, Ki-67, TUNEL	Animal	Nebulizer	Plastic cage	^Citation49
Wittgen et al^Citation42	CIS	–	Iiposome	–	–	–	–		HEPA filter,	Human	Nebulizer	HEPA	^Citation42
Wittgen et al^Citation42	CIS	Nausea, fatigue, dyspnea, vomiting hoarseness, bronchitis bronchial wall thickening	Liposome	√	√	√	–	–	Blood samples, HRCT	Human	Jet nebulizer	Negative pressure room Protective clothing equipment	^Citation53
Selting et al^Citation41	CIS	Cough, pneumonitis, fibrotic lesions	–	–	–	–	–	–	Blood samples, chest x-ray, histopathological urine analysis	Animal	Nebulizer	Intracorporal catheter	^Citation41
Tseng et al^Citation45	CIS	Weight loss	Biotinylated EGF gelatin	–	–	–	–	–	Blood samples, histopathological	Animal, In vitro	Nebulizer	–	^Citation45
Gagnadoux et al^Citation242	GEM	Pulmonary edema	–	–+	–	–	–	–	Chest x-ray, V/Q, histopathological	Animal	Microsprayer	Hood	^Citation242
Koshkina and Kleinerman^Citation62	GEM	–	–	–	–	–	–	–	HPLC, Immunohistochemistry, FasL pathway, histopathological	In vitro Animal	Jet nebulizer	Plastic cage	^Citation62
Gagnadoux et al^Citation241	GEM	–	–	–	–	–	–	–	V/Q, filter system, histological, HPLC	In vitro, Animal	Nebulizer	Inhalation cabin	^Citation241
Min et al^Citation244	GEM	Acute lung injury	–	–	–	–	–	–	Blood samples, TNF, BALF	Animal	Nebulizer	Controlled environment	^Citation244
Lemarie et al^Citation243	GEM	Cough, dyspnea, vomiting, severe bronchospasm	–	–	–	–	–	–	V/Q, blood samples	Human	Nebulizer	Protective chamber	^Citation243
Rodriguez et al^Citation61	GEM	Vascular connective tissue into the airway lumina	–	–	–	–	–	–	Histological, Immunohistochemistry chest x-ray, TUNEL, blood samples, FasL	Animal	Minimate compressor nebulizer	Controlled environment	^Citation61
Azarmi et al^Citation59	DOX	–	Nanoparticle loaded	–	–	–	–	–	XTT CLSM	In vitro	Spray freeze-drying	Hood	^Citation59
Otterson et al^Citation52	DOX	>20% drop in PFTs Necessary steroid use wheezing, chest pain hypoxia	–	√	√	√	–	–	Thorax CT, RECIST, HPLC, V/Q, blood samples	Human	Nebulizer	HEPA	^Citation52
Garbuzenko et al^Citation51	DOX	Alveolar hemorrhage, Peribronchial inflammatory cells	Liposome	–	–	–	–	–	Bioluminescent image, ultrasound, histological	Animal	Nebulizer	Nose only chamber	^Citation51
Otterson et al^Citation37	DOX	> 20% drop in PFTs Necessary steroid use	–	√	√	√	–	–	Thorax CT, RECIST, V/Q	Human	Nebulizer	Controlled environment	^Citation37
Roa et al^Citation47	DOX	Cardiac toxicity, weight loss	Effervescent/noninhalable nanoparticles	–	–	–	–	–	HPLC, MRI, histopathological	Animal	DP-4M insufflator	Controlled environment	^Citation47
Koshkina et al^Citation63	9NC	–	Liposome	–	–	–	–	–	HPLC, histological, Blood samples	Animal	Nebulizer	Plastic cage	^Citation63
Knight et al^Citation240	9NC	–	Liposome	–	–	–	–	–	HPLC, histopathological	Animal	Nebulizer	Plastic cage	^Citation240
Verschraegen et al^Citation56	9NC	Bronchitis, pharyngitis, cough	Liposome	√	√	√	–	√	HRCT, blood, BAL, urine analysis	Human	Nebulizer	HEPA	^Citation56
Lawson et al^Citation57	9NC	–	a-TEA, Liposome	–	–	–	–	–	Histological, HPLC, Ki-67, TUNEL, CD31	Animal	Nebulizer	Plastic cage	^Citation57
Lawson et al^Citation238	a-TEA	–	Liposome	–	–	–	–	–	Histopathological, TUNEL	Animal	Nebulizer	Plastic cage	^Citation238
Sharma et al^Citation64	Review	Review	Review	Review	Review	Review	Review	Review	Review	Review	Review	Review	^Citation64
Khanna et al^Citation39	Review	Review	Review	Review	Review	Review	Review	Review	Review	Animal	Review	Review	^Citation39
Gagnadoux et al^Citation40	Review	Review	Review	Review	Review	Review	Review	Review	Review	Review	Review	Review	^Citation40

