RECENT MODALITIES IN DRUG DELIVERY VIA INHALATION THERAPY – AN ADVANCED TREATMENT STRATEGY FOR PULMONARY CARCINOMA

The potential benefit of nanoparticles (NPs) as a colloidal delivery system for pharmaceutical relevance has earned substantial concern in the past decades. Fatality rate due to cancer sustained to hike; advances in nanotechnology have quite become a trenchant approach for enhancing effective drug targeting to cancer tissues by circumventing all the imperfections of traditional chemotherapy. Inhalation drug delivery directly targeting the lungs through respiratory tract is a rapidly maturing field of research and most recently explored approaches for both local and systemic therapy. With the recent advances in synthesis and manipulation of nanoparticles, inhalation drug delivery has shown great impact on pulmonary practice. Inhalation drug delivery has diverse actions over traditional chemotherapy including a) non-invasive b) avoiding first pass metabolism and systemic toxicity c) minimized frequent dosing and d) target delivery of drug to the lung epithelium thereby enhancing local drug concentrations. Dry powder inhalers, meter dose inhalers and nebulizers are some few efficient methods to deliver therapeutic agents directly targeting to the lungs. The ultimatum of inhalation therapy is to generate particles with an ample range of particle sizes. With the recent interest in the development of pulmonary targeted therapy, this review presents how the inhalation drug delivery overcomes conventional chemotherapy and focuses the recent treatment modalities that have been established for pulmonary carcinoma by the route of inhalation as well as discusses the advantages of inhalation drug delivery.

[1]  E. Golunski,et al.  Improved respiratory delivery of the anticancer drugs, camptothecin and paclitaxel, with 5% CO2-enriched air: pharmacokinetic studies , 2001, Cancer Chemotherapy and Pharmacology.

[2]  H. Boushey,et al.  Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone. , 1984, The American review of respiratory disease.

[3]  I. Haririan,et al.  Preparation of 5-fluorouracil nanoparticles by supercritical antisolvents for pulmonary delivery , 2010, International journal of nanomedicine.

[4]  H. Okamoto,et al.  Pulmonary gene delivery by chitosan-pDNA complex powder prepared by a supercritical carbon dioxide process. , 2003, Journal of pharmaceutical sciences.

[5]  R. Kiss,et al.  In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy. , 2010, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[6]  M. Tang,et al.  Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons. , 2000, Journal of the National Cancer Institute.

[7]  H. Heinzer,et al.  Efficacy and safety of inhaled recombinant interleukin-2 in high-risk renal cell cancer patients compared with systemic interleukin-2: an outcome study. , 2003, Folia biologica.

[8]  R. Löbenberg,et al.  Nanoparticles: Characteristics, Mechanisms of Action, and Toxicity in Pulmonary Drug Delivery—A Review , 2007 .

[9]  S. Lai-Fook Mechanical factors in lung liquid distribution. , 1993, Annual review of physiology.

[10]  M. Dolovich,et al.  Labiris NR, Dolovich MB. Pulmonary drug delivery: part II. the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications , 2004 .

[11]  W. Seeger,et al.  Inhaled prostanoids in the therapy of pulmonary hypertension. , 2008, Journal of aerosol medicine and pulmonary drug delivery.

[12]  C. Cho,et al.  Poly(beta-amino ester) as a carrier for si/shRNA delivery in lung cancer cells. , 2008, Biomaterials.

[13]  K. Yamamoto,et al.  [New chemotherapeutic method for the treatment of tracheal and bronchial cancers--nebulization chemotherapy]. , 1983, Gan no rinsho. Japan journal of cancer clinics.

[14]  R. Löbenberg,et al.  Formulation and cytotoxicity of doxorubicin nanoparticles carried by dry powder aerosol particles. , 2006, International journal of pharmaceutics.

[15]  C. Densmore,et al.  Aerosol delivery of PEI–p53 complexes inhibits B16-F10 lung metastases through regulation of angiogenesis , 2002, Cancer Gene Therapy.

[16]  J. Brachmann,et al.  Enhancement of Aerosol Cisplatin Chemotherapy with Gene Therapy Expressing ABC10 protein in Respiratory System , 2014, Journal of Cancer.

