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Stabilization of Plasmid DNA and Lipid-Based Therapeutics as Dehydrated Formulations

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Lyophilized Biologics and Vaccines

Abstract

The ability to deliver nucleic acids in vivo offers the promise to develop potent pharmaceutical medicines (e.g., vaccines) to treat many human diseases such as cancer, AIDS, and others that are currently considered incurable. It is well recognized that nonviral gene delivery systems exhibit high instability as liquid formulations. Therefore, the development of dehydrated nucleic acid-based formulations represents a valuable approach for stabilization and storage of large standardized batches of naked DNA or lipid/DNA complexes. The most common method taken to dehydrate, and therefore stabilize, macromolecules is freeze-drying. Lyophilization has the benefit of increasing formulation stability during storage due to the reduction of mobility and deleterious reactions (e.g., hydrolysis, oxidation) involving water. This chapter reviews the development to date of nonviral vectors as dehydrated formulations and focuses primarily on the stability challenges currently found during processing and storage of individual components (naked DNA and lipids) and lipid/DNA complexes. Furthermore, the significance of the role of water and different formulation strategies used to improve stability of naked DNA as well as lipid-based formulations during storage are discussed.

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References

  1. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–8.

    Article  CAS  PubMed  Google Scholar 

  2. Rosenberg SA, Aebersold P, Cornetta K., Kasid A, Morgan RA, Moen R, Karson EM, Lotze, MT, Yang JC, Topalian SL, et al. Gene transfer into humans–immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990;323:570–8.

    Article  CAS  PubMed  Google Scholar 

  3. Gene therapy clinical trials. J. Gene Med. http://www.wiley.co.uk/genmed/clinical. Accessed 4 Jan 2014.

  4. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012—an update. J Gene Med. 2013;15:65–77.

    Article  CAS  PubMed  Google Scholar 

  5. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fisher A. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288:669–72.

    Article  CAS  PubMed  Google Scholar 

  6. Chuah MK, Nair N, VandenDriessche T. Recent progress in gene therapy for hemophilia. Hum Gene Ther. 2012;23:557–65.

    Article  CAS  PubMed  Google Scholar 

  7. Koo T, Wood MJ. Clinical trials using antisense oligonucleotides in duchenne muscular dystrophy. Hum Gene Ther. 2013;24:479–88.

    Article  CAS  PubMed  Google Scholar 

  8. McGarrity GJ, Hoyah G, Winemiller A, Andre K, Stein D, Blick G, Greenberg RN, Kinder C, Zolopa A, Binder-Scholl G, Tebas P, June CH, Humeau LM, Rebello T. Patient monitoring and follow-up in lentiviral clinical trials. J Gene Med. 2013;15:78–82.

    Article  CAS  PubMed  Google Scholar 

  9. Moss RB, Rodman D, Spencer LT, Aitken ML, Zeitlin PL, Waltz D, Milla C, Brody AS, Clancy JP, Ramsey B, Hamblett N, Heald AE. Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest. 2004;125:509–21.

    Article  PubMed  Google Scholar 

  10. Kordower JH, Kirik D. Introduction: gene therapy has gone from a pipe dream to clinical reality. Neurobiol Dis. 2012;48:151–2.

    Article  PubMed  Google Scholar 

  11. Cotrim AP, Baum BJ. Gene therapy: some history, applications, problems, and prospects. Toxicol Pathol. 2008;36:97–103.

    Article  CAS  PubMed  Google Scholar 

  12. Flotte TR. Gene therapy: the first two decades and the current state-of-the-art. J Cell Physiol. 2007;213:301–5.

    Article  CAS  PubMed  Google Scholar 

  13. Li SD, Huang L. Non-viral is superior to viral gene delivery. J Cont Release. 2007;123:181–3.

    Article  CAS  Google Scholar 

  14. Nowrouzi A, Glimm H, von Kalle C, Schmidt M. Retroviral vectors: post entry events and genomic alterations. Viruses. 2011;3:429–55.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Yi Y, Noh MJ, Lee KH. Current advances in retroviral gene therapy. Curr Gene Ther. 2011;11:218–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Matrai J, Chuah MK, VandenDriessche T. Recent advances in lentiviral vector development and applications. Mol Ther. 2005;18:477–90.

    Article  Google Scholar 

  17. Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM, Batshaw ML. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80:148–58.

