Nanomedicine in pulmonary delivery

The lung is an attractive target for drug delivery due to noninvasive administration via inhalation aerosols, avoidance of first-pass metabolism, direct delivery to the site of action for the treatment of respiratory diseases, and the availability of a huge surface area for local drug action and systemic absorption of drug. Colloidal carriers (ie, nanocarrier systems) in pulmonary drug delivery offer many advantages such as the potential to achieve relatively uniform distribution of drug dose among the alveoli, achievement of improved solubility of the drug from its own aqueous solubility, a sustained drug release which consequently reduces dosing frequency, improves patient compliance, decreases incidence of side effects, and the potential of drug internalization by cells. This review focuses on the current status and explores the potential of colloidal carriers (ie, nanocarrier systems) in pulmonary drug delivery with special attention to their pharmaceutical aspects. Manufacturing processes, in vitro/in vivo evaluation methods, and regulatory/toxicity issues of nanomedicines in pulmonary delivery are also discussed.

[1]  B. Shekunov,et al.  Optimisation of powders for pulmonary delivery using supercritical fluid technology. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[2]  Stephen R Byrn,et al.  Solid-state analysis of the active pharmaceutical ingredient in drug products. , 2003, Drug discovery today.

[3]  K. Johnston,et al.  Spray freezing into liquid nitrogen for highly stable protein nanostructured microparticles. , 2004, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[4]  J. Finkelstein,et al.  Acute pulmonary effects of ultrafine particles in rats and mice. , 2000, Research report.

[5]  A. Hickey,et al.  Powder properties and their influence on dry powder inhaler delivery of an antitubercular drug , 2002, AAPS PharmSciTech.

[6]  Kenneth A Howard,et al.  RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[7]  H. Steckel,et al.  Alternative sugars as potential carriers for dry powder inhalations. , 2004, International journal of pharmaceutics.

[8]  M. Joshi,et al.  Pulmonary disposition of budesonide from liposomal dry powder inhaler. , 2001, Methods and findings in experimental and clinical pharmacology.

[9]  S. Cryan,et al.  Increased intracellular targeting to airway cells using octaarginine-coated liposomes: in vitro assessment of their suitability for inhalation. , 2006, Molecular pharmaceutics.

[10]  E. Merisko-Liversidge,et al.  Insulin Nanoparticles: A Novel Formulation Approach for Poorly Water Soluble Zn-Insulin , 2004, Pharmaceutical Research.

[11]  B. Shekunov Nanoparticle technology for drug delivery: from nanoparticles to cutting-edge delivery strategies - part II. , 2005, IDrugs : the investigational drugs journal.

[12]  Chong-K. Kim,et al.  Polyethylenimine‐based antisense oligodeoxynucleotides of IL‐4 suppress the production of IL‐4 in a murine model of airway inflammation , 2006, The journal of gene medicine.

[13]  D. Papadopoulos,et al.  Physical characterization of component particles included in dry powder inhalers. I. Strategy review and static characteristics. , 2007, Journal of pharmaceutical sciences.

[14]  H. Kristensen,et al.  Preparation and purification of cationic solid lipid nanospheres--effects on particle size, physical stability and cell toxicity. , 2003, International journal of pharmaceutics.

[15]  Robert Gelein,et al.  Pulmonary Tissue Access of Ultrafine Particles , 1991 .

[16]  X. Estivill,et al.  Non‐viral vector‐mediated uptake, distribution, and stability of chimeraplasts in human airway epithelial cells , 2002, The journal of gene medicine.

[17]  Xin-guo Jiang,et al.  Galactose-poly(ethylene glycol)-polyethylenimine for improved lung gene transfer. , 2008, Biochemical and biophysical research communications.

[18]  Sadhna Sharma,et al.  Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis. , 2005, International journal of antimicrobial agents.

[19]  N. Colburn,et al.  Aerosol-delivered programmed cell death 4 enhanced apoptosis, controlled cell cycle and suppressed AP-1 activity in the lungs of AP-1 luciferase reporter mice , 2007, Gene Therapy.

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

[21]  K. Johnston,et al.  Targeted High Lung Concentrations of Itraconazole Using Nebulized Dispersions in a Murine Model , 2006, Pharmaceutical Research.

[22]  R. Morishita,et al.  Nanoparticle-Mediated Delivery of Nuclear Factor &kgr;B Decoy Into Lungs Ameliorates Monocrotaline-Induced Pulmonary Arterial Hypertension , 2009, HYPERTENSION.

