Lung cancer can be classified as primary and secondary cancers [Citation1]. The primary lung cancer has the carcinoma cells originated from the lung tissues. The secondary lung cancer is characterized by carcinoma cells contracted through blood or lymphatic system. The lung cancer is histologically divided into small cell lung carcinoma and non-small cell lung carcinoma representing about 96% of lung cancer, mesothelioma, carcinoid, and sarcoma. Small cell lung carcinoma locates in the central area of the lungs mainly in the bronchi. The non-small cell lung carcinoma tends to locate in the peripheral lungs. Globally, lung cancer is the main and second cause of cancer-related death among men and women, respectively, with very low survival rates.
Patients with lung cancer are treated with several therapeutic procedures such as surgery, radiotherapy, chemotherapy, and molecular-targeted therapies. Chemotherapy is usually administered to the patients as neo-adjuvant or adjuvant therapy. It is an essential treatment mode especially in advanced lung cancer where metastasis prevails. Gene therapy has been the recent focus of research [Citation2,Citation3]. Small interfering ribonucleic acid (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA) are examples of RNAi-based therapeutics that can either be delivered through systemic administration or local administration to negate the expression of intended gene and cancer. The delivery of RNAi-based therapeutics through systemic administration may bring about adverse effects such as liver toxicity, therapeutic instability, and stimulation of immune response. Pulmonary administration of RNAi-based therapeutics is deemed to be a better delivery approach in targeting the cancer tissue [Citation4].
The United States Food and Drug Administration (US FDA) stated two ‘points to consider’ in defining an FDA-regulated nanoproduct. First, the material or end product is engineered to have at least one external dimension or an internal or surface structure, in the nanoscale ranges approximately 1 nm to 100 nm. Alternatively, the material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to 1000 nm [Citation1,Citation5]. Nanocarriers are entities that are constructed from nanomaterials which add additional functionality to the therapeutics. Examples of nanocarriers are nanocrystals, nanosuspension, lipid-based nanocarriers, polymeric-based nanocarriers, and inorganic nanocarriers. The nanocarrier is adopted to protect drugs from degradation, sustain its delivery, improve its dissolution, effect drug targeting, overcoming absorption barrier and increasing drug bioavailability to enable the reduction of drug dose and related adverse effects. The conjugation of nanocarrier with a targeting ligand to drive the therapeutics to cancer cells or organelles instead of the normal population promotes the specificity of drug action and minimizes the drug toxicity.
With reference to inhalation, dry powder inhalers and nebulizers are devices commonly being exploited for pulmonary delivery of therapeutical nanocarrier to deeper lung regions. Nebulizers generate liquid aerosols by breaking down the liquid dosage form into fine tiny droplets for inhalation by either compressed air or ultrasonic power. Dry powder inhaler mediates inhalation with the airflow created by the user directing through a drug powder thus generating inhalable dry powder aerosol. The late evaluation of inhalation profiles of liquid and solid nanotherapeutics from nebulizer and dry powder inhaler, respectively, shows that the percentages of therapeutic inhaled are generally lower with dry powder inhalation than liquid nebulization by more than two folds [Citation6,Citation7].
Dry powder inhalation has been advocated as the choice of pulmonary drug delivery as a solid product is characterized by a high physicochemical quality [Citation8]. Nonetheless, the delivery of nanocarrier via dry powder inhalation is limited by their submicron size. A large fraction of nanocarrier will be exhaled after inhalation thus failing deep and peripheral lung drug deposition for cancer treatment. The nanocarrier is aggregative due to its large specific surface area and inter-particle forces. The formed aggregates are less able to redisperse to release nanocarrier again, and the powder becomes very difficult to handle [Citation9]. To enable dry nanopowder inhalation, the nanocarrier has been transformed into nanoagglomerates, nanocomposites, nanocarrier loaded microparticles and lyophilized floccules with mass median aerodynamic diameter between 1 and 5 μm [Citation1]. Nonetheless, poor nanocarrier redispersibility and changes in its nanoscale due to further processing may affect the size-dependent biological performances of nanotherapeutics. In the case of lyophilized floccules, a high percentage of stabilizer is used. Different surfactants are employed to control nanoagglomeration and redispersibility of nanocarrier. The summative effort could induce pulmonary irritation.
Recent studies indicate that the blending of solid nanocarrier with solid microparticles (<5 µm) through the surface adsorption phenomenon may negate the abovementioned shortfalls [Citation6]. The microparticles serve as the pulmonary vehicle of nanocarrier, and the detachment of nanocarrier from microparticles in lung renders drug/nanocarrier being freely deposited at the deep or peripheral lung. The nanocarrier or microparticles alone are aggregative and cohesive. Blending of them reduces the nanocarrier aggregation through dispersing the nanocarrier over the microparticulate surfaces. The adsorbed nanocarrier can function as a glidant. Their presence on microparticulate surfaces reduces the aggregation tendency of the microparticles, thereby producing an inhalable and flowable powder. In spite of such advantages, dry powder inhalation using a nanocarrier–microparticle physical blend remains unsatisfactory with a percent inhalation lower than 50%.