    Article  CAS  PubMed  Google Scholar 

  18. Fischer A, Abina SH, Thrasher A, von Kalle C, Cavazzana-Calvo M. LMO2 and gene therapy for severe combined immunodeficiency N Engl J Med. 2004;350:2526–7 (author reply 2526–7).

    Article  CAS  PubMed  Google Scholar 

  19. Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kuhlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Luthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006;12:401–9.

    Article  CAS  PubMed  Google Scholar 

  20. Edelstein ML, Abedi MR, Wixon J, Edelstein RM. Gene therapy clinical trials worldwide 1989–2004-an overview. J Gene Med. 2004;6:597–602.

    Article  PubMed  Google Scholar 

  21. Caplen NJ, Alton EWFW, Middleton PG, Dorin JR, Stevinson BJ, Gao X, Durham SR, Jeffrey PK, Hodson ME, Coutelle C, Huang L, Porteous DJ, Williamson R, Geddes DM. Liposome-mediated CTFR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nature Med. 1995;1:39–46.

    Article  CAS  PubMed  Google Scholar 

  22. Gao X, Kim K-S, Liu D. Nonviral gene delivery: what we know and what is next. AAPS J. 2007;9:E92–E104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Li SD, Huang L. Gene therapy progress and prospects: non-viral gene therapy by systemic delivery. Gene Ther. 2006;13:1313–9.

    Article  CAS  PubMed  Google Scholar 

  24. Guo X, Huang L. Recent advances in nonviral vectors for gene delivery. Acc Chem Res. 2012;45:971–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Kommareddy S, Tiwari SB, Amiji MM. Long-circulating polymeric nanovectors for tumor-selective gene delivery. Technol Cancer Res Treat. 2005;4:615–25.

    Article  CAS  PubMed  Google Scholar 

  26. Ahmad S, Sweeney P, Sullivan GC, Tangney M. DNA vaccination for prostate cancer, from preclinical to clinical trials—where we stand? Genet Vaccines Ther. 2012;10:9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Bins AD, van den Berg JH, Oosterhuis K, Haanen JB. Recent advances towards the clinical application of DNA vaccines. Neth J Med. 2013;71:109–17.

    CAS  PubMed  Google Scholar 

  28. Senovilla L, Vacchelli E, Garcia P, Eggermont A, Fridman WH, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: DNA vaccines for cancer therapy. Oncoimmunology. 2013;2:e23803.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Shirota H, Petrenko L, Hong C, Klinman DM. Potential of transfected muscle cells to contribute to DNA vaccine immunogenicity. J Immunol. 2007;179:329–36.

    Article  CAS  PubMed  Google Scholar 

  30. Kalams SA, Parker S, Jin X, Elizaga M, Metch B, Wang M, Hural J, Lubeck M, Eldridge J, Cardinali M, Blattner WA, Sobieszczyk M, Suriyanon V, Kalichman A, Weiner DB, Baden LR. Safety and immunogenicity of an HIV-1 gag DNA vaccine with or without IL-12 and/or IL-15 plasmid cytokine adjuvant in healthy, HIV-1 uninfected adults. PLoS ONE. 2012;7:e29231.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Pavlenko M, Roos AK, Lundqvist A, Palmborg A, Miller AM, Ozenci V, Bergman B, Egevad L, Hellstrom M, Kiessling R, Masucci G, Wersall P, Nilsson S, Pisa PA. phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer. Br J Cancer. 2004;91:688–94.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Tang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992;356:152–4.