Abbreviations: DOX, doxorubicin; CIS, cisplatin; PTX, paclitaxel; 9NC, 9-nitro-camptothecin; CARBO, carboplatin; GEM, gemcitabine; 5-FU, 5-fluorouracil; CYS A, cyclosporin; CD31, endothelial antigen also referred to as PECAM1 (platelet-endothelial cell adhesion molecule), is an indicator of small capillaries in primary tumor tissue; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling, is a method for detecting DNA fragmentation by labeling the terminal end of nucleic acids; Ki-67, antigen Ki-67, also known as MKI67, is a protein that in humans is encoded by the MKI67 gene, it is a nuclear protein that is associated with and may be necessary for cellular proliferation; A-TEA, alpha-tocopherol ether analog; HPLC, high-performance liquid chromatography or high-pressure liquid chromatography, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify, and purify the individual components of a mixture; FasL pathway, Fas ligand or CD95 L is a type II transmembrane protein that belongs to the TNF family, its binding with its receptor induces apoptosis, Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer; BALF, bronchoalveolar lavage fluid; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; 6MIN, 6-minute walking test; TLC, total lung capacity; TNF, tumor necrosis factor-alpha is a cytokine involved in systemic inflammation and also stimulates the acute phase reaction; V/Q, ventilation/perfusion ratio; XTT, colorimetric assay for cell proliferation, viability, and cytotoxicity; CLSM, confocal laser scanning microscopy, a technique for obtaining high-resolution optical images with depth selectivity; TEM, transmission electron microscopy, a technique that a beam of electrons is transmitted and converted to a sensor charged coupled device, photographic film or fluorescent screen; DSC, differential scanning calorimetry, a thermoanalytical technique; TGA, thermogravimetric analysis is a type of testing performed on samples that determines changes in weight in relation to change in temperature.

Table 3 Summary of inhaled chemotherapy in lung cancer

Although there is a variety of inhalation devices available on the market, each one with advantages and disadvantages, administration of an inhaled chemotherapy formulation is currently feasible through a nebulization system. The aerosol compound time release can be enhanced by either adding a carrier which provides sustain release, or by adding 5%–7% CO2 to the inhalable aerosol. Aerosol chemotherapy studies previously published provide conclusions with safety and feasibility of this treatment modality. Nevertheless, more trials are needed with patients of early stages to present long term data regarding adverse effects to the lung parenchyma. In addition, more single-agent or double-agent trials for the aerosol are needed to present indisputable data regarding the safety and effectiveness of this treatment modality in comparison with intravenous administration. A question remains whether this treatment modality is proper for early lung cancer stages or as neoadjuvant/adjuvant, since tumor size is a limitation for patients to be candidates. A new methodology of manipulating the aerosol deposition site according to cancer lesions has been proposed and developed, but is still under investigation. Inhaled chemotherapy has been evaluated in a number of studies (high efficiency particulate air system) and the results indicate that certain drug administration systems are efficient enough to eliminate diffuse/spilling of the aerosolized agent to the environment. The next step of aerosol chemotherapy agent administered inhouse has also been tested successfully with proper education and use by patients. Administration of inhaled bronchodilators, corticosteroids, and N-acetylcysteine could prevent and protect the lung parenchyma from adverse effects. The crucial question of whether such a treatment modality should be pursued will remain unanswered if further studies are not performed. The concept of a treatment modality for cancer patients free of systemic side effects is very tempting. This treatment modality in order to have widespread acceptance, solid data regarding the safety and feasibility needs to be pursued.

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