[23]  G. Zografi,et al.  The relationship between water vapor absorption and desorption by phospholipids and bilayer phase transitions. , 2007, Journal of pharmaceutical sciences.

[24]  C. Sioutas,et al.  Observations of Twelve USEPA Priority Polycyclic Aromatic Hydrocarbons in the Aitken Size Range (10–32 nm D p ) , 2005 .

[25]  P. Artursson,et al.  Targeted gene delivery with trisaccharide-substituted chitosan oligomers in vitro and after lung administration in vivo. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[26]  F. Ahsan,et al.  Synthesis and Evaluation of Pegylated Dendrimeric Nanocarrier for Pulmonary Delivery of Low Molecular Weight Heparin , 2009, Pharmaceutical Research.

[27]  Gerrit Borchard,et al.  Pulmonary delivery of chitosan-DNA nanoparticles enhances the immunogenicity of a DNA vaccine encoding HLA-A*0201-restricted T-cell epitopes of Mycobacterium tuberculosis. , 2004, Vaccine.

[28]  W. Kreyling,et al.  TRANSLOCATION OF ULTRAFINE INSOLUBLE IRIDIUM PARTICLES FROM LUNG EPITHELIUM TO EXTRAPULMONARY ORGANS IS SIZE DEPENDENT BUT VERY LOW , 2002, Journal of toxicology and environmental health. Part A.

[29]  J. Kuo,et al.  Preparation of DNA dry powder for non‐viral gene delivery by spray‐freeze drying: effect of protective agents (polyethyleneimine and sugars) on the stability of DNA , 2004, The Journal of pharmacy and pharmacology.

[30]  R. O. Williams,et al.  Influence of micronization method on the performance of a suspension triamcinolone acetonide pressurized metered-dose inhaler formulation. , 1999, Pharmaceutical development and technology.

[31]  A. Almeida,et al.  Lymphatic uptake of lipid nanoparticles following endotracheal administration , 2006, Journal of microencapsulation.

[32]  M. Rad-Malekshahi,et al.  Preparation and antibacterial activity evaluation of rifampicin-loaded poly lactide-co-glycolide nanoparticles. , 2007, Nanomedicine : nanotechnology, biology, and medicine.

[33]  J. Marier,et al.  Liposomal tobramycin against pulmonary infections of Pseudomonas aeruginosa: a pharmacokinetic and efficacy study following single and multiple intratracheal administrations in rats. , 2003, The Journal of antimicrobial chemotherapy.

[34]  E. Chiellini,et al.  A new biocompatible nanoparticle delivery system for the release of fibrinolytic drugs. , 2008, International journal of pharmaceutics.

[35]  C. Berkland,et al.  Nanoparticle formulations in pulmonary drug delivery , 2009, Medicinal research reviews.

[36]  B. Kinsey,et al.  Gene transfer by guanidinium‐cholesterol: dioleoylphosphatidyl‐ethanolamine liposome‐DNA complexes in aerosol , 1999, The journal of gene medicine.

[37]  P. Couvreur,et al.  Nanoparticles in cancer therapy and diagnosis. , 2002, Advanced drug delivery reviews.

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

[39]  D. Bar-Sagi,et al.  Cell phenotype specific kinetics of expression of intratracheally injected manganese superoxide dismutase–plasmid/liposomes (MnSOD–PL) during lung radioprotective gene therapy , 2003, Gene Therapy.

[40]  Yu Zhang,et al.  Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung. , 2004, International journal of pharmaceutics.

[41]  Myung-Haing Cho,et al.  Aerosol delivery of urocanic acid–modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle, and angiogenesis in lungs of K-ras null mice , 2006, Molecular Cancer Therapeutics.

[42]  The Effect of Film Thickness on Thermal Aerosol Generation , 2007, Pharmaceutical Research.

[43]  P. Young,et al.  The influence of lactose pseudopolymorphic form on salbutamol sulfate-lactose interactions in DPI formulations. , 2008, Drug development and industrial pharmacy.

[44]  A. Fushimi,et al.  Collection characteristics of low-pressure impactors with various impaction substrate materials , 2006 .

[45]  C. Lehr,et al.  Cell culture models of the respiratory tract relevant to pulmonary drug delivery. , 2005, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[46]  A. Misra,et al.  Development of Liposomal Amphotericin B Dry Powder Inhaler Formulation , 2004, Drug delivery.

[47]  Y. Barenholz,et al.  Characterization and in vivo performance of dextran-spermine polyplexes and DOTAP/cholesterol lipoplexes administered locally and systemically. , 2007, Biomaterials.

[48]  V. H. Lee,et al.  Respiratory epithelial cell culture models for evaluation of ion and drug transport , 1996 .

[49]  R. Löbenberg,et al.  Effervescent dry powder for respiratory drug delivery. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[50]  P. Morrow,et al.  Volumetric loading of alveolar macrophages (AM): a possible basis for diminished AM-mediated particle clearance. , 1992, Experimental lung research.

[51]  K. Johnston,et al.  Solution-Based Particle Formation of Pharmaceutical Powders by Supercritical or Compressed Fluid Co2 and Cryogenic Spray-Freezing Technologies , 2001, Drug development and industrial pharmacy.

[52]  I. Kwon,et al.  In Vivo Gene Transfer to the Mouse Nasal Cavity Mucosa Using a Stable Cationic Lipid Emulsion , 2000, Molecules and cells.

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

[54]  H. Linden,et al.  The effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation. , 2002, International journal of pharmaceutics.

[55]  R. Müller,et al.  Solid lipid nanoparticles (SLN) for controlled drug delivery. I. Production, characterization and sterilization , 1994 .

[56]  P. Mcmurry,et al.  Relationship between particle mass and mobility for diesel exhaust particles. , 2003, Environmental science & technology.

[57]  M. Vidgrén,et al.  Comparison of physical and inhalation properties of spray-dried and mechanically micronized disodium cromoglycate , 1987 .

[58]  Ching-Hua Wang,et al.  Pulmonary delivery of insulin by liposomal carriers. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[59]  S. Kawakami,et al.  Efficient targeting to alveolar macrophages by intratracheal administration of mannosylated liposomes in rats. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[60]  H. Kristensen,et al.  Particle Formation and Capture During Spray Drying of Inhalable Particles , 2005, Pharmaceutical development and technology.

[61]  A. Hickey Lung Deposition and Clearance of Pharmaceutical Aerosols: What Can Be Learned from Inhalation Toxicology and Industrial Hygiene? , 1993 .

[62]  Yun-Jaie Choi,et al.  Highly efficient gene transfer with degradable poly(ester amine) based on poly(ethylene glycol) diacrylate and polyethylenimine in vitro and in vivo , 2008, The journal of gene medicine.

[63]  R. Bhandari,et al.  Potential of solid lipid nanoparticles in brain targeting. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[64]  R. Pandey,et al.  Chemotherapeutic activity against murine tuberculosis of once weekly administered drugs (isoniazid and rifampicin) encapsulated in liposomes. , 2002, International journal of antimicrobial agents.

[65]  J. Rabinowitz,et al.  Fast Onset Medications through Thermally Generated Aerosols , 2004, Journal of Pharmacology and Experimental Therapeutics.

[66]  Pratibhash Chattopadhyay,et al.  Nanoparticles of Poorly Water-Soluble Drugs Prepared by Supercritical Fluid Extraction of Emulsions , 2006, Pharmaceutical Research.

[67]  R. Pandey,et al.  Solid lipid particle-based inhalable sustained drug delivery system against experimental tuberculosis. , 2005, Tuberculosis.

[68]  A. Hickey,et al.  Formulation challenges of powders for the delivery of small molecular weight molecules as aerosols , 2002 .

[69]  C. Remuñán-López,et al.  Microencapsulated chitosan nanoparticles for lung protein delivery. , 2005, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[70]  A. Miller,et al.  Non–invasive liposome–mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice , 1993 .

[71]  Hiroshi Terada,et al.  Preparation and properties of inhalable nanocomposite particles for treatment of lung cancer. , 2009, Colloids and surfaces. B, Biointerfaces.

[72]  Joshua D. Rabinowitz,et al.  Recirculatory Pharmacokinetic Model of the Uptake, Distribution, and Bioavailability of Prochlorperazine Administered as a Thermally Generated Aerosol in a Single Breath to Dogs , 2007, Drug Metabolism and Disposition.

[73]  M. Rymaszewski,et al.  Intravascular and endobronchial DNA delivery to murine lung tissue using a novel, nonviral vector. , 2000, Human gene therapy.

[74]  I. Kwon,et al.  A Cationic Lipid Emulsion/DNA Complex as a Physically Stable and Serum-Resistant Gene Delivery System , 2000, Pharmaceutical Research.

[75]  Huiming Yang,et al.  Liposome delivery of ciprofloxacin against intracellular Francisella tularensis infection. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[76]  A. Misra,et al.  A preliminary pharmacokinetic study of liposomal leuprolide dry powder inhaler: A technical note , 2005, AAPS PharmSciTech.

[77]  O. Danos,et al.  Polyethylenimine‐mediated gene delivery: a mechanistic study , 2001, The journal of gene medicine.

[78]  S. B. Tiwari,et al.  A review of nanocarrier-based CNS delivery systems. , 2006, Current drug delivery.

[79]  B. Padhi,et al.  Nano-liposomal dry powder inhaler of tacrolimus: Preparation, characterization, and pulmonary pharmacokinetics , 2007, International journal of nanomedicine.

[80]  J. Lehn,et al.  Gene transfer by guanidinium-cholesterol cationic lipids into airway epithelial cells in vitro and in vivo. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[81]  J. Benoit,et al.  Progress in developing cationic vectors for non-viral systemic gene therapy against cancer. , 2008, Biomaterials.

[82]  Güunter Oberdürster Toxicology of ultrafine particles: in vivo studies , 2000, Philosophical Transactions of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[83]  K. Mäder,et al.  Solid lipid nanoparticles: production, characterization and applications. , 2001, Advanced drug delivery reviews.

[84]  M. Hindle,et al.  Control of particle size by coagulation of novel condensation aerosols in reservoir chambers. , 2002, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[85]  A. D. Fougerolles Delivery vehicles for small interfering RNA in vivo. , 2008 .

[86]  M. Rafiee-Tehrani,et al.  The effect of water to ethanol feed ratio on physical properties and aerosolization behavior of spray dried cromolyn sodium particles. , 2005, Journal of pharmaceutical sciences.

[87]  F. Liu,et al.  Effect of Non-Ionic Surfactants on the Formation of DNA/Emulsion Complexes and Emulsion-Mediated Gene Transfer , 1996, Pharmaceutical Research.

[88]  Sanyog Jain,et al.  Design of liposomal aerosols for improved delivery of rifampicin to alveolar macrophages. , 2004, International journal of pharmaceutics.

[89]  Qun Wang,et al.  Spray-freeze-dried dry powder inhalation of insulin-loaded liposomes for enhanced pulmonary delivery. , 2008, Journal of drug targeting.

[90]  R. Müller,et al.  In vivo gene delivery to the lung using polyethylenimine and fractured polyamidoamine dendrimers , 2000, The journal of gene medicine.

[91]  Albert H. L. Chow,et al.  Particle Engineering for Pulmonary Drug Delivery , 2007, Pharmaceutical Research.

[92]  P. Barry,et al.  An in vitro analysis of the output of budesonide from different nebulizers. , 1999, The Journal of allergy and clinical immunology.

[93]  J. Rabinowitz,et al.  Ultra-fast absorption of amorphous pure drug aerosols via deep lung inhalation. , 2006, Journal of pharmaceutical sciences.

[94]  P. Heegaard,et al.  Dendrimers in drug research. , 2004, Chemical Society reviews.

[95]  B. Bistrian,et al.  Physicochemical stability of total nutrient admixtures. , 1995, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[96]  N. Rasenack,et al.  Micronization of anti-inflammatory drugs for pulmonary delivery by a controlled crystallization process. , 2003, Journal of pharmaceutical sciences.

[97]  A. Goetz,et al.  Colloidal gold particles as a new in vivo marker of early acute lung injury. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[98]  H. Okamoto,et al.  Dual imaging of pulmonary delivery and gene expression of dry powder inhalant by fluorescence and bioluminescence. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[99]  Ji-Eun Kim,et al.  Poly(ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis. , 2008, American journal of respiratory and critical care medicine.

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

[101]  C. Sioutas,et al.  A Methodology for Measuring Size-Dependent Chemical Composition of Ultrafine Particles , 2002 .

[102]  Andreas Zimmer,et al.  Microspheres and nanoparticles used in ocular delivery systems , 1995 .

[103]  M. Ogris,et al.  Tumor-Targeted Gene Transfer with DNA Polyplexes , 2002, Somatic cell and molecular genetics.

[104]  Byron Ballou,et al.  Noninvasive imaging of quantum dots in mice. , 2004, Bioconjugate chemistry.

[105]  T. Wagner,et al.  Incorporation of biodegradable nanoparticles into human airway epithelium cells-in vitro study of the suitability as a vehicle for drug or gene delivery in pulmonary diseases. , 2004, Biochemical and biophysical research communications.

[106]  Â. M. Moraes,et al.  Incorporation of Antibiotics in Liposomes Designed for Tuberculosis Therapy by Inhalation , 2003, Drug delivery.

[107]  R. Prassl,et al.  Association of vasoactive intestinal peptide with polymer-grafted liposomes: structural aspects for pulmonary delivery. , 2007, Biochimica et biophysica acta.

[108]  H. Katinger,et al.  Increased biological half-life of aerosolized liposomal recombinant human Cu/Zn superoxide dismutase in pigs. , 2008, Journal of aerosol medicine and pulmonary drug delivery.

[109]  J. Kreuter Nanoparticle-based dmg delivery systems , 1991 .

[110]  Y. Maa,et al.  Spray-drying performance of a bench-top spray dryer for protein aerosol powder preparation. , 1998, Biotechnology and bioengineering.

[111]  Shuhua Bai,et al.  Dendrimers as a carrier for pulmonary delivery of enoxaparin, a low-molecular weight heparin. , 2007, Journal of pharmaceutical sciences.

[112]  S. Vyas,et al.  Aerosolized liposome-based delivery of amphotericin B to alveolar macrophages. , 2005, International journal of pharmaceutics.

[113]  K. Taylor,et al.  The stability of liposomes to nebulisation , 1990 .

[114]  S. Bates,et al.  Analysis of Amorphous and Nanocrystalline Solids from Their X-Ray Diffraction Patterns , 2006, Pharmaceutical Research.

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

[116]  M. Sakagami,et al.  In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery. , 2006, Advanced drug delivery reviews.

[117]  Shohei Sugimoto,et al.  Surface-modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellular tight junctions. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[118]  C. Verschraegen,et al.  Clinical Evaluation of the Delivery and Safety of Aerosolized Liposomal 9-Nitro-20(S)-Camptothecin in Patients with Advanced Pulmonary Malignancies , 2004, Clinical Cancer Research.

[119]  A. Misra,et al.  Liposomal amphotericin B dry powder inhaler: effect of fines on in vitro performance. , 2004, Die Pharmazie.

[120]  H. Schreier,et al.  Pulmonary delivery of liposomes , 1993 .

[121]  Günter Oberdörster,et al.  Toxicology of ultrafine particles: in vivo studies , 2000 .

[122]  W. Gu,et al.  Gene transfer of vascular endothelial growth factor reduces bleomycin‐induced pulmonary hypertension in immature rabbits , 2005, Pediatrics international : official journal of the Japan Pediatric Society.

[123]  K. Westesen,et al.  Novel lipid-based colloidal dispersions as potential drug administration systems – expectations and reality , 2000 .

[124]  C. Densmore,et al.  Pulmonary cytokine responses associated with PEI–DNA aerosol gene therapy , 2001, Gene Therapy.

[125]  Ick Chan Kwon,et al.  Polymeric nanomedicine for cancer therapy , 2008 .

[126]  R. Prassl,et al.  Inhalable liposomal formulation for vasoactive intestinal peptide. , 2008, International journal of pharmaceutics.

[127]  W. Kreyling,et al.  Translocation of Inhaled Ultrafine Particles to the Brain , 2004, Inhalation toxicology.

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

[129]  A. Saleki-Gerhardt,et al.  Assessment of disorder in crystalline solids , 1994 .

[130]  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.

[131]  J. Coll,et al.  Side‐effects of a systemic injection of linear polyethylenimine–DNA complexes , 2002, The journal of gene medicine.

[132]  Stephanie E. A. Gratton,et al.  The effect of particle design on cellular internalization pathways , 2008, Proceedings of the National Academy of Sciences.

[133]  S. Cryan,et al.  Carrier-based strategies for targeting protein and peptide drugs to the lungs , 2005, The AAPS Journal.

[134]  M. Botelho,et al.  Lymphatic Uptake of Pulmonary Delivered Radiolabelled Solid Lipid Nanoparticles , 2002, Journal of drug targeting.

[135]  G. P. Martin,et al.  The use of different grades of lactose as a carrier for aerosolised salbutamol sulphate. , 1999, International journal of pharmaceutics.

[136]  Nilesh Patel,et al.  Drug permeability in 16HBE14o- airway cell layers correlates with absorption from the isolated perfused rat lung. , 2005, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[137]  G. Oberdörster,et al.  Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles , 2005, Environmental health perspectives.

[138]  Hiromitsu,et al.  Effect of Surface Morphology of Carrier Lactose on Dry Powder Inhalation Property of Pranlukast Hydrate. , 1998 .

[139]  Min-Ki Lee,et al.  Air-liquid interface (ALI) culture of human bronchial epithelial cell monolayers as an in vitro model for airway drug transport studies. , 2007, Journal of pharmaceutical sciences.

[140]  Barrett E. Rabinow,et al.  Nanosuspensions in drug delivery , 2004, Nature Reviews Drug Discovery.

[141]  B. Müller,et al.  Metered-dose inhaler formulation of fluticasone-17-propionate micronized with supercritical carbon dioxide using the alternative propellant HFA-227 , 1998 .

[142]  A. Misra,et al.  Disposition kinetics of ketotifen from liposomal dry powder for inhalation in rat lung , 2003, Clinical and experimental pharmacology & physiology.

[143]  David B. Kittelson,et al.  Impact of Ambient Temperatures and Driving Conditions on the Chemical Composition of Particulate Matter Emissions from Non-Smoking Gasoline-Powered Motor Vehicles , 2008 .

[144]  A. Zimmer,et al.  Depot formulation of vasoactive intestinal peptide by protamine-based biodegradable nanoparticles. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[145]  K. Johnston,et al.  High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers. , 2008, International journal of pharmaceutics.

[146]  F. Separovic,et al.  Physicochemical characterization and stability of rifampicin liposome dry powder formulations for inhalation. , 2009, Journal of pharmaceutical sciences.

[147]  Joseph Rosenecker,et al.  Application of Novel Solid Lipid Nanoparticle (SLN)-Gene Vector Formulations Based on a Dimeric HIV-1 TAT-Peptide in Vitro and in Vivo , 2004, Pharmaceutical Research.

[148]  B. Shekunov,et al.  Production of solid lipid nanoparticle suspensions using supercritical fluid extraction of emulsions (SFEE) for pulmonary delivery using the AERx system. , 2007, Advanced drug delivery reviews.

[149]  F. Vanderbist,et al.  Optimization of a Dry Powder Inhaler Formulation of Nacystelyn, a New Mucoactive Agent , 1999, The Journal of pharmacy and pharmacology.

[150]  Jean W. Tom,et al.  Particle formation with supercritical fluids—a review , 1991 .

[151]  M. Gilchrist,et al.  Inhibition of Allergic Inflammation in the Airways Using Aerosolized Antisense to Syk Kinase1 , 2002, The Journal of Immunology.

[152]  K. Audus,et al.  Characterization of the A549 cell line as a type II pulmonary epithelial cell model for drug metabolism. , 1998, Experimental cell research.

[153]  Ji Guo,et al.  Nanofabricated particles for engineered drug therapies: a preliminary biodistribution study of PRINT nanoparticles. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[154]  P. Anderson,et al.  Interleukin‐2 liposome inhalation therapy is safe and effective for dogs with spontaneous pulmonary metastases , 1997, Cancer.

[155]  K. Järvinen,et al.  Effects of carriers and storage of formulation on the lung deposition of a hydrophobic and hydrophilic drug from a DPI. , 2003, International journal of pharmaceutics.

[156]  J. Lagacé,et al.  Aerosolization of low phase transition temperature liposomal tobramycin as a dry powder in an animal model of chronic pulmonary infection caused by Pseudomonas aeruginosa. , 1999, Journal of drug targeting.

[157]  Wen-Yinn Lin,et al.  Characteristics of metals in nano/ultrafine/fine/coarse particles collected beside a heavily trafficked road. , 2005, Environmental science & technology.

[158]  K. Audus,et al.  Characterization of the Calu-3 cell line as a tool to screen pulmonary drug delivery. , 2000, International journal of pharmaceutics.

[159]  E. Kleinerman,et al.  Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI– p53 complexes , 2001, Cancer Gene Therapy.

[160]  Satya Sardar,et al.  Size-fractionated measurements of ambient ultrafine particle chemical composition in Los Angeles using the NanoMOUDI. , 2005, Environmental science & technology.

[161]  Leaf Huang,et al.  An efficient and low immunostimulatory nanoparticle formulation for systemic siRNA delivery to the tumor. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[162]  C. Roberts,et al.  Towards screening of inhalation formulations: measuring interactions with atomic force microscopy , 2005, Expert opinion on drug delivery.

[163]  W. Seeger,et al.  Pulmonary drug delivery with aerosolizable nanoparticles in an ex vivo lung model. , 2009, International journal of pharmaceutics.

[164]  Xiuli Wang,et al.  Solid lipid nanoparticles for pulmonary delivery of insulin. , 2008, International journal of pharmaceutics.

[165]  E. Munson,et al.  Nifedipine nanoparticle agglomeration as a dry powder aerosol formulation strategy. , 2009, International journal of pharmaceutics.

[166]  Rajesh Pandey,et al.  Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis. , 2003, The Journal of antimicrobial chemotherapy.

[167]  N. McElvaney,et al.  Delivery of rSLPI in a liposomal carrier for inhalation provides protection against cathepsin L degradation , 2009, Journal of microencapsulation.

[168]  Stephen P. Newman,et al.  Improved Lung Delivery from a Passive Dry Powder Inhaler Using an Engineered PulmoSphere® Powder , 2002, Pharmaceutical Research.

[169]  F. Szoka,et al.  The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complexes , 1997, Gene Therapy.

[170]  W. Seeger,et al.  Effects of cell‐penetrating peptides and pegylation on transfection efficiency of polyethylenimine in mouse lungs , 2008, The journal of gene medicine.

[171]  K. Johnston,et al.  Single dose and multiple dose studies of itraconazole nanoparticles. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[172]  Steven J. Shire,et al.  Protein Inhalation Powders: Spray Drying vs Spray Freeze Drying , 1999, Pharmaceutical Research.

[173]  A. Rolland,et al.  Ultrasonic Nebulization of Cationic Lipid-Based Gene Delivery Systems for Airway Administration , 1998, Pharmaceutical Research.

[174]  M. Bando,et al.  Evidence that exogenous substances can be phagocytized by alveolar epithelial cells and transported into blood capillaries , 2002, Cell and Tissue Research.

[175]  D. Liggitt,et al.  Aerosol gene delivery in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[176]  Ben Forbes,et al.  Human respiratory epithelial cell culture for drug delivery applications. , 2005, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[177]  J. Greenberger,et al.  Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage , 2005, Gene Therapy.

[178]  J. Rodarte,et al.  Tolerance of volunteers to cyclosporine A-dilauroylphosphatidylcholine liposome aerosol. , 1997, American journal of respiratory and critical care medicine.

[179]  Robert Gelein,et al.  EXTRAPULMONARY TRANSLOCATION OF ULTRAFINE CARBON PARTICLES FOLLOWING WHOLE-BODY INHALATION EXPOSURE OF RATS , 2002, Journal of toxicology and environmental health. Part A.

[180]  I. Kellaway,et al.  Preparation and subsequent degradation of poly(l-lactic acid) microspheres suitable for aerosolisation: a physico-chemical study , 1997 .

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

[182]  Stefaan C. De Smedt,et al.  Cationic Polymer Based Gene Delivery Systems , 2000, Pharmaceutical Research.

[183]  H. Talsma,et al.  Particle size in parenteral fat emulsions, what are the true limitations? , 1996 .

[184]  G. P. Martin,et al.  The controlled delivery of drugs to the lung , 1995 .

[185]  D. Scherman,et al.  Sterically stabilized BGTC‐based lipoplexes: structural features and gene transfection into the mouse airways in vivo , 2001, The journal of gene medicine.

[186]  Rainer H. Müller,et al.  Cytotoxicity of Solid Lipid Nanoparticles as a Function of the Lipid Matrix and the Surfactant , 1997, Pharmaceutical Research.

[187]  S J Prestrelski,et al.  Biopharmaceutical powders: particle formation and formulation considerations. , 2000, Current pharmaceutical biotechnology.

[188]  W. Finlay,et al.  Spray-freeze-dried liposomal ciprofloxacin powder for inhaled aerosol drug delivery. , 2005, International journal of pharmaceutics.

[189]  J. DeSimone,et al.  Microfabricated Particles for Engineered Drug Therapies: Elucidation into the Mechanisms of Cellular Internalization of PRINT Particles , 2008, Pharmaceutical Research.