    Article  CAS  PubMed  Google Scholar 

  33. Tavel JA, Martin JE, Kelly GG, Enama ME, Shen JM, Gomez PL, Andrews CA, Koup RA, Bailer RT, Stein JA, Roederer M, Nabel GJ, Graham BS. Safety and immunogenicity of a Gag-Pol candidate HIV-1 DNA vaccine administered by a needle-free device in HIV-1-seronegative subjects. J Acquir Immune Defic Syndr. 2007;44:601–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Vasan S, Schlesinger SJ, Huang Y, Hurley A, Lombardo A, Chen Z, Than S, Adesanya P, Bunce C, Boaz M, Boyle R, Sayeed E, Clark L, Dugin D, Schmidt C, Song Y, Seamons L, Dally L, Ho M, Smith C, Markowitz M, Cox J, Gill DK, Gilmour J, Keefer MC, Fast P, Ho DD. Phase 1 safety and immunogenicity evaluation of ADVAX, a multigenic, DNA-based clade C/B’ HIV-1 candidate vaccine. PLoS ONE. 2010;5:e8617.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Jiao H, Pan Z, Yin Y, Geng S, Sun L, Jiao X. Oral and nasal DNA vaccines delivered by attenuated Salmonella enterica serovar Typhimurium induce a protective immune response against infectious bronchitis in chickens. Clin Vaccine Immunol. 2011;18:1041–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Davis BS, Chang GJ, Cropp B, Roehrig JT, Martin DA, Mitchell CJ, Bowen R, Bunning ML. West Nile virus recombinant DNA vaccine protects mouse and horse from virus challenge and expresses in vitro a noninfectious recombinant antigen that can be used in enzyme-linked immunosorbent assays. J Virol. 2001;75:4040–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Anderson ED, Mourich DV, Fahrenkrug SC, LaPatra S, Shepherd J, Leong JA. Genetic immunization of rainbow trout (Oncorhynchus mykiss) against infectious hematopoietic necrosis virus. Mol Mar Biol Biotechnol. 1996;5:114–22.

    CAS  PubMed  Google Scholar 

  38. Liao JC, Gregor P, Wolchok JD, Orlandi F, Craft D, Leung C, Houghton AN, Bergman PJ. Vaccination with human tyrosinase DNA induces antibody responses in dogs with advanced melanoma. Cancer Immun. 2006;6:8.

    PubMed Central  PubMed  Google Scholar 

  39. Knapp JE, Liu D. Hydrodynamic delivery of DNA. Methods Mol Biol. 2004;245:245–50.

    CAS  PubMed  Google Scholar 

  40. Mahato RI, Kim SW. Pharmaceutical perspectives of nucleic acid-based therapeutics. London: Taylor & Francis; 2002.

    Book  Google Scholar 

  41. Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, Northrop JP, Ringold GM, Danielsen M. Lipofection- A, highly efficient, lipid-mediated DNA transfection procedure. Proc Natl Acad Sci U S A. 1987;87:7413–7.

    Google Scholar 

  42. Ahmad A, Evans HM, Ewert K, George CX, Samuel CE, Safinys CR. New multivalent cationic lipids reveal bell curve for transfection efficiency versus membrane charge density: lipid-DNA complexes for gene delivery. J Gene Med. 2005;7:739–48.

    Google Scholar 

  43. Boussif O, Zanta MA, Behr JP. Optimized galenics improve in vitro gene transfer with cationic molecules up to 1000-fold. Gene Ther. 1996;3:1074–80.

    Google Scholar 

  44. Bouxsein NF, McAllister CS, Ewert KK, Samuel CE, Safinya CR. Structure and gene silencing activities of monovalent and pentavalent cationic lipid vectors complexed with siRNA. BioChemistry. 2007;46:4785–92.

    Google Scholar 

  45. Heyes J, Palmer L, Bremner K, MacLachlan I. Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J Control Release. 2005;107:276–87.

    Google Scholar 

  46. Mahato RI, Rolland A, Tomlinson E. Cationic lipid-based gene delivery systems: pharmaceutical perspectives. Pharm Res. 1997;14:853–9.

    Google Scholar 

  47. Richards JM, Bedikian A, Gonzalez R, Atkins MB, Whitman E, Lutzky J, Morse MA., Amatruda T, Galanis E, Thompson J. High-dose Allovectin7R in patients with advanced metastatic melanoma: final phase 2 data and design of phase 3 registration trial (Abstract 7543). J Clin Oncol. 2005;23:720.

    Google Scholar 

  48. Gowen BB, Fairman J, Dow S, Troyer R, Wong MH, Jung KH, Melby PC, Morrey JD. Prophylaxis with cationic liposome-DNA complexes protects hamsters from phleboviral disease: importance of liposomal delivery and CpG motifs. Antiviral Res. 2009;81:37–46.

    Google Scholar 

  49. Wilson A, Pitt B, Li S. Complex roles of CpG in liposomal delivery of DNA and oligonucleotides. Biosci Rep. 2002;22:309–22.

    Google Scholar 

  50. Keasey N, Herse Z, Chang S, Liggitt DH, Fairman J, Lay M, Claxton DF. A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects. Cancer Biol Ther. 2010;10:625–31.