The latest report by Credence Research Inc. on ‘Nanoemulsion market – Growth, future prospects and competitive analysis 2018–2026’ highlights that the nanoemulsion market was valued at USD 6827.5 million in 2017, and is expected to reach USD 14760.4 million by 2026 at a compound annual growth rate expansion of 8.9% from 2018 to 2026 [Citation10]. One of the main applications of nanoemulsion is drug delivery and cancer therapy. Oil-in-water nanoemulsion has been adopted as the drug vehicle of choice in pulmonary delivery [Citation11,Citation12]. The safety of excipients/surfactants is the primary consideration in the development of a pulmonary nanoemulsion [Citation13]. In contrast to solid dosage form, the cell- or organelle-targeting activity of nanoemulsion is envisaged to be impeded by its fluidic nature at oil–water interface where the targeting ligand is located and is susceptible to leaching into the non-drug continuous phase, specifically when the drug is encapsulated in the dispersed droplets without covalently conjugated to a common backbone as targeting ligand.
Balancing the pros and cons of nanoemulsion versus dry powder, it is deemed that the dry powder inhalation, with a relatively low inhalation efficiency, may require a higher drug load to achieve the intended therapeutical response. This, in turn, raises the risks of toxicity development from the cancer therapeutics, more than that possibly be introduced from the surfactants of the nanoemulsion. The nanoemulsion appears to be a favorable option in the pulmonary delivery of cancer therapeutics. The nanoemulsion can be designed with single- or multiple-receptor targeting characteristics through covalently conjugating both drug and targeting ligand to a common polymeric backbone, and having the conjugate decorated at the oil–water interface of the nanoemulsion. The conjugate can be synthesized via a judicious choice of polymeric backbone and excipients, with reference to drug and targeting ligand used, to produce an amphiphilic compound that can simultaneously act as the emulgent as well as a vehicle to drug and targeting ligand, to reduce the quantum of surfactant used and its associated health risks. The drug-polymeric backbone conjugative bonding can be designed to be enzymatically digestible instead of hydrolysis prone to confer the nanoemulsion with a higher degree of storage stability. Alternatively, reconstitutable dry nanoemulsion can be prepared for the same purpose [Citation14]. The summative potentials of nanoemulsion open up a vast range of research opportunities in material design and processing innovation with the aim of achieving safe and efficient pulmonary delivery of cancer therapeutics.
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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
- Alhajj N, Chee CF, Wong TW, et al. Lung cancer: active therapeutic targeting and inhalational nanoproduct design. Exp Opin Drug Deliv. 2018;15(12):1223–1247.
- Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642–655.
- Cox DBT, Platt RJ, Zhang F. Therapeutic genome editing: prospects and challenges. Nat Med. 2015;21(2):121–131.
- Fujita Y, Kuwano K, Ochiya T. Development of small RNA delivery systems for lung cancer therapy. Int J Mol Sci. 2015;16(3):5254–5270.
- Sheshala R, Anuar NK, Abu Samah NH, et al. In vitro drug dissolution/permeation testing of nanocarrier for skin application: A comprehensive review. AAPS PharmSciTech. 2019;20:164.
- Alhajj N, Zakaria Z, Naharudin I, et al. Critical physicochemical attributes of chitosan nanoparticles admixed lactose-PEG3000 microparticles in pulmonary inhalation. Asian J Pharm Sci. In Press. doi: 10.1016/j.ajps.2019.02.001.
- UllahShah K, Chan LW, Wong TW. Critical physicochemical and biological attributes of nanoemulsions for pulmonary delivery of rifampicin by nebulization technique in tuberculosis treatment. Drug Deliv. 2017;24(1):1631–1647.
- Traini D, Young PM. Formulation of inhalation medicines. In: Colombo P, Traini D, Buttini F, editors. Inhalation drug delivery: techniques and products. West Sussex: John Wiley & Sons, Ltd.; 2012. p. 31–45.
- Carvalho TC, Peters JI, Williams RO. Influence of particle size on regional lung deposition–what evidence is there? Int J Pharm. 2011;406:1–10.
- [cited 2019 Jul 29]. Available from: https://www.credenceresearch.com/report/nanoemulsion-market
- Pereira FG, Marquete R, Oliveira-Cruz L, et al. de Lima Moreira D. Cytotoxic effects of the essential oil from leaves of Casearia sylvestris Sw. (Salicaceae) and its nanoemulsion on A549 tumor cell line. Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas. 2017;16(5):506–512.
- Khan I, Bahuguna A, Kumar P, et al. In vitro and in vivo antitumor potential of carvacrol nanoemulsion against human lung adenocarcinoma A549 cells via mitochondrial mediated apoptosis. Sci Rep. 2018;8(1):144.
- Vater C, Adamovic A, Ruttensteiner L, et al. Cytotoxicity of lecithin-based nanoemulsions on human skin cells and ex vivo skin permeation: comparison to conventional surfactant types. Int J Pharm. 2019;566:383–390.
- Zhu L, Li M, Dong J, et al. Dimethyl silicone dry nanoemulsion inhalations: formulation study and anti-acute lung injury effect. Int J Pharm. 2015;491:292–298.