[17]  R. C. Silva,et al.  New approach to improve encapsulation and antitumor activity of doxorubicin loaded in solid lipid nanoparticles. , 2013, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[18]  S. Schürch,et al.  Surfactant displaces particles toward the epithelium in airways and alveoli. , 1990, Respiration physiology.

[19]  Devaki Thiruvengadam,et al.  GREEN SYNTHESIS, CHARACTERIZATION, ANTIMICROBIAL AND CYTOTOXIC EFFECTS OF SILVER NANOPARTICLES USING ORIGANUM HERACLEOTICUM L. LEAF EXTRACT , 2015 .

[20]  G. Peters,et al.  Phase I Study of Aerosolized SLIT Cisplatin in the Treatment of Patients with Carcinoma of the Lung , 2007, Clinical Cancer Research.

[21]  S. Büttgenbach,et al.  In vitro and ex vivo toxicological testing of sildenafil-loaded solid lipid nanoparticles , 2013, Inhalation toxicology.

[22]  S. Safe,et al.  Inhalation Delivery of a Novel Diindolylmethane Derivative for the Treatment of Lung Cancer , 2010, Molecular Cancer Therapeutics.

[23]  Synthesis and in vitro anticancer evaluation of 2-isopropyl-5-methylphenol Loaded PLGA based iron oxide nanoparticles , 2014 .

[24]  Chao-Liang Wu,et al.  Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model. , 2007, Molecular pharmaceutics.

[25]  H. Okamoto,et al.  Chitosan-interferon-β gene complex powder for inhalation treatment of lung metastasis in mice. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[26]  B. Ames,et al.  The Causes and Prevention of Cancer: The Role of Environment , 1998, Biotherapy.

[27]  Marianne Geiser,et al.  Update on macrophage clearance of inhaled micro- and nanoparticles. , 2010, Journal of aerosol medicine and pulmonary drug delivery.

[28]  P. Diot,et al.  Gemcitabine aerosol: in vitro antitumor activity and deposition imaging for preclinical safety assessment in baboons , 2006, Cancer Chemotherapy and Pharmacology.

[29]  N. Krug,et al.  Low cytotoxicity of solid lipid nanoparticles in in vitro and ex vivo lung models , 2009, Inhalation toxicology.

[30]  Nuo Wang,et al.  Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers. Part II: Biodegradation , 2001, Journal of biomaterials science. Polymer edition.

[31]  C. Densmore,et al.  Biodistribution and pharmacokinetics of aerosol and intravenously administered DNA-polyethyleneimine complexes: optimization of pulmonary delivery and retention. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[32]  Christel C. Müller-Goymann,et al.  Nanoparticle-Mediated Pulmonary Drug Delivery: A Review , 2014, International journal of molecular sciences.

[33]  M. Singh,et al.  Formulation and Evaluation of Aerosolized Celecoxib for the Treatment of Lung Cancer , 2005, Pharmaceutical Research.

[34]  T. Minko,et al.  Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[35]  R. Proctor Tobacco and the global lung cancer epidemic , 2001, Nature Reviews Cancer.

[36]  D. Postma,et al.  Physiotherapy and bronchial mucus transport. , 1999, The European respiratory journal.

[37]  Yuquan Wei,et al.  Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine–plasmid interleukin‐15 complexes in murine models of lung metastasis , 2011, Cancer science.

[38]  W. Kreyling Lung deposition and biokinetics of inhaled nanoparticles , 2013 .

[39]  Hua Yue,et al.  Porous quaternized chitosan nanoparticles containing paclitaxel nanocrystals improved therapeutic efficacy in non-small-cell lung cancer after oral administration. , 2011, Biomacromolecules.

[40]  T. Minko,et al.  Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA , 2011, Journal of drug targeting.

[41]  Clement Kleinstreuer,et al.  Modeling airflow and particle transport/deposition in pulmonary airways , 2008, Respiratory Physiology & Neurobiology.

[42]  Terry W. J. Steele,et al.  Fast degrading polyesters as siRNA nano-carriers for pulmonary gene therapy , 2008, Journal of Controlled Release.

[43]  B. Giraudeau,et al.  Aerosolized gemcitabine in patients with carcinoma of the lung: feasibility and safety study. , 2011, Journal of aerosol medicine and pulmonary drug delivery.