    Google Scholar 

  51. D. Claxton MD, Milton S. Hershey Medical Center. JVRS-100 for the treatment of patients with relapsed or refractory leukemia, identifier: NCT00860522 http://clinicaltrials.gov. Accessed 4 Jan 2014.

  52. Jackson DA, Juranek S, Lipps HJ. Designing nonviral vectors for efficient gene transfer and long-term gene expression. Mol Ther. 2006;14:613–26.

    Google Scholar 

  53. Zhi D, Zhang S, Cui S, Zhao Y, Wang Y, Zhao D. The headgroup evolution of cationic lipids for gene delivery. Bioconjug Chem. 2013;24:487–519.

    Google Scholar 

  54. Anchordoquy TJ. Nonviral gene delivery systems: physical stability. BioPharm. 1999;12:42–8.

    Google Scholar 

  55. Anchordoquy TJ, Allison SD, Molina MC, Girouard LG, Carson TK. Physical stabilization of DNA-based therapeutics. Drug Discov Today. 2001;6:463–70.

    Google Scholar 

  56. Anchordoquy TJ, Armstrong TK, Molina MC, Allison DS, Zhang Y, Patel MM, Lentz YK, Koe GS, Lu DR, Oie S, editors. Cellular drug delivery: principles and practice. New Jersey: Humana; 2004. pp. 237–64

    Google Scholar 

  57. Kong S, Rock CF, Booth A, Willoughby N, O’Kennedy RD, Relton J, Ward JM, Hoare M, Levy MS. Large-scale plasmid DNA processing: evidence that cell harvesting and storage methods affect yield of supercoiled plasmid DNA. Biotechnol Appl Biochem. 2008;51:43–51.

    Google Scholar 

  58. Mahato RI, Kawabata K, Nomura T, Takakura Y, Hashida M. Physicochemical and pharmokinetic characteristics of plasmid DNA cationic liposome complexes. J Pharm Sci. 1995;84:1267–71.

    Google Scholar 

  59. Shamlou PA. Scaleable processes for the manufacture of therapeutic quantities of plasmid DNA. Biotechnol Appl Biochem. 2003;37:207–18.

    Google Scholar 

  60. Walther W, Stein U, Voss C, Schmidt T, Schleef M, Schlag PM. Stability analysis for long-term storage of naked DNA: impact on nonviral in vivo gene transfer. Anal Biochem. 2003;318:230–5.

    Google Scholar 

  61. Evans RK, Xu Z, Bohannon KE, Wang B, Brunner MW, Volkin DB. Evaluation of degradation pathways for plasmid DNA in pharmaceutical formulations via accelerated stability studies. J Pharm Sci. 2000;89:76–87.

    Google Scholar 

  62. Middaugh CR, Evans RK, Montgomery DL, Casimiro DR. Analysis of plasmid DNA from a pharmaceutical perspective. J Pharm Sci. 1998;87:130–46.

    Google Scholar 

  63. Pogocki D, Schoneich C. Chemical stability of nucleic acid-derived drugs. J Pharm Sci. 2000;89:443–56.

    Google Scholar 

  64. Zeng Y, Ramsey JD, King R, Leviten M, McGuire R, Volkin DB, Joshi SB, Middaugh CR. Identifying stabilizers of plasmid DNA for pharmaceutical use. J Pharm Sci. 2011;100:904–14.

    Google Scholar 

  65. Grit M, Crommelin DJ. Chemical stability of liposomes: implications for their physical stability. Chem Phys Lipids. 1993;64:3–18.

    Google Scholar 

  66. Li Q-T, Yeo MH, Tan BK. Lipid peroxidation in small and large phospholipid unilamellar vesicles induced by water-soluble free radical sources. Biochem Biophys Res Commun. 2000;273:72–6.

    Google Scholar 

  67. Zhang JA, Pawelchak J. Effect of pH, ionic strength and oxygen burden on the chemical stability of EPC/cholesterol liposomes under accelerated conditions. Part 1: Lipid hydrolysis. Eur J Pharm Biopharm. 2000;50:357–64.

    Google Scholar 

  68. Gustafsson J, Arvidson G, Karlsson G, Almgren M. Complexes between cationic liposomes and DNA visualized by cryo–TEM. Biochim Biophys Acta. 1995;1235:305–12.

    Google Scholar 

  69. Anchordoquy TJ, Koe GS. Physical stability of nonviral plasmid-based therapeutics. J Pharm Sci. 2000;89:289–96.

    Google Scholar 

  70. Meyer O, Schughart K, Pavirani A, Kolve HVJ. Multiple systemic expression of human interferon-β in mice can be achieved upon repeated administration of optimized pcTG90-lipoplex. Gene Ther. 2000;7:1606–11.

    Google Scholar 

  71. Zelphati O, Nguyen C, Ferrari M, Felgner J, Tsai Y, Felgner PL. Stable and monodisperse lipoplex formulations for gene delivery. Gene Ther. 1998;5:1272–82.

    Google Scholar 

  72. Anchordoquy TJ, Girouard, LG, Carpenter JF, Kroll DJ. Stability of lipid/DNA complexes during agitation and freeze-thawing. J Pharm Sci. 1998;87:1046–51.

    Google Scholar 

  73. Lindahl T, Nyberg B. Rate of depurination of native deoxyribonucleic acid. BioChemistry. 1972;11:3610–7.

    Google Scholar 

  74. Shapiro R, Klein RS. The deamination of cytidine and cytosine by acidic buffer solutions. Mutagenic implications. BioChemistry. 1966;5:2358–62.

    Google Scholar 

  75. Lindahl T, Karlstrom O. Heat-induced depyrimidination of deoxyribonucleic acid in neutral solution. BioChemistry. 1973;12:5151–4.

    Google Scholar 

  76. Zoltewicz JA, Clark DF, Sharpless TW, Grahe G. Kinetics and mechanism of the acid-catalized hydrolysis of some purine nucleosides. J Am Chem Soc. 1970;92:1741–50.

    Google Scholar 

  77. Buettner GR, Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat Res. 1996;145:532–41.

    Google Scholar 

  78. Toyokuni S, Sagripanti JL. Association between 8-hydroxy-2′-deoxyguanosine formation and DNA strand breaks mediated by copper and iron. Free Radic Biol Med. 1996;20:859–64.

    Google Scholar 

  79. Djuric Z, Potter DW, Taffe BG, Strasburg GM. Comparison of iron-catalyzed DNA and lipid oxidation. J Biochem Mol Toxicol. 2001;15:114–9.

    Google Scholar 

  80. Anchordoquy TJ, Armstrong TK, Molina Md, Allison DS, Zhang Y, Patel MM, Lentz YK, Koe GS, Constantino HR, Pikal MJ, editors. Lyophilization of biopharmaceuticals. Arlington: AAPS; 2004. pp. 605–41.

    Google Scholar 

  81. Hofland HEJ, Shephard L, Sullivan SM. Formation of stable cationic lipid/DNA complexes for gene transfer. Proc Natl Acad Sci U S A. 1996;93:7305–9.

    Google Scholar 

  82. Anchordoquy TJ, Molina MC. Preservation of DNA. Cell Preserv Technol. 2007;5:180–8.

    Google Scholar 

  83. Allison SD, Anchordoquy TJ. Mechanisms of protection of cationic lipid-DNA complexes during lyophilization. J Pharm Sci. 2000;89:682–91.

    Google Scholar 

  84. Kasper JC, Kuchler S, Fries W. Lyophilization of synthetic gene carriers. Methods Mol Biol. 2013;948:133–47.

    Google Scholar 

  85. Anchordoquy TJ, Armstrong TK, Molina MC. Low molecular weight dextrans stabilize nonviral vectors during lyophilization at low osmolalities: concentrating suspensions by rehydration to reduced volumes. J Pharm Sci. 2005;94:1226–36.

    Google Scholar 

  86. Anchordoquy TJ, Carpenter JF, Kroll DJ. Maintenance of transfection rates and physical characterization of lipid/DNA complexes after freeze-drying and rehydration. Arch Biochem Biophys. 1997;348:199–206.

    Google Scholar 

  87. Brus C, Kleemann E, Aigner A, Czubayko F, Kissel T. Stabilization of oligonucleotide-polyethylenimine complexes by freeze-drying: physicochemical and biological characterization. J Control Release. 2004;95:119–31.

    Google Scholar 

  88. Cherng J-Y, van de Watering P, Talsma H, Crommelin DJA, Hennik WE. