Pharmaceutical Research

, Volume 26, Issue 7, pp 1752–1763 | Cite as

Combination Chemotherapeutic Dry Powder Aerosols via Controlled Nanoparticle Agglomeration

  • Nashwa El-Gendy
  • Cory BerklandEmail author
Research Paper



To develop an aerosol system for efficient local lung delivery of chemotherapeutics where nanotechnology holds tremendous potential for developing more valuable cancer therapies. Concurrently, aerosolized chemotherapy is generating interest as a means to treat certain types of lung cancer more effectively with less systemic exposure to the compound.


Nanoparticles of the potent anticancer drug, paclitaxel, were controllably assembled to form low density microparticles directly after preparation of the nanoparticle suspension. The amino acid, l-leucine, was used as a colloid destabilizer to drive the assembly of paclitaxel nanoparticles. A combination chemotherapy aerosol was formed by assembling the paclitaxel nanoparticles in the presence of cisplatin in solution.


Freeze-dried powders of the combination chemotherapy possessed desirable aerodynamic properties for inhalation. In addition, the dissolution rates of dried nanoparticle agglomerate formulations (∼60% to 66% after 8 h) were significantly faster than that of micronized paclitaxel powder as received (∼18% after 8 h). Interestingly, the presence of the water soluble cisplatin accelerated the dissolution of paclitaxel.


Nanoparticle agglomerates of paclitaxel alone or in combination with cisplatin may serve as effective chemotherapeutic dry powder aerosols to enable regional treatment of certain lung cancers.


cisplatin combination chemotherapy dry powder nanoparticle agglomerates paclitaxel 



We would like to acknowledge support for this work from the Coulter Foundation, the Higuchi Biosciences Center, and the Cystic Fibrosis Foundation as well as additional lab funding from the American Heart Association, the NIH (R03 AR054035, P20 RR016443 and T32 GM08359-11) and the Department of Defense. In addition, we acknowledge the support of the NSF (CHE 0719464). We also thank Prof. C. Russ Middaugh for the use of laboratory equipment and The Microscopy Lab for assistance with electron microscopy.

Supplementary material

11095_2009_9886_MOESM1_ESM.pdf (2.5 mb)
Supplementary Figure 1. Viability of A549 cells in the presence of formulation components A) F1 and B) F2 paclitaxel nanoparticle agglomerates as determined by an MTS assay. (PDF 2.50 MB)