[44]  S. Gettinger,et al.  Phase I/II Study of Inhaled Doxorubicin Combined with Platinum-Based Therapy for Advanced Non–Small Cell Lung Cancer , 2010, Clinical Cancer Research.

[45]  S. Newman,et al.  Efficient delivery to the lungs of flunisolide aerosol from a new portable hand-held multidose nebulizer. , 1996, Journal of pharmaceutical sciences.

[46]  Zachary Gagnon,et al.  AC electrospray biomaterials synthesis. , 2005, Biomaterials.

[47]  H. Heinzer,et al.  Inhaled interleukin-2 in combination with low-dose systemic interleukin-2 and interferon α in patients with pulmonary metastatic renal-cell carcinoma: effectiveness and toxicity of mainly local treatment , 2005, Journal of Cancer Research and Clinical Oncology.

[48]  E. Lemos-Senna,et al.  Preparation and characterization of quercetin-loaded solid lipid microparticles for pulmonary delivery , 2013 .

[49]  W. Ahn,et al.  Low toxicity of cationic lipid-based emulsion for gene transfer. , 2004, Biomaterials.

[50]  S. L. Hyatt,et al.  Transfection of airway epithelium by stable PEGylated poly-L-lysine DNA nanoparticles in vivo. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[51]  D. Jaroszewski,et al.  Video-assisted thoracic surgery (VATS) as a safe alternative for the resection of pulmonary metastases: a retrospective cohort study , 2009, Journal of cardiothoracic surgery.

[52]  D. Lamprou,et al.  Preparation and characterization of ibuprofen solid lipid nanoparticles with enhanced solubility , 2011, Journal of microencapsulation.

[53]  B. Dautzenberg,et al.  European Respiratory Society Guidelines on the use of nebulizers. , 2001, The European respiratory journal.

[54]  E. Bateman,et al.  A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. , 2010, Respiratory medicine.

[55]  Yaping Li,et al.  Synergistic inhibition of breast cancer metastasis by silibinin-loaded lipid nanoparticles containing TPGS. , 2013, International journal of pharmaceutics.

[56]  W. Seeger,et al.  Nano-carriers for DNA delivery to the lung based upon a TAT-derived peptide covalently coupled to PEG-PEI. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[57]  V. Steele,et al.  Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipropionate and by the combination of aerosolized budesonide and dietary myo-inositol. , 2000, Carcinogenesis.

[58]  R. Perez-soler,et al.  p53 Aerosol Formulation with Low Toxicity and High Efficiency for Early Lung Cancer Treatment , 2007, Clinical Cancer Research.

[59]  Yuchao Dong,et al.  Paclitaxel-loaded poly(glycolide-co-ε-caprolactone)-b-D-α-tocopheryl polyethylene glycol 2000 succinate nanoparticles for lung cancer therapy , 2013, International journal of nanomedicine.

[60]  A. Gomez,et al.  The electrospray and its application to targeted drug inhalation. , 2002, Respiratory care.

[61]  J. McQuillan,et al.  Chemopreventive effect of aerosolized polyphenon E on lung tumorigenesis in A/J mice. , 2007, Neoplasia.

[62]  P. Diot,et al.  Safety of pulmonary administration of gemcitabine in rats. , 2005, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[63]  Newman Sp Aerosol generators and delivery systems. , 1991 .

[64]  E. Vellaichamy,et al.  Rapid synthesis of biocompatible silver nanoparticles using aqueous extract of Rosa damascena petals and evaluation of their anticancer activity. , 2014, Asian Pacific journal of tropical medicine.

[65]  H. Shinohara Distribution of lymphatic stomata on the pleural surface of the thoracic cavity and the surface topography of the pleural mesothelium in the golden hamster , 1997, The Anatomical record.

[66]  W. Seeger,et al.  Inhaled iloprost for severe pulmonary hypertension. , 2002, The New England journal of medicine.

[67]  K. Neoh,et al.  Methotrexate-conjugated and hyperbranched polyglycerol-grafted Fe₃O₄ magnetic nanoparticles for targeted anticancer effects. , 2013, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[68]  S. Vyas,et al.  Liposome-based drug delivery to alveolar macrophages , 2007, Expert opinion on drug delivery.

[69]  J Yu,et al.  Pulmonary drug delivery: physiologic and mechanistic aspects. , 1997, Critical reviews in therapeutic drug carrier systems.

[70]  A. Kendrick,et al.  Selecting and using nebuliser equipment , 1997, Thorax.

[71]  T. Kissel,et al.  Polymeric nanocarriers for drug delivery to the lung , 2010 .

[72]  M. Siddiqui,et al.  Novolizer® , 2012, Drugs.

[73]  T. Corcoran Inhaled delivery of aerosolized cyclosporine. , 2006, Advanced drug delivery reviews.

[74]  R. Kinget,et al.  The lung as a route for systemic delivery of therapeutic proteins and peptides , 2001, Respiratory research.

[75]  Mansoor Amiji,et al.  Tumor-Targeted Gene Delivery Using Poly(Ethylene Glycol)-Modified Gelatin Nanoparticles: In Vitro and in Vivo Studies , 2005, Pharmaceutical Research.

[76]  M. Sakagami Systemic delivery of biotherapeutics through the lung: opportunities and challenges for improved lung absorption. , 2013, Therapeutic delivery.

[77]  C. Reinero,et al.  Feasibility and safety of targeted cisplatin delivery to a select lung lobe in dogs via the AeroProbe intracorporeal nebulization catheter. , 2008, Journal of aerosol medicine and pulmonary drug delivery.

[78]  K. Kang,et al.  Doxorubicin-loaded solid lipid nanoparticles to overcome multidrug resistance in cancer therapy. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[79]  T. Tagami,et al.  Drug/polymer nanoparticles prepared using unique spray nozzles and recent progress of inhaled formulation , 2014 .

[80]  C. Ehrhardt,et al.  In vitro assessment of transferrin-conjugated liposomes as drug delivery systems for inhalation therapy of lung cancer. , 2006, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[81]  David A Edwards,et al.  Bioengineering of therapeutic aerosols. , 2002, Annual review of biomedical engineering.

[82]  Wolfgang Kreyling,et al.  Toxicological hazards of inhaled nanoparticles--potential implications for drug delivery. , 2004, Journal of nanoscience and nanotechnology.

[83]  A. Almeida,et al.  Solid lipid nanoparticles as a drug delivery system for peptides and proteins. , 2007, Advanced drug delivery reviews.

[84]  J Devane,et al.  A new approach to modelling the relationship between in vitro and in vivo drug dissolution/absorption. , 1999, Statistics in medicine.

[85]  Ji-Eun Kim,et al.  Suppression of lung cancer progression by biocompatible glycerol triacrylate–spermine-mediated delivery of shAkt1 , 2012, International journal of nanomedicine.

[86]  W. Finlay,et al.  Farnesol for aerosol inhalation: nebulization and activity against human lung cancer cells. , 2003, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[87]  T. Martonen,et al.  Factors affecting the deposition of inhaled porous drug particles. , 2002, Journal of pharmaceutical sciences.

[88]  D. Traini,et al.  The nanoscale in pulmonary delivery. Part 2: formulation platforms , 2007, Expert opinion on drug delivery.

[89]  S. Hecht,et al.  Inhibition of lung tumorigenesis in A/J mice by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine and myo-inositol, individually and in combination. , 2002, Carcinogenesis.

[90]  Shiladitya Sengupta,et al.  Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system , 2005, Nature.

[91]  B. Ramsey,et al.  Effect of nebulizer type and antibiotic concentration on device performance , 1997, Pediatric pulmonology.

[92]  M. Kris,et al.  Phase I Study of Inhaled Doxorubicin for Patients with Metastatic Tumors to the Lungs , 2007, Clinical Cancer Research.

[93]  S. Kagamimori,et al.  Further study of nebulisation chemotherapy, a new chemotherapeutic method in the treatment of lung carcinomas: fundamental and clinical. , 1993, British Journal of Cancer.

[94]  S. Newman,et al.  Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices. , 1998, Chest.

[95]  Mandip Singh,et al.  Inhalation Delivery and Anti-tumor Activity of Celecoxib in Human Orthotopic Non-Small Cell Lung Cancer Xenograft Model , 2006, Pharmaceutical Research.

[96]  G. Haas,et al.  Systemic treatment with interleukin-4 induces regression of pulmonary metastases in a murine renal cell carcinoma model. , 1995, Cellular immunology.

[97]  Yuanjie Liu,et al.  Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer , 2012, International journal of nanomedicine.

[98]  L. Delattre,et al.  Solid lipid microparticles as a sustained release system for pulmonary drug delivery. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[99]  A. Akbarzadeh,et al.  Preparation and in vitro evaluation of doxorubicin-loaded Fe3O4 magnetic nanoparticles modified with biocompatible copolymers , 2012, International journal of nanomedicine.

[100]  B. Bhushan,et al.  Emerging applications of nanoparticles for lung cancer diagnosis and therapy , 2013, International Nano Letters.

[101]  T. Arakawa,et al.  Some Factors Associated with the Ultrasonic Nebulization of Proteins , 2004, Pharmaceutical Research.

[102]  J. L. Rau,et al.  Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. , 2005, Chest.

[103]  Peter R. Byron,et al.  Inhaling medicines: delivering drugs to the body through the lungs , 2007, Nature Reviews Drug Discovery.

[104]  T. Jacks,et al.  Inhibition of oncogenic K-ras signaling by aerosolized gene delivery in a mouse model of human lung cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[105]  Insoo Kim,et al.  Doxorubicin-loaded highly porous large PLGA microparticles as a sustained- release inhalation system for the treatment of metastatic lung cancer. , 2012, Biomaterials.

[106]  R. Müller,et al.  Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[107]  R. Löbenberg,et al.  Targeted delivery of nanoparticles for the treatment of lung diseases. , 2008, Advanced drug delivery reviews.

[108]  E. Kleinerman,et al.  9‐Nitrocamptothecin Liposome Aerosol Treatment of Human Cancer Subcutaneous Xenografts and Pulmonary Cancer Metastases in Mice , 2000, Annals of the New York Academy of Sciences.

[109]  D. Paolino,et al.  Gemcitabine-loaded chitosan microspheres. Characterization and biological in vitro evaluation , 2011, Biomedical microdevices.

[110]  William Y. Kim,et al.  Systemic delivery of gemcitabine triphosphate via LCP nanoparticles for NSCLC and pancreatic cancer therapy. , 2013, Biomaterials.

[111]  J. Kjems,et al.  Bioresponsive hyperbranched polymers for siRNA and miRNA delivery , 2010, Journal of drug targeting.

[112]  J. Patton Unlocking the opportunity of tight glycaemic control , 2005, Diabetes, obesity & metabolism.

[113]  J. Mulshine,et al.  Inhaled isotretinoin (13-cis retinoic acid) is an effective lung cancer chemopreventive agent in A/J mice at low doses: a pilot study. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[114]  G. Speranza,et al.  Multifunctional branched gold-carbon nanotube hybrid for cell imaging and drug delivery. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[115]  F. Lin,et al.  The fabrication and characterization of dicalcium phosphate dihydrate-modified magnetic nanoparticles and their performance in hyperthermia processes in vitro. , 2009, Biomaterials.

[116]  P. Thompson Drug delivery to the small airways. , 1998, American journal of respiratory and critical care medicine.

[117]  D A Groneberg,et al.  Fundamentals of pulmonary drug delivery. , 2003, Respiratory medicine.

[118]  Ling Wang,et al.  Novel peptide–dendrimer conjugates as drug carriers for targeting nonsmall cell lung cancer , 2010, International journal of nanomedicine.

[119]  F. Alla,et al.  Is there a relationship between the presence of lung mucosa preinvasive lesions and lung cancer incidence? Influence of tobacco consumption. , 2014, Lung cancer.

[120]  Ching-Li Tseng,et al.  The use of biotinylated-EGF-modified gelatin nanoparticle carrier to enhance cisplatin accumulation in cancerous lungs via inhalation. , 2009, Biomaterials.

[121]  B. Pulliam,et al.  Nanoparticles for drug delivery to the lungs. , 2007, Trends in biotechnology.

[122]  Denis Wirtz,et al.  Micro- and macrorheology of mucus. , 2009, Advanced drug delivery reviews.

[123]  Chris Corrigan,et al.  Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. , 2008, Respiratory medicine.

[124]  Juliane Nguyen,et al.  Biodegradable polymeric nanocarriers for pulmonary drug delivery , 2008 .

[125]  A G Mikos,et al.  Controlled release of rhBMP-2 loaded poly(dl-lactic-co-glycolic acid)/calcium phosphate cement composites in vivo. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[126]  R. L. Jones,et al.  Unique cellular interaction of silver nanoparticles: size-dependent generation of reactive oxygen species. , 2008, The journal of physical chemistry. B.

[127]  S. Anderson,et al.  Regional deposition of saline aerosols of different tonicities in normal and asthmatic subjects. , 1994, The European respiratory journal.

[128]  J. Joachim,et al.  Compritol 888 ATO: an innovative hot-melt coating agent for prolonged-release drug formulations. , 1999, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[129]  J. Hanes,et al.  Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. , 2009, Advanced drug delivery reviews.

[130]  D. Swift Aerosols and humidity therapy. Generation and respiratory deposition of therapeutic aerosols. , 1980, The American review of respiratory disease.

[131]  N. K. Jain,et al.  Development and characterization of dexamethasone mesylate anchored on multi walled carbon nanotubes , 2013, Journal of drug targeting.

[132]  H. Burris,et al.  Shortcomings of current therapies for non-small-cell lung cancer: unmet medical needs , 2009, Oncogene.

[133]  E. Kleinerman,et al.  Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases , 2005, International journal of cancer.

[134]  H. Junginger,et al.  Cationic submicron emulsions for pulmonary DNA immunization. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[135]  D. Pavia,et al.  The effect of changes in particle size on the deposition of pressurized inhalation aerosols , 1984 .

[136]  S. Balakumar,et al.  Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats. , 2015, Environmental toxicology and pharmacology.

[137]  Hannu Raunio,et al.  Expression and Regulation of Xenobiotic-Metabolizing Cytochrome P450 (CYP) Enzymes in Human Lung , 2002, Critical reviews in toxicology.

[138]  Byeong-Hyeok Sohn,et al.  Specific targeting, cell sorting, and bioimaging with smart magnetic silica core-shell nanomaterials. , 2006, Small.

[139]  P. Barry,et al.  Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature. , 2001, Health technology assessment.

[140]  A. K. Rao,et al.  Development of Cisplatin Nanoparticles as Dry Powder Inhalers for Lung Cancer , 2013 .

[141]  C. Schans,et al.  Bronchial mucus transport , 2007 .

[142]  Karla A. Lawson,et al.  Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis , 2004, Cancer Chemotherapy and Pharmacology.

[143]  Jui-Sheng Sun,et al.  Ex vivo magnetofection with magnetic nanoparticles: a novel platform for nonviral tissue engineering. , 2008, Artificial organs.

[144]  G. Cavallaro,et al.  Phospholipid-polyaspartamide micelles for pulmonary delivery of corticosteroids. , 2011, International journal of pharmaceutics.

[145]  C Kleinstreuer,et al.  Targeted drug-aerosol delivery in the human respiratory system. , 2008, Annual review of biomedical engineering.

[146]  J. Minna,et al.  MRI-visible micellar nanomedicine for targeted drug delivery to lung cancer cells. , 2010, Molecular pharmaceutics.

[147]  E. C. Smith,et al.  Comparison of twenty three nebulizer/compressor combinations for domiciliary use. , 1995, European Respiratory Journal.

[149]  S. Lakshminarayan,et al.  The Bronchial Circulation , 1991 .

[150]  Sami Nazzal,et al.  Paclitaxel loaded PEG(5000)-DSPE micelles as pulmonary delivery platform: formulation characterization, tissue distribution, plasma pharmacokinetics, and toxicological evaluation. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[151]  P. Postmus,et al.  Assessing a system to capture stray aerosol during inhalation of nebulized liposomal cisplatin. , 2006, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[152]  I. Katz,et al.  Deposition Patterns of Polydisperse Aerosols Within Human Lungs , 1993 .

[153]  S. Lakshminarayan,et al.  The bronchial circulation. Small, but a vital attribute of the lung. , 1987, The American review of respiratory disease.

[154]  J. Patton,et al.  Drug delivery via the respiratory tract. , 1994, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[155]  R. Doijad,et al.  Formulation and Targeting Efficiency of Cisplatin Engineered Solid Lipid Nanoparticles , 2008, Indian journal of pharmaceutical sciences.

[156]  R. Mumper,et al.  Development of idarubicin and doxorubicin solid lipid nanoparticles to overcome Pgp-mediated multiple drug resistance in leukemia. , 2009, Journal of biomedical nanotechnology.

[157]  P. Byron Prediction of drug residence times in regions of the human respiratory tract following aerosol inhalation. , 1986, Journal of pharmaceutical sciences.

[158]  D. Shieh,et al.  A new photothermal therapeutic agent: core-free nanostructured Au x Ag1-x dendrites. , 2008, Chemistry.

[159]  A. Hershey,et al.  Inhalation chemotherapy for macroscopic primary or metastatic lung tumors: proof of principle using dogs with spontaneously occurring tumors as a model. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[160]  Wei Yang,et al.  Inhaled nanoparticles--a current review. , 2008, International journal of pharmaceutics.

[161]  D A Weitz,et al.  Trojan particles: Large porous carriers of nanoparticles for drug delivery , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[162]  Shaker A Mousa,et al.  Nanoparticles and cancer therapy: A concise review with emphasis on dendrimers , 2009, International journal of nanomedicine.

[163]  B. Zierenberg Optimizing the in vitro performance of Respimat. , 1999, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[164]  J. Vincent,et al.  Kinetics of deposition and clearance of inhaled mineral dusts during chronic exposure. , 1985, British journal of industrial medicine.

[165]  J. Brain Inhalation, deposition, and fate of insulin and other therapeutic proteins. , 2007, Diabetes technology & therapeutics.

[166]  R. Löbenberg,et al.  Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[167]  G Pohlmann,et al.  A toxicological evaluation of inhaled solid lipid nanoparticles used as a potential drug delivery system for the lung. , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[168]  Gediminas Mainelis,et al.  Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance , 2010, Proceedings of the National Academy of Sciences.

[169]  Tingting Li,et al.  Pulmonary gemcitabine delivery for treating lung cancer: pharmacokinetics and acute lung injury aspects in animals. , 2008, Canadian journal of physiology and pharmacology.

[170]  Dae-Duk Kim,et al.  Lung-specific delivery of paclitaxel by chitosan-modified PLGA nanoparticles via transient formation of microaggregates. , 2009, Journal of pharmaceutical sciences.

[171]  R. A. Jain,et al.  The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. , 2000, Biomaterials.

[172]  T. Vandamme,et al.  Pulmonary drug delivery systems: recent developments and prospects. , 2002, Critical reviews in therapeutic drug carrier systems.

[173]  C. Cho,et al.  Urocanic acid-modified chitosan-mediated PTEN delivery via aerosol suppressed lung tumorigenesis in K-rasLA1 mice , 2008, Cancer Gene Therapy.

[174]  P. Zarogoulidis,et al.  Feasibility and effectiveness of inhaled carboplatin in NSCLC patients , 2012, Investigational New Drugs.

[175]  Zhirong Zhang,et al.  Lung-targeting delivery of dexamethasone acetate loaded solid lipid nanoparticles , 2007, Archives of pharmacal research.

[176]  Leaf Huang,et al.  Calcium phosphate nanoparticles with an asymmetric lipid bilayer coating for siRNA delivery to the tumor. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[177]  R Langer,et al.  New methods of drug delivery. , 1990, Science.

[178]  D. Katti,et al.  Combination of single walled carbon nanotubes/graphene oxide with paclitaxel: a reactive oxygen species mediated synergism for treatment of lung cancer. , 2013, Nanoscale.

[179]  R. Patlolla,et al.  Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[180]  Ming-Jium Shieh,et al.  Targeting efficiency and biodistribution of biotinylated-EGF-conjugated gelatin nanoparticles administered via aerosol delivery in nude mice with lung cancer. , 2008, Biomaterials.

[181]  E. Golunski,et al.  Cyclosporin A aerosol improves the anticancer effect of paclitaxel aerosol in mice. , 2004, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[182]  J. Choo,et al.  Highly sensitive immunoassay of lung cancer marker carcinoembryonic antigen using surface-enhanced Raman scattering of hollow gold nanospheres. , 2009, Analytical chemistry.

[183]  C. Lehr,et al.  Pulmonary drug delivery: from generating aerosols to overcoming biological barriers-therapeutic possibilities and technological challenges. , 2013, The Lancet. Respiratory medicine.