[190]  P. Artursson,et al.  Improved chitosan-mediated gene delivery based on easily dissociated chitosan polyplexes of highly defined chitosan oligomers , 2004, Gene Therapy.

[191]  D. Resnik,et al.  Ethical issues in clinical trials involving nanomedicine. , 2007, Contemporary clinical trials.

[192]  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.

[193]  P. Gangadharam,et al.  Efficacy of liposomal budesonide in experimental asthma. , 2003, The Journal of allergy and clinical immunology.

[194]  H. Okada,et al.  One-step preparation of rifampicin/poly(lactic-co-glycolic acid) nanoparticle-containing mannitol microspheres using a four-fluid nozzle spray drier for inhalation therapy of tuberculosis. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[195]  C. Ehrhardt,et al.  Drug absorption by the respiratory mucosa: cell culture models and particulate drug carriers. , 2002, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[196]  C. Densmore Advances in noninvasive pulmonary gene therapy. , 2006, Current drug delivery.

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

[198]  Qiang Zhang,et al.  Prolonged hypoglycemic effect of insulin-loaded polybutylcyanoacrylate nanoparticles after pulmonary administration to normal rats. , 2001, International journal of pharmaceutics.

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

[200]  Gregory W. Sluggett,et al.  EXUBERA: pharmaceutical development of a novel product for pulmonary delivery of insulin. , 2005, Diabetes technology & therapeutics.

[201]  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.

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

[203]  N. Templeton Nonviral Delivery for Genomic Therapy of Cancer , 2009, World Journal of Surgery.

[204]  Xihao Li,et al.  Stability and characterization of perphenazine aerosols generated using the capillary aerosol generator. , 2005, International journal of pharmaceutics.

[205]  C. Densmore,et al.  Inhibition of experimental lung metastasis by aerosol delivery of PEI-p53 complexes. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[206]  Leaf Huang,et al.  Surface‐Modified LPD Nanoparticles for Tumor Targeting , 2006, Annals of the New York Academy of Sciences.

[207]  G. Hochhaus,et al.  Methods used to assess pulmonary deposition and absorption of drugs. , 2001, Drug discovery today.

[208]  T. Seki,et al.  Influence of particle size on drug delivery to rat alveolar macrophages following pulmonary administration of ciprofloxacin incorporated into liposomes , 2006, Journal of drug targeting.

[209]  R. Müller,et al.  Nonviral gene delivery to the lung with copolymer-protected and transferrin-modified polyethylenimine. , 2002, Biochimica et biophysica acta.

[210]  P. Hopke,et al.  Characterization of Wintertime Reactive Oxygen Species Concentrations in Flushing, New York , 2007 .

[211]  U. Klotz,et al.  The influence of chitosan content in cationic chitosan/PLGA nanoparticles on the delivery efficiency of antisense 2'-O-methyl-RNA directed against telomerase in lung cancer cells. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

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

[213]  B. Müller,et al.  Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide , 1997 .

[214]  B. Shekunov,et al.  Drug encapsulation using supercritical fluid extraction of emulsions. , 2006, Journal of pharmaceutical sciences.

[215]  B. Gander,et al.  Ultrasonic atomisation into reduced pressure atmosphere--envisaging aseptic spray-drying for microencapsulation. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[216]  Vladimir P Torchilin,et al.  Self-assembling micelle-like nanoparticles based on phospholipid-polyethyleneimine conjugates for systemic gene delivery. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[217]  N. Behan,et al.  Factors controlling particle size during nebulization of DNA-polycation complexes. , 2007, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[218]  S. L. Hyatt,et al.  Minimal toxicity of stabilized compacted DNA nanoparticles in the murine lung. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[219]  S. Carotta,et al.  Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo , 2001, The journal of gene medicine.

[220]  Nanoparticle technology for drug delivery: from nanoparticles to cutting-edge delivery strategies - part I. , 2005, IDrugs : the investigational drugs journal.

[221]  Douglas D. Mcrae,et al.  Investigation of a Novel Condensation Aerosol Generator: Solute and Solvent Effects , 2003 .

[222]  H. Junginger,et al.  Transport and local metabolism of budesonide and fluticasone propionate in a human bronchial epithelial cell line (Calu-3). , 2002, Journal of pharmaceutical sciences.

[223]  D. Geddes,et al.  Safety of a single aerosol administration of escalating doses of the cationic lipid GL-67/DOPE/DMPE-PEG5000 formulation to the lungs of normal volunteers , 1998, Gene Therapy.