Nanocarriers in effective pulmonary delivery of siRNA: current approaches and challenges

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669), 806 (1998). •• Explain how siRNA works in gene silencing.
  Medline CASGoogle Scholar
• 2. Fire AZ, Mello CC. The nobel prize in physiology or medicine 2006. (2006) http://www.nobelprize.org/nobel_prizes/medicine/laureates
  Google Scholar
• 3. Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8(2), 129 (2009).
  Medline CASGoogle Scholar
• 4. Zamore PD. RNA interference: listening to the sound of silence. Nat. Struct. Mol. Biol. 8(9), 746 (2001).
  CASGoogle Scholar
• 5. Kaiser PK, Symons RA, Shah SM et al. RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027. Am. J. Ophthalmol. 150(1), 33–39. e32 (2010).
  Medline CASGoogle Scholar
• 6. Kim DH, Rossi JJ. RNAi mechanisms and applications. BioTechniques 44(5), 613–616 (2008).
  CASGoogle Scholar
• 7. Li S-D, Huang L. Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells. Mol. Pharm. 3(5), 579–588 (2006).
  Medline CASGoogle Scholar
• 8. Li B-j, Tang Q, Cheng D et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat. Med. 11(9), 944 (2005).
  Medline CASGoogle Scholar
• 9. Lee C-C, Chiang B-L. RNA interference: new therapeutics in allergic diseases. Curr. Gene Ther. 8(4), 236–246 (2008). •• Depicts the fate of siRNA through pulmonary deliver.
  Medline CASGoogle Scholar
• 10. Lam JK-W, Liang W, Chan H-K. Pulmonary delivery of therapeutic siRNA. Adv. Drug Deliv. Rev. 64(1), 1–15 (2012).
  Medline CASGoogle Scholar
• 11. Paranjpe M, Müller-Goymann C. Nanoparticle-mediated pulmonary drug delivery: a review. Int. J. Mol. Sci. 15(4), 5852–5873 (2014).
  Medline CASGoogle Scholar
• 12. Carvalho TC, Peters JI, Williams III RO. Influence of particle size on regional lung deposition – what evidence is there? Int. J. Pharm. 406(1-2), 1–10 (2011).
  Medline CASGoogle Scholar
• 13. Sakagami M. In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery. Adv. Drug Deliv. Rev. 58(9-10), 1030–1060 (2006). • Describes in vitro and in vivo models for assessment of pulmonary absorption and deposition.
  Medline CASGoogle Scholar
• 14. Agu RU, Ugwoke MI, Armand M, Kinget R, Verbeke N. The lung as a route for systemic delivery of therapeutic proteins and peptides. Respir. Res. 2(4), 198 (2001).
  Medline CASGoogle Scholar
• 15. Merkel OM, Rubinstein I, Kissel T. siRNA delivery to the lung: what's new? Adv. Drug Deliv. Rev. 75, 112–128 (2014).
  Medline CASGoogle Scholar
• 16. Ngan CL, Asmawi AA. Lipid-based pulmonary delivery system: a review and future considerations of formulation strategies and limitations. Drug Deliv. Transl. Res. 8(5), 1527–1544 (2018).
  Medline CASGoogle Scholar
• 17. Roy I, Vij N. Nanodelivery in airway diseases: challenges and therapeutic applications. Nanomedicine 6(2), 237–244 (2010).
  Medline CASGoogle Scholar
• 18. Sanders N, Rudolph C, Braeckmans K, De Smedt SC, Demeester J. Extracellular barriers in respiratory gene therapy. Adv. Drug Deliv. Rev. 61(2), 115–127 (2009).
  Medline CASGoogle Scholar
• 19. Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Invest. 109(5), 571–577 (2002).
  Medline CASGoogle Scholar
• 20. Kolte A, Patil S, Lesimple P, Hanrahan JW, Misra A. PEGylated composite nanoparticles of PLGA and polyethylenimine for safe and efficient delivery of pDNA to lungs. Int. J. Pharm. 524(1-2), 382–396 (2017).
  Medline CASGoogle Scholar
• 21. Patil S, Lalani R, Bhatt P et al. Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics. RSC Adv. 8(62), 35461–35473 (2018).
  CASGoogle Scholar
• 22. Rosenecker J, Naundorf S, Gersting S et al. Interaction of bronchoalveolar lavage fluid with polyplexes and lipoplexes: analysing the role of proteins and glycoproteins. J. Gene Med. 5(1), 49–60 (2003).
  Medline CASGoogle Scholar
• 23. Merkel OM, Beyerle A, Librizzi D et al. Nonviral siRNA delivery to the lung: investigation of PEG− PEI polyplexes and their in vivo performance. Mol. Pharm. 6(4), 1246–1260 (2009).
  Medline CASGoogle Scholar
• 24. De Backer L, Braeckmans K, Stuart MC, Demeester J, De Smedt SC, Raemdonck K. Bio-inspired pulmonary surfactant-modified nanogels: a promising siRNA delivery system. J. Control. Rel. 206, 177–186 (2015).
  MedlineGoogle Scholar
• 25. Benfer M, Kissel T. Cellular uptake mechanism and knockdown activity of siRNA-loaded biodegradable DEAPA-PVA-g-PLGA nanoparticles. Eur. J. Pharm. Biopharm. 80(2), 247–256 (2012).
  Medline CASGoogle Scholar
• 26. Groneberg D, Eynott P, Lim S et al. Expression of respiratory mucins in fatal status asthmaticus and mild asthma. Histopathology 40(4), 367–373 (2002).
  Medline CASGoogle Scholar
• 27. Khalil IA, Kogure K, Akita H, Harashima H. Uptake pathways and subsequent intracellular trafficking in nonviral gene delivery. Pharmacol. Rev. 58(1), 32–45 (2006).
  Medline CASGoogle Scholar
• 28. Lebhardt T, Roesler S, Beck-Broichsitter M, Kissel T. Polymeric nanocarriers for drug delivery to the lung. J. Drug. Deliv. Sci. Technol. 20(3), 171–180 (2010).
  CASGoogle Scholar
• 29. Boussif O, Lezoualc'h F, Zanta MA et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc. Natl Acad. Sci. USA 92(16), 7297–7301 (1995).
  Medline CASGoogle Scholar
• 30. Hatakeyama H, Ito E, Akita H et al. A pH-sensitive fusogenic peptide facilitates endosomal escape and greatly enhances the gene silencing of siRNA-containing nanoparticles in vitro and in vivo. J. Control. Rel. 139(2), 127–132 (2009).
  Medline CASGoogle Scholar
• 31. Lee SH, Kim SH, Park TG. Intracellular siRNA delivery system using polyelectrolyte complex micelles prepared from VEGF siRNA-PEG conjugate and cationic fusogenic peptide. Biochem. Biophys. Res. Commun. 357(2), 511–516 (2007).
  Medline CASGoogle Scholar
• 32. Choi SW, Lee SH, Mok H, Park TG. Multifunctional siRNA delivery system: polyelectrolyte complex micelles of six-arm PEG conjugate of siRNA and cell penetrating peptide with crosslinked fusogenic peptide. Biotechnol. Prog. 26(1), 57–63 (2010).
  Medline CASGoogle Scholar
• 33. Parton RG, Richards AA. Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms. Traffic 4(11), 724–738 (2003).
  Medline CASGoogle Scholar
• 34. Yacobi NR, Malmstadt N, Fazlollahi F et al. Mechanisms of alveolar epithelial translocation of a defined population of nanoparticles. Am. J. Respir. Cell Mol. Biol. 42(5), 604–614 (2010).
  Medline CASGoogle Scholar
• 35. Macro L, Jaiswal JK, Simon SM. Dynamics of clathrin-mediated endocytosis and its requirement for organelle biogenesis in Dictyostelium. J. Cell Sci. 125(23), 5721–5732 (2012).
  Medline CASGoogle Scholar
• 36. Rejman J, Bragonzi A, Conese M. Role of clathrin-and caveolae-mediated endocytosis in gene transfer mediated by lipo-and polyplexes. Mol. Ther. 12(3), 468–474 (2005).
  Medline CASGoogle Scholar
• 37. Chiang P-C, Alsup JW, Lai Y, Hu Y, Heyde BR, Tung D. Evaluation of aerosol delivery of nanosuspension for pre-clinical pulmonary drug delivery. Nanoscale Res. Lett. 4(3), 254 (2009).
  Medline CASGoogle Scholar
• 38. Hickey AJ, Garcia-Contreras L. Immunological and toxicological implications of short-term studies in animals of pharmaceutical aerosol delivery to the lungs: relevance to humans. Crit. Rev. Ther. Drug Carrier Syst. 18(4), (2001).
  MedlineGoogle Scholar
• 39. Chen Y, Gao D-Y, Huang L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv. Drug Deliv. Rev. 81, 128–141 (2015).
  Medline CASGoogle Scholar
• 40. Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int. J. Pharm. 392(1-2), 1–19 (2010).
  Medline CASGoogle Scholar
• 41. Scaggiante B, Dapas B, Farra R et al. Improving siRNA bio-distribution and minimizing side effects. Curr. Drug Metab. 12(1), 11–23 (2011).
  Medline CASGoogle Scholar
• 42. Zhang X, Shan P, Jiang D et al. Small interfering RNA targeting heme oxygenase-1 enhances ischemia-reperfusion-induced lung apoptosis. J. Biol. Chem. 279(11), 10677–10684 (2004).
  Medline CASGoogle Scholar
• 43. Bitko V, Musiyenko A, Shulyayeva O, Barik S. Inhibition of respiratory viruses by nasally administered siRNA. Nat. Med. 11(1), 50 (2005).
  Medline CASGoogle Scholar
• 44. Fulton A, Peters ST, Perkins GA et al. Effective treatment of respiratory alphaherpesvirus infection using RNA interference. PLoS ONE 4(1), e4118 (2009).
  MedlineGoogle Scholar
• 45. Choi M, Gu J, Lee M, Rhim T. A new combination therapy for asthma using dual-function dexamethasone-conjugated polyethylenimine and vitamin D binding protein siRNA. Gene Ther. 24(11), 727 (2017).
  Medline CASGoogle Scholar
• 46. Patil S, Bhatt P, Lalani R et al. Low molecular weight chitosan–protamine conjugate for siRNA delivery with enhanced stability and transfection efficiency. RSC Adv. 6(112), 110951–110963 (2016).
  CASGoogle Scholar
• 47. Miwata K, Okamoto H, Nakashima T et al. Intratracheal administration of siRNA dry powder targeting vascular endothelial growth factor inhibits lung tumor growth in mice. Mol. Ther. Nucleic Acids 12, 698–706 (2018).
  Medline CASGoogle Scholar
• 48. Garbuzenko OB, Ivanova V, Kholodovych V et al. Combinatorial treatment of idiopathic pulmonary fibrosis using nanoparticles with prostaglandin E and siRNA (s). Nanomedicine 13(6), 1983–1992 (2017).
  Medline CASGoogle Scholar
• 49. Okuda T, Morishita M, Mizutani K, Shibayama A, Okazaki M, Okamoto H. Development of spray-freeze-dried siRNA/PEI powder for inhalation with high aerosol performance and strong pulmonary gene silencing activity. J. Control. Rel. 279, 99–113 (2018).
  Medline CASGoogle Scholar
• 50. Rosas-Taraco AG, Higgins DM, Sánchez-Campillo J, Lee EJ, Orme IM, González-Juarrero M. Local pulmonary immunotherapy with siRNA targeting TGFβ1 enhances antimicrobial capacity in Mycobacterium tuberculosis infected mice. Tuberculosis 91(1), 98–106 (2011).
  Medline CASGoogle Scholar
• 51. Merckx P, De Backer L, Van Hoecke L et al. Surfactant protein B (SP-B) enhances the cellular siRNA delivery of proteolipid coated nanogels for inhalation therapy. Acta Biomater. 78, 236–246 (2018).
  Medline CASGoogle Scholar
• 52. Otsuka M, Shiratori M, Chiba H et al. Treatment of pulmonary fibrosis with siRNA against a collagen-specific chaperone HSP47 in vitamin A-coupled liposomes. Exp. Lung Res. 43(6-7), 271–282 (2017).
  Medline CASGoogle Scholar
• 53. Kim D-H, Park H-J, Lim S et al. Regulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis. Nat. Commun. 9(1), 503 (2018).
  MedlineGoogle Scholar
• 54. Tomaru A, Kobayashi T, Hinneh J et al. Oligonucleotide-targeting periostin ameliorates pulmonary fibrosis. Gene Ther. 24(11), 706 (2017).
  Medline CASGoogle Scholar
• 55. Bohr A, Tsapis N, Andreana I et al. Anti-inflammatory effect of anti-TNF-α SiRNA cationic phosphorus dendrimer nanocomplexes administered intranasally in a murine acute lung injury model. Biomacromolecules 18(8), 2379–2388 (2017).
  Medline CASGoogle Scholar
• 56. Jamali A, Mottaghitalab F, Abdoli A et al. Inhibiting influenza virus replication and inducing protection against lethal influenza virus challenge through chitosan nanoparticles loaded by siRNA. Drug Deliv. Transl. Res. 8(1), 12–20 (2018).
  Medline CASGoogle Scholar
• 57. Reischl D, Zimmer A. Drug delivery of siRNA therapeutics: potentials and limits of nanosystems. Nanomedicine 5(1), 8–20 (2009).
  Medline CASGoogle Scholar
• 58. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat. Rev. Genet. 4(5), 346 (2003). • Depicts problem associated with viral vectors for gene delivery.
  Medline CASGoogle Scholar
• 59. Lee SJ, Son S, Yhee JY et al. Structural modification of siRNA for efficient gene silencing. Biotechnol. Adv. 31(5), 491–503 (2013).
  Medline CASGoogle Scholar
• 60. Shen C, Buck AK, Liu X, Winkler M, Reske SN. Gene silencing by adenovirus-delivered siRNA. FEBS Lett. 539(1-3), 111–114 (2003).
  Medline CASGoogle Scholar
• 61. Hosono T, Mizuguchi H, Katayama K et al. Adenovirus vector-mediated doxycycline-inducible RNA interference. Hum. Gene Ther. 15(8), 813–819 (2004).
  Medline CASGoogle Scholar
• 62. Davé UP, Jenkins NA, Copeland NG. Gene therapy insertional mutagenesis insights. Science 303(5656), 333–333 (2004).
  MedlineGoogle Scholar
• 63. Kohn DB, Sadelain M, Glorioso JC. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat. Rev. Cancer 3(7), 477 (2003).
  Medline CASGoogle Scholar
• 64. Ruigrok M, Frijlink H, Hinrichs W. Pulmonary administration of small interfering RNA: The route to go? J. Control. Rel. 235, 14–23 (2016).
  Medline CASGoogle Scholar
• 65. Ghosh S, Lalani R, Patel V et al. Combinatorial nanocarriers against drug resistance in hematological cancers: opportunities and emerging strategies. J Control. Rel. 296, 114–139 (2019).
  Medline CASGoogle Scholar
• 66. Qiu Y, Lam J, Leung S, Liang W. Delivery of RNAi therapeutics to the airways—from bench to bedside. Molecules 21(9), 1249 (2016).
  MedlineGoogle Scholar
• 67. De Backer L, Cerrada A, Perez-Gil J, De Smedt SC, Raemdonck K. Bio-inspired materials in drug delivery: exploring the role of pulmonary surfactant in siRNA inhalation therapy. J. Control. Rel. 220(Pt B), 642–650 (2015).
  MedlineGoogle Scholar
• 68. Tseng Y-C, Mozumdar S, Huang L. Lipid-based systemic delivery of siRNA. Adv. Drug Deliv. Rev. 61(9), 721–731 (2009).
  Medline CASGoogle Scholar
• 69. Lin Q, Chen J, Zhang Z, Zheng G. Lipid-based nanoparticles in the systemic delivery of siRNA. Nanomedicine 9(1), 105–120 (2014).
  Medline CASGoogle Scholar
• 70. Dokka S, Toledo D, Shi X, Castranova V, Rojanasakul Y. Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes. Pharm. Res. 17(5), 521–525 (2000).
  Medline CASGoogle Scholar
• 71. Wang J, Lu Z, Wientjes MG, Au JL-S. Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 12(4), 492–503 (2010).
  Medline CASGoogle Scholar
• 72. Clark KL, Hughes SA, Bulsara P et al. Pharmacological characterization of a novel ENaCα siRNA (GSK2225745) with potential for the treatment of cystic fibrosis. Mol. Ther. Nucleic Acids 2 (2013).
  Google Scholar
• 73. Thanki K, Blum KG, Thakur A, Rose F, Foged C. Formulation of RNA interference-based drugs for pulmonary delivery: challenges and opportunities. Ther. Deliv. 9(10), 731–749 (2018). •• Describes challenges and opportunities in pulmonary delivery of RNAi based drug products.
  CASGoogle Scholar
• 74. Zamora-Avila DE, Zapata-Benavides P, Franco-Molina MA et al. WT1 gene silencing by aerosol delivery of PEI-RNAi complexes inhibits B16-F10 lung metastases growth. Cancer Gene Ther. 16(12), 892–899 (2009).
  Medline CASGoogle Scholar
• 75. Griesenbach U, Kitson C, Garcia ES et al. Inefficient cationic lipid-mediated siRNA and antisense oligonucleotide transfer to airway epithelial cells in vivo. Respir. Res. 7(1), 26 (2006).
  MedlineGoogle Scholar
• 76. Chernikov IV, Gladkikh DV, Meschaninova MI et al. Cholesterol-containing nuclease-resistant siRNA accumulates in tumors in a carrier-free mode and silences MDR1 gene. Mol. Ther. Nucleic Acids 6, 209–220 (2017).
  Medline CASGoogle Scholar
• 77. Moschos SA, Jones SW, Perry MM et al. Lung delivery studies using siRNA conjugated to TAT(48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug. Chem. 18(5), 1450–1459 (2007).
  Medline CASGoogle Scholar
• 78. Semple SC, Klimuk SK, Harasym TO et al. Efficient encapsulation of antisense oligonucleotides in lipid vesicles using ionizable aminolipids: formation of novel small multilamellar vesicle structures. Biochim. Biophys. Acta 1510(1-2), 152–166 (2001). • Describes role of cationic lipids for pulmonary delivery of siRNA.
  Medline CASGoogle Scholar
• 79. Semple SC, Akinc A, Chen J et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28(2), 172 (2010).
  Medline CASGoogle Scholar
• 80. Love KT, Mahon KP, Levins CG et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107(5), 1864–1869 (2010).
  Medline CASGoogle Scholar
• 81. Akinc A, Zumbuehl A, Goldberg M et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 26(5), 561 (2008).
  Medline CASGoogle Scholar
• 82. Pack DW, Hoffman AS, Pun S, Stayton PS. Design and development of polymers for gene delivery. Nat. Rev. Drug Discov. 4(7), 581 (2005).
  Medline CASGoogle Scholar
• 83. Xie Y, Merkel OM. Pulmonary delivery of siRNA via polymeric vectors as therapies of asthma. Arch. Pharm. (Weinheim) 348(10), 681–688 (2015).
  Medline CASGoogle Scholar
• 84. Zhao M-D, Cheng J-L, Yan J-J et al. Hyaluronic acid reagent functional chitosan-PEI conjugate with AQP2-siRNA suppressed endometriotic lesion formation. Int. J. Nanomedicine 11, 1323 (2016).
  Medline CASGoogle Scholar
• 85. Singha K, Namgung R, Kim WJ. Polymers in small-interfering RNA delivery. Nucleic Acid Ther. 21(3), 133–147 (2011).
  Medline CASGoogle Scholar
• 86. Putnam D. Polymers for gene delivery across length scales. Nat. Mater. 5(6), 439 (2006).
  Medline CASGoogle Scholar
• 87. Richard I, Thibault M, De Crescenzo G, Buschmann MD, Lavertu M. Ionization behavior of chitosan and chitosan–DNA polyplexes indicate that chitosan has a similar capability to induce a proton-sponge effect as PEI. Biomacromolecules 14(6), 1732–1740 (2013).
  Medline CASGoogle Scholar
• 88. Cun D, Jensen LB, Nielsen HM, Moghimi M, Foged C. Polymeric nanocarriers for siRNA delivery: challenges and future prospects. J. Biomed. Nanotechnol. 4(3), 258–275 (2008).
  CASGoogle Scholar
• 89. Hsu CY, Uludağ H. Cellular uptake pathways of lipid-modified cationic polymers in gene delivery to primary cells. Biomaterials 33(31), 7834–7848 (2012).
  Medline CASGoogle Scholar
• 90. Xie Y, Kim NH, Nadithe V et al. Targeted delivery of siRNA to activated T cells via transferrin-polyethylenimine (Tf-PEI) as a potential therapy of asthma. J. Control. Rel. 229, 120–129 (2016).
  Medline CASGoogle Scholar
• 91. Steele TW, Zhao X, Tarcha P, Kissel T. Factors influencing polycation/siRNA colloidal stability toward aerosol lung delivery. Eur. J. Pharm. Biopharm. 80(1), 14–24 (2012).
  Medline CASGoogle Scholar
• 92. Xu C-X, Jere D, Jin H et al. Poly (ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis. Am. J. Respir. Crit. Care Med. 178(1), 60–73 (2008).
  Medline CASGoogle Scholar
• 93. Luo Y, Zhai X, Ma C et al. An inhalable β2-adrenoceptor ligand-directed guanidinylated chitosan carrier for targeted delivery of siRNA to lung. J. Control. Rel. 162(1), 28–36 (2012).
  Medline CASGoogle Scholar
• 94. Park S-C, Nam J-P, Kim Y-M, Kim J-H, Nah J-W, Jang M-K. Branched polyethylenimine-grafted-carboxymethyl chitosan copolymer enhances the delivery of pDNA or siRNA in vitro and in vivo. Int. J. Nanomedicine 8, 3663 (2013).
  MedlineGoogle Scholar
• 95. Bao Y, Jin Y, Chivukula P et al. Effect of PEGylation on biodistribution and gene silencing of siRNA/lipid nanoparticle complexes. Pharm. Res. 30(2), 342–351 (2013). • Describes effect of PEGtlation on siRNA delivery.
  Medline CASGoogle Scholar
• 96. Werfel TA, Jackson MA, Kavanaugh TE et al. Combinatorial optimization of PEG architecture and hydrophobic content improves ternary siRNA polyplex stability, pharmacokinetics, and potency in vivo. J. Control. Rel. 255, 12–26 (2017).
  Medline CASGoogle Scholar
• 97. Yu H, Xu Z, Chen X et al. Reversal of lung cancer multidrug resistance by p H-R esponsive micelleplexes mediating co-d elivery of siRNA and paclitaxel. Macromol. Biosci. 14(1), 100–109 (2014).
  Medline CASGoogle Scholar
• 98. Yu H, Zou Y, Jiang L et al. Induction of apoptosis in non-small cell lung cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPA/siRNA complex nanoparticles. Biomaterials 34(11), 2738–2747 (2013).
  Medline CASGoogle Scholar
• 99. Liu S, Nugroho AE, Shudou M, Maeyama K. Regulation of mucosal mast cell activation by short interfering RNAs targeting syntaxin4. Immunol. Cell Biol. 90(3), 337–345 (2012).
  Medline CASGoogle Scholar
• 100. Cheng Y, Yumul RC, Pun SH. Virus-inspired polymer for efficient in vitro and in vivo gene delivery. Angew. Chem. Int. Ed. 55(39), 12013–12017 (2016).
  Medline CASGoogle Scholar
• 101. Feldmann DP, Cheng Y, Kandil R et al. In vitro and in vivo delivery of siRNA via VIPER polymer system to lung cells. J. Control. Rel. 276, 50–58 (2018).
  Medline CASGoogle Scholar
• 102. Patil Y, Panyam J. Polymeric nanoparticles for siRNA delivery and gene silencing. Int. J. Pharm. 367(1-2), 195–203 (2009).
  Medline CASGoogle Scholar
• 103. Kong W-H, Sung D-K, Shim Y-H et al. Efficient intracellular siRNA delivery strategy through rapid and simple two steps mixing involving noncovalent post-PEGylation. J. Control. Rel. 138(2), 141–147 (2009).
  Medline CASGoogle Scholar
• 104. Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Préat V. PLGA-based nanoparticles: an overview of biomedical applications. J. Control. Rel. 161(2), 505–522 (2012).
  Medline CASGoogle Scholar
• 105. Panyam J, Zhou W-Z, Prabha S, Sahoo SK, Labhasetwar V. Rapid endo-lysosomal escape of poly (DL-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. FASEB J. 16(10), 1217–1226 (2002).
  Medline CASGoogle Scholar
• 106. Qaddoumi MG, Gukasyan HJ, Davda J, Labhasetwar V, Kim K-J, Lee V. Clathrin and caveolin-1 expression in primary pigmented rabbit conjunctival epithelial cells: role in PLGA nanoparticle endocytosis. Mol. Vis. 9, 559–568 (2003).
  Medline CASGoogle Scholar
• 107. Das J, Das S, Paul A, Samadder A, Bhattacharyya SS, Khuda-Bukhsh AR. Assessment of drug delivery and anticancer potentials of nanoparticles-loaded siRNA targeting STAT3 in lung cancer, in vitro and in vivo. Toxicol. Lett. 225(3), 454–466 (2014).
  Medline CASGoogle Scholar
• 108. Su W-P, Cheng F-Y, Shieh D-B, Yeh C-S, Su W-C. PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells. Int. J. Nanomedicine 7, 4269 (2012).
  Medline CASGoogle Scholar
• 109. Grabowski N, Hillaireau H, Vergnaud J et al. Toxicity of surface-modified PLGA nanoparticles toward lung alveolar epithelial cells. Int. J. Pharm. 454(2), 686–694 (2013).
  Medline CASGoogle Scholar
• 110. Ali H, Kalashnikova I, White MA, Sherman M, Rytting E. Preparation, characterization, and transport of dexamethasone-loaded polymeric nanoparticles across a human placental in vitro model. Int. J. Pharm. 454(1), 149–157 (2013).
  Medline CASGoogle Scholar
• 111. Germershaus O, Mao S, Sitterberg J, Bakowsky U, Kissel T. Gene delivery using chitosan, trimethyl chitosan or polyethylenglycol-graft-trimethyl chitosan block copolymers: establishment of structure–activity relationships in vitro. J. Control. Rel. 125(2), 145–154 (2008).
  Medline CASGoogle Scholar
• 112. Alameh M, DeJesus D, Jean M et al. Low molecular weight chitosan nanoparticulate system at low N: P ratio for nontoxic polynucleotide delivery. Int. J. Nanomedicine 7, 1399 (2012).
  Medline CASGoogle Scholar
• 113. Nascimento AV, Singh A, Bousbaa H, Ferreira D, Sarmento B, Amiji MM. Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles. Acta Biomater. 47, 71–80 (2017).
  Medline CASGoogle Scholar
• 114. Lavertu M, Methot S, Tran-Khanh N, Buschmann MD. High efficiency gene transfer using chitosan/DNA nanoparticles with specific combinations of molecular weight and degree of deacetylation. Biomaterials 27(27), 4815–4824 (2006).
  Medline CASGoogle Scholar
• 115. Jere D, Jiang H-L, Kim Y-K et al. Chitosan-graft-polyethylenimine for Akt1 siRNA delivery to lung cancer cells. Int. J. Pharm. 378(1-2), 194–200 (2009).
  Medline CASGoogle Scholar
• 116. Akhtar S, Benter IF. Nonviral delivery of synthetic siRNAs in vivo. J. Clin. Invest. 117(12), 3623–3632 (2007).
  Medline CASGoogle Scholar
• 117. Kesharwani P, Jain K, Jain NK. Dendrimer as nanocarrier for drug delivery. Prog. Polym. Sci. 39(2), 268–307 (2014).
  CASGoogle Scholar
• 118. Thakur S, Kesharwani P, Tekade RK, Jain NK. Impact of pegylation on biopharmaceutical properties of dendrimers. Polymer 59, 67–92 (2015).
  CASGoogle Scholar
• 119. Wu J, Zhou J, Qu F, Bao P, Zhang Y, Peng L. Polycationic dendrimers interact with RNA molecules: polyamine dendrimers inhibit the catalytic activity of Candida ribozymes. Chem. Commun. (3), 313–315 (2005).
  MedlineGoogle Scholar
• 120. Navarro G, de ILarduya CT. Activated and non-activated PAMAM dendrimers for gene delivery in vitro and in vivo. Nanomedicine 5(3), 287–297 (2009).
  Medline CASGoogle Scholar
• 121. Shcharbin D, Dzmitruk V, Shakhbazau A et al. Fourth generation phosphorus-containing dendrimers: prospective drug and gene delivery carrier. Pharmaceutics 3(3), 458–473 (2011).
  Medline CASGoogle Scholar
• 122. Conti DS, Brewer D, Grashik J, Avasarala S, da Rocha SR. Poly (amidoamine) dendrimer nanocarriers and their aerosol formulations for siRNA delivery to the lung epithelium. Mol. Pharm. 11(6), 1808–1822 (2014).
  Medline CASGoogle Scholar
• 123. Bielski E, Zhong Q, Mirza H et al. TPP-dendrimer nanocarriers for siRNA delivery to the pulmonary epithelium and their dry powder and metered-dose inhaler formulations. Int. J. Pharm. 527(1-2), 171–183 (2017).
  Medline CASGoogle Scholar
• 124. Biswas S, Deshpande PP, Navarro G, Dodwadkar NS, Torchilin VP. Lipid modified triblock PAMAM-based nanocarriers for siRNA drug co-delivery. Biomaterials 34(4), 1289–1301 (2013).
  Medline CASGoogle Scholar
• 125. Taratula O, Garbuzenko OB, Kirkpatrick P et al. Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery. J. Control. Rel. 140(3), 284–293 (2009).
  Medline CASGoogle Scholar
• 126. Cabral-Marques H, Almeida R. Optimisation of spray-drying process variables for dry powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes. Eur. J. Pharm. Biopharm. 73(1), 121–129 (2009).
  Medline CASGoogle Scholar
• 127. Hibbitts A, O'mahony A, Forde E et al. Early-stage development of novel cyclodextrin-siRNA nanocomplexes allows for successful postnebulization transfection of bronchial epithelial cells. J. Aerosol. Med. Pulm. Drug. Deliv. 27(6), 466–477 (2014).
  Medline CASGoogle Scholar
• 128. Menuel S, Fontanay S, Clarot I, Duval RE, Diez L, Marsura A. Synthesis and complexation ability of a novel bis-(guanidinium)-tetrakis-(β-cyclodextrin) dendrimeric tetrapod as a potential gene delivery (DNA and siRNA) system. Study of cellular siRNA transfection. Bioconjug. Chem. 19(12), 2357–2362 (2008).
  Medline CASGoogle Scholar
• 129. Mandal B, Bhattacharjee H, Mittal N et al. Core–shell-type lipid–polymer hybrid nanoparticles as a drug delivery platform. Nanomedicine 9(4), 474–491 (2013). •• Depicts role of Hybrid nanoparticle in the pulmonary delivery of siRNA.
  Medline CASGoogle Scholar
• 130. Jensen DK, Jensen LB, Koocheki S et al. Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA. J. Control. Rel. 157(1), 141–148 (2012).
  Medline CASGoogle Scholar
• 131. Yang Y, Cheow WS, Hadinoto K. Dry powder inhaler formulation of lipid–polymer hybrid nanoparticles via electrostatically-driven nanoparticle assembly onto microscale carrier particles. Int. J. Pharm. 434(1-2), 49–58 (2012).
  Medline CASGoogle Scholar
• 132. Eguchi A, Dowdy SF. siRNA delivery using peptide transduction domains. Trends Pharmacol. Sci. 30(7), 341–345 (2009).
  Medline CASGoogle Scholar
• 133. Meade BR, Dowdy SF. Exogenous siRNA delivery using peptide transduction domains/cell penetrating peptides. Adv. Drug Deliv. Rev. 59(2-3), 134–140 (2007).
  Medline CASGoogle Scholar
• 134. Turner JJ, Jones S, Fabani MM, Ivanova G, Arzumanov AA, Gait MJ. RNA targeting with peptide conjugates of oligonucleotides, siRNA and PNA. Blood Cells Mol. Dis. 38(1), 1–7 (2007).
  Medline CASGoogle Scholar
• 135. Simeoni F, Morris MC, Heitz F, Divita G. Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells. Nucleic Acids Res. 31(11), 2717–2724 (2003).
  Medline CASGoogle Scholar
• 136. Veldhoen S, Laufer SD, Trampe A, Restle T. Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect. Nucleic Acids Res. 34(22), 6561–6573 (2006).
  Medline CASGoogle Scholar
• 137. Moschos SA, Williams AE, Lindsay MA. Cell-penetrating-peptide-mediated siRNA lung delivery. Biochemical Society Transactions, Volume 35, part 4, Cell penetrating peptide. Portland Press Limited, 807–810 (2007)
  Google Scholar
• 138. Varshosaz J, Taymouri S. Hollow inorganic nanoparticles as efficient carriers for siRNA delivery: a comprehensive review. Curr. Pharm. Des. 21(29), 4310–4328 (2015).
  Medline CASGoogle Scholar
• 139. Cai R-Q, Liu D-Z, Cui H et al. Charge reversible calcium phosphate lipid hybrid nanoparticle for siRNA delivery. Oncotarget 8(26), 42772 (2017).
  MedlineGoogle Scholar
• 140. Taratula O, Garbuzenko OB, Chen AM, Minko T. Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA. J. Drug. Target. 19(10), 900–914 (2011).
  Medline CASGoogle Scholar
• 141. Conde J, Tian F, Hernández Y et al. In vivo tumor targeting via nanoparticle-mediated therapeutic siRNA coupled to inflammatory response in lung cancer mouse models. Biomaterials 34(31), 7744–7753 (2013).
  Medline CASGoogle Scholar
• 142. Durcan N, Murphy C, Cryan S-A. Inhalable siRNA: potential as a therapeutic agent in the lungs. Mol. Pharm. 5(4), 559–566 (2008). •• The importance of N/P ratio has been justify.
  Medline CASGoogle Scholar
• 143. Mainelis G, Seshadri S, Garbuzenko O, Han T, Wang Z, Minko T. Characterization and application of a nose-only exposure chamber for inhalation delivery of liposomal drugs and nucleic acids to mice. J. Aerosol. Med. Pulm. Drug. Deliv. 26(6), 345–354 (2013).
  Medline CASGoogle Scholar
• 144. Xue W, Dahlman JE, Tammela T et al. Small RNA combination therapy for lung cancer. Proc. Natl Acad. Sci. USA 111 (34), E3553–E3561 (2014).
  Medline CASGoogle Scholar
• 145. Sung DK, Kong WH, Park K et al. Noncovalenly PEGylated CTGF siRNA/PDMAEMA complex for pulmonary treatment of bleomycin-induced lung fibrosis. Biomaterials 34(4), 1261–1269 (2013).
  Medline CASGoogle Scholar
• 146. Ding L, Zhu C, Yu F et al. Pulmonary delivery of polyplexes for combined PAI-1 gene silencing and CXCR4 inhibition to treat lung fibrosis. Nanomedicine 14(6), 1765–1776 (2018).
  Medline CASGoogle Scholar
• 147. Garbuzenko OB, Ivanova V, Kholodovych V et al. Combinatorial treatment of idiopathic pulmonary fibrosis using nanoparticles with prostaglandin E and siRNA(s). Nanomedicine 13(6), 1983–1992 (2017).
  Medline CASGoogle Scholar
• 148. Patel V, Lalani R, Bardoliwala D, Ghosh S, Misra A. Lipid-based oral formulation strategies for lipophilic drugs. AAPS PharmSciTech 8, 1–22 (2018).
  Google Scholar
• 149. Mukherjee B, Maji R, Roychowdhury S, Ghosh S. Toxicological concerns of engineered nanosize drug delivery systems. Am. J. Ther. 23(1), e139–e150 (2016).
  MedlineGoogle Scholar
• 150. Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm. Res. 10(7), 1093–1095 (1993).
  Medline CASGoogle Scholar
• 151. Cryan S-A, Sivadas N, Garcia-Contreras L. In vivo animal models for drug delivery across the lung mucosal barrier. Adv. Drug Deliv. Rev. 59(11), 1133–1151 (2007).
  Medline CASGoogle Scholar
• 152. DeVincenzo J, Lambkin-Williams R, Wilkinson T et al. A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc. Natl Acad. Sci. USA 107(19), 8800–8805 (2010).
  Medline CASGoogle Scholar
• 153. Ulanova M, Duta F, Puttagunta L, Schreiber AD, Befus AD. Spleen tyrosine kinase (Syk) as a novel target for allergic asthma and rhinitis. Expert Opin. Ther. Targets 9(5), 901–921 (2005).
  Medline CASGoogle Scholar
• 154. Borreli L. FDA approved patisiran, first treatment for polyneuropathy in hAATR. Neurology Today (2018).
  Google Scholar
• 155. Tatiparti K, Sau S, Kashaw S, Iyer A. siRNA delivery strategies: a comprehensive review of recent developments. Nanomaterials 7(4), 77 (2017). •• Gives brief information about first US FDA approved formulation of siRNA for polyneuropathy.
  MedlineGoogle Scholar