  1. 1.
    Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008;15:504–14. doi: 10.1038/sj.cdd.4402283.PubMedCrossRefGoogle Scholar
  2. 2.
    Collins LG, Haines C, Perkel R, Enck RE. Lung cancer: diagnosis and management. Am Fam Phys 2007;75:56–63.Google Scholar
  3. 3.
    Hitzman CJ, Wattenberg LW, Wiedmann TS. Pharmacokinetics of 5-fluorouracil in the hamster following inhalation delivery of lipid-coated nanoparticles. J Pharm Sci 2006;95:1196–211. doi: 10.1002/jps.20607.PubMedCrossRefGoogle Scholar
  4. 4.
    Maillet A, Congy-Jolivet N, Le Guellec S, Vecellio L, Hamard S, Courty Y, et al. Aerodynamical, immunological and pharmacological properties of the anticancer antibody cetuximab following nebulization. Pharm Res 2008;25:1318–26. doi: 10.1007/s11095-007-9481-3.PubMedCrossRefGoogle Scholar
  5. 5.
    Scheuch G, Kohlhaeufl MJ, Brand P, Siekmeier R. Clinical perspectives on pulmonary systemic and macromolecular delivery. Adv Drug Deliv Rev 2006;58:996–1008. doi: 10.1016/j.addr.2006.07.009.PubMedCrossRefGoogle Scholar
  6. 6.
    Chougule MB, Padhi BK, Jinturkar KA, Misra A. Development of dry powder inhalers. Recent Pat Drug Deliv Formul 2007;1:11–21. doi: 10.2174/187221107779814159.PubMedCrossRefGoogle Scholar
  7. 7.
    Bosquillon C, Lombry C, Preat V, Vanbever R. Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance. J Control Release 2001;70:329–39. doi: 10.1016/S0168-3659(00)00362-X.PubMedCrossRefGoogle Scholar
  8. 8.
    Gagnadoux F, Hureaux J, Vecellio L, Urban T, Le Pape A, Valo I, et al. Aerosolized chemotherapy. J Aerosol Med Pulm Drug Deliv 2008;21:61–70. doi: 10.1089/jamp.2007.0656.PubMedCrossRefGoogle Scholar
  9. 9.
    Gagnadoux F, Pape AL, Lemarie E, Lerondel S, Valo I, Leblond V, et al. Aerosol delivery of chemotherapy in an orthotopic model of lung cancer. Eur Respir J 2005;26:657–61. doi: 10.1183/09031936.05.00017305.PubMedCrossRefGoogle Scholar
  10. 10.
    Praetorius NP, Mandal TK. Engineered nanoparticles in cancer therapy. Recent Pat Drug Deliv Formul 2007;1:37–51. doi: 10.2174/187221107779814104.PubMedCrossRefGoogle Scholar
  11. 11.
    Medina C, Santos-Martinez MJ, Radomski A, Corrigan OI, Radomski MW. Nanoparticles: pharmacological and toxicological significance. Br J Pharmacol 2007;150:552–8. doi: 10.1038/sj.bjp.0707130.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang Z, Feng SS. Nanoparticles of poly(lactide)/vitamin E TPGS copolymer for cancer chemotherapy: synthesis, formulation, characterization and in vitro drug release. Biomaterials 2006;27:262–70. doi: 10.1016/j.biomaterials.2005.05.104.PubMedCrossRefGoogle Scholar
  13. 13.
    Lindfors L, Skantze P, Skantze U, Westergren J, Olsson U. Amorphous drug nanosuspensions. 3. Particle dissolution and crystal growth. Langmuir 2007;23:9866–74. doi: 10.1021/la700811b.PubMedCrossRefGoogle Scholar
  14. 14.
    Matteucci ME, Hotze MA, Johnston KP, Williams RO 3rd. Drug nanoparticles by antisolvent precipitation: mixing energy versus surfactant stabilization. Langmuir 2006;22:8951–9. doi: 10.1021/la061122t.PubMedCrossRefGoogle Scholar
  15. 15.
    Rabinow BE. Nanosuspensions in drug delivery. Nat Rev Drug Discov 2004;3:785–96. doi: 10.1038/nrd1494.PubMedCrossRefGoogle Scholar
  16. 16.
    Tam JM, McConville JT, Williams RO 3rd, Johnston KP. Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution. J Pharm Sci 2008;97:4915–33. doi: 10.1002/jps.21367.PubMedCrossRefGoogle Scholar
  17. 17.
    Sepassi S, Goodwin DJ, Drake AF, Holland S, Leonard G, Martini L, et al. Effect of polymer molecular weight on the production of drug nanoparticles. J Pharm Sci 2007;96:2655–66. doi: 10.1002/jps.20979.PubMedCrossRefGoogle Scholar
  18. 18.
    Young PM, Chan HK, Chiou H, Edge S, Tee TH, Traini D. The influence of mechanical processing of dry powder inhaler carriers on drug aerosolization performance. J Pharm Sci 2007;96:1331–41. doi: 10.1002/jps.20933.PubMedCrossRefGoogle Scholar
  19. 19.
    Lindfors L, Forssen S, Skantze P, Skantze U, Zackrisson A, Olsson U. Amorphous drug nanosuspensions. 2. Experimental determination of bulk monomer concentrations. Langmuir 2006;22:911–6. doi: 10.1021/la052367t.PubMedCrossRefGoogle Scholar
  20. 20.
    Telkoand MJ, Hickey AJ. Dry powder inhaler formulation. Respir Care 2005;50:1209–27.Google Scholar
  21. 21.
    Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 2003;56:588–99. doi: 10.1046/j.1365-2125.2003.01892.x.PubMedCrossRefGoogle Scholar
  22. 22.
    Bhavna, Ahmad FJ, Khar RK, Sultana S, Bhatnagar A. Techniques to develop and characterize nanosized formulation for salbutamol sulfate. J Mater Sci Mater Med. 2008.Google Scholar
  23. 23.
    Chan H-K, Chew NYK. Novel alternative methods for the delivery of drugs for the treatment of asthma. Adv Drug Deliv Rev 2003;55:793–805. doi: 10.1016/S0169-409X(03)00078-4.PubMedCrossRefGoogle Scholar
  24. 24.
    N.C.C.N. Lung Cancer. Treatment Guidelines for patients. Version III:1–88 (2006).Google Scholar
  25. 25.
    Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, et al. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 2002;13:1539–49. doi: 10.1093/annonc/mdf332.PubMedCrossRefGoogle Scholar
  26. 26.
    Loehrer PJ Sr, Rynard S, Ansari R, Songer J, Pennington K, Einhorn L. Etoposide, ifosfamide, and cisplatin in extensive small cell lung cancer. Cancer 1992;69:669–73. doi: 10.1002/1097-0142(19920201)69:3<669::AID-CNCR2820690312>3.0.CO;2-V.PubMedCrossRefGoogle Scholar
  27. 27.
    Samelis GF, Ekmektzoglou KA, Xanthos T, Zografos GC. Small-cell lung cancer: an unusual therapeutic approach with more than 10-year overall survival. Case report and review of the literature. Tumori 2008;94:612–6.PubMedGoogle Scholar
  28. 28.
    Bhutani M, Pathak AK, Mohan A, Guleria R, Kochupillai V. Small cell lung cancer: an update on therapeutic aspects. Indian J Chest Dis Allied Sci 2006;48:49–57.PubMedGoogle Scholar
  29. 29.
    Earle CC, Coyle D, Evans WK. Cost-effectiveness analysis in oncology. Ann Oncol 1998;9:475–82. doi: 10.1023/A:1008292128615.PubMedCrossRefGoogle Scholar
  30. 30.
    Peltier S, Oger JM, Lagarce F, Couet W, Benoit JP. Enhanced oral paclitaxel bioavailability after administration of paclitaxel-loaded lipid nanocapsules. Pharm Res 2006;23:1243–50. doi: 10.1007/s11095-006-0022-2.PubMedCrossRefGoogle Scholar
  31. 31.
    Koziara JM, Lockman PR, Allen DD, Mumper RJ. Paclitaxel nanoparticles for the potential treatment of brain tumors. J Control Release 2004;99:259–69. doi: 10.1016/j.jconrel.2004.07.006.PubMedCrossRefGoogle Scholar
  32. 32.
    Yamamoto K, Kikuchi Y, Kudoh K, Hirata J, Kita T, Nagata I. Treatment with paclitaxel alone rather than combination with paclitaxel and cisplatin may be selective for cisplatin-resistant ovarian carcinoma. Jpn J Clin Oncol 2000;30:446–9. doi: 10.1093/jjco/hyd116.PubMedCrossRefGoogle Scholar
  33. 33.
    Singla AK, Garg A, Aggarwal D. Paclitaxel and its formulations. Int J Pharm 2002;235:179–92. doi: 10.1016/S0378-5173(01)00986-3.PubMedCrossRefGoogle Scholar
  34. 34.
    Liu Y, Chen GS, Chen Y, Cao DX, Ge ZQ, Yuan YJ. Inclusion complexes of paclitaxel and oligo(ethylenediamino) bridged bis(beta-cyclodextrin)s: solubilization and antitumor activity. Bioorg Med Chem 2004;12:5767–75. doi: 10.1016/j.bmc.2004.08.040.PubMedCrossRefGoogle Scholar
  35. 35.
    Ramachandran S, Quist AP, Kumar S, Lal R. Cisplatin nanoliposomes for cancer therapy: AFM and fluorescence imaging of cisplatin encapsulation, stability, cellular uptake, and toxicity. Langmuir 2006;22:8156–62. doi: 10.1021/la0607499.PubMedCrossRefGoogle Scholar
  36. 36.
    Uchino H, Matsumura Y, Negishi T, Koizumi F, Hayashi T, Honda T, et al. Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats. Br J Cancer 2005;93:678–87. doi: 10.1038/sj.bjc.6602772.PubMedCrossRefGoogle Scholar
  37. 37.
    Nishiyama N, Okazaki S, Cabral H, Miyamoto M, Kato Y, Sugiyama Y, et al. Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. Cancer Res 2003;63:8977–83.PubMedGoogle Scholar
  38. 38.
    Staniforth JN. Powder flow. In: Aulton ME, editor. Pharmaceutics: the science of dosage form design. London: Churchill Livingstone; 2002. p. 205–8.Google Scholar
  39. 39.
    Kumar V, Kothari SH, Banker GS. Compression, compaction, and disintegration properties of low crystallinity celluloses produced using different agitation rates during their regeneration from phosphoric acid solutions. AAPS PharmSciTech 2001;2:E7. doi: 10.1208/pt020207.PubMedCrossRefGoogle Scholar
  40. 40.
    Chow AHL, Tong HHY, Chattopadhyay P, Shekunov BY. Particle engineering for pulmonary drug delivery. Pharm Res 2007;24:411–37. doi: 10.1007/s11095-006-9174-3.PubMedCrossRefGoogle Scholar
  41. 41.
    Vanbever R, Mintzes JD, Wang J, Nice J, Chen D, Batycky R, et al. Formulation and physical characterization of large porous particles for inhalation. Pharm Res 1999;16:1735–42. doi: 10.1023/A:1018910200420.PubMedCrossRefGoogle Scholar
  42. 42.
    Fiegel J, Garcia-Contreras L, Thomas M, VerBerkmoes J, Elbert K, Hickey A, et al. Preparation and in vivo evaluation of a dry powder for inhalation of capreomycin. Pharm Res 2008;25:805–11. doi: 10.1007/s11095-007-9381-6.PubMedCrossRefGoogle Scholar
  43. 43.
    Yang ZY, Le Y, Hu TT, Shen Z, Chen JF, Yun J. Production of ultrafine sumatriptan succinate particles for pulmonary delivery. Pharm Res 2008;25:2012–8. doi: 10.1007/s11095-008-9586-3.PubMedCrossRefGoogle Scholar
  44. 44.
    Lechuga-Ballesteros D, Charan C, Stults CL, Stevenson CL, Miller DP, Vehring R, et al. Trileucine improves aerosol performance and stability of spray-dried powders for inhalation. J Pharm Sci 2008;97:287–302. doi: 10.1002/jps.21078.PubMedCrossRefGoogle Scholar
  45. 45.
    Pham S, Wiedmann TS. Note: dissolution of aerosol particles of budesonide in Survanta, a model lung surfactant. J Pharm Sci 2001;90:98–104. doi: 10.1002/1520-6017(200101)90:1<98::AID-JPS11>3.0.CO;2-5.PubMedCrossRefGoogle Scholar
  46. 46.
    Vanbever R, Ben-Jebria A, Mintzes JD, Langer R, Edwards DA. Sustained release of insulin from insoluble inhaled particles. Drug Dev Res 1999;48:178–85. doi: 10.1002/(SICI)1098-2299(199912)48:4<178::AID-DDR5>3.0.CO;2-I.CrossRefGoogle Scholar
  47. 47.
    Hu Y, Xie J, Tong YW, Wang CH. Effect of PEG conformation and particle size on the cellular uptake efficiency of nanoparticles with the HepG2 cells. J Control Release 2007;118:7–17. doi: 10.1016/j.jconrel.2006.11.028.PubMedCrossRefGoogle Scholar
  48. 48.
    Avgoustakis K, Beletsi A, Panagi Z, Klepetsanis P, Karydas AG, Ithakissios DS. PLGA-mPEG nanoparticles of cisplatin: in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties. J Control Release 2002;79:123–35. doi: 10.1016/S0168-3659(01)00530-2.PubMedCrossRefGoogle Scholar
  49. 49.
    Lu Z, Yeh TK, Tsai M, Au JL, Wientjes MG. Paclitaxel-loaded gelatin nanoparticles for intravesical bladder cancer therapy. Clin Cancer Res 2004;10:7677–84. doi: 10.1158/1078-0432.CCR-04-1443.PubMedCrossRefGoogle Scholar
  50. 50.
    Soundara Manickam D, Bisht HS, Wan L, Mao G, Oupicky D. Influence of TAT-peptide polymerization on properties and transfection activity of TAT/DNA polyplexes. J Control Release 2005;102:293–306. doi: 10.1016/j.jconrel.2004.09.018.PubMedCrossRefGoogle Scholar
  51. 51.
    Bandi N, Kompella UB. Budesonide reduces multidrug resistance-associated protein 1 expression in an airway epithelial cell line (Calu-1). Eur J Pharmacol 2002;437:9–17. doi: 10.1016/S0014-2999(02)01267-0.PubMedCrossRefGoogle Scholar
  52. 52.
    Matteucci ME, Brettmann BK, Rogers TL, Elder EJ, Williams RO 3rd, Johnston KP. Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Mol Pharm 2007;4:782–93. doi: 10.1021/mp0700211.PubMedCrossRefGoogle Scholar
  53. 53.
    Bilati U, Allemann E, Doelker E. Development of a nanoprecipitation method intended for the entrapment of hydrophilic drugs into nanoparticles. Eur J Pharm Sci 2005;24:67–75. doi: 10.1016/j.ejps.2004.09.011.PubMedCrossRefGoogle Scholar
  54. 54.
    Govender T, Stolnik S, Garnett MC, Illum L, Davis SS. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J Control Release 1999;57:171–85. doi: 10.1016/S0168-3659(98)00116-3.PubMedCrossRefGoogle Scholar
  55. 55.
    Kumar PV, Jain NK. Suppression of agglomeration of ciprofloxacin-loaded human serum albumin nanoparticles. AAPS PharmSciTech 2007;8:17. doi: 10.1208/pt0801017.PubMedCrossRefGoogle Scholar
  56. 56.
    Shi LJ, Berkland C. pH-Triggered dispersion of nanoparticle clusters. Adv Mater 2006;18:2315–9. doi: 10.1002/adma.200600610.CrossRefGoogle Scholar
  57. 57.
    Shi L, Plumley CJ, Berkland C. Biodegradable nanoparticle flocculates for dry powder aerosol formulation. Langmuir 2007;23:10897–901. doi: 10.1021/la7020098.PubMedCrossRefGoogle Scholar
  58. 58.
    Fiegel J, Fu J, Hanes J. Poly(ether-anhydride) dry powder aerosols for sustained drug delivery in the lungs. J Control Release 2004;96:411–23. doi: 10.1016/j.jconrel.2004.02.018.PubMedCrossRefGoogle Scholar
  59. 59.
    Shur J, Nevell TG, Ewen RJ, Price R, Smith A, Barbu E, et al. Cospray-dried unfractionated heparin with L-leucine as a dry powder inhaler mucolytic for cystic fibrosis therapy. J Pharm Sci 2008;97:4857–68. doi: 10.1002/jps.21362.PubMedCrossRefGoogle Scholar
  60. 60.
    Young PM, Cocconi D, Colombo P, Bettini R, Price R, Steele DF, et al. Characterization of a surface modified dry powder inhalation carrier prepared by “particle smoothing”. J Pharm Pharmacol 2002;54:1339–44. doi: 10.1211/002235702760345400.PubMedCrossRefGoogle Scholar
  61. 61.
    Chew NY, Shekunov BY, Tong HH, Chow AH, Savage C, Wu J, et al. Effect of amino acids on the dispersion of disodium cromoglycate powders. J Pharm Sci 2005;94:2289–300. doi: 10.1002/jps.20426.PubMedCrossRefGoogle Scholar
  62. 62.
    Liggins RT, Hunter WL, Burt HM. Solid-state characterization of paclitaxel. J Pharm Sci 1997;86:1458–63. doi: 10.1021/js9605226.PubMedCrossRefGoogle Scholar
  63. 63.
    Gi U-S, Min B, Lee JH, Kim J-H. Preparation and characterization of paclitaxel from plant cell culture. Korean J Chem Eng 2004;21:816–20. doi: 10.1007/BF02705526.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Pharmaceutical ChemistryThe University of KansasLawrenceUSA
  2. 2.Department of Chemical and Petroleum EngineeringThe University of KansasLawrenceUSA
  3. 3.The University of KansasLawrenceUSA

Personalised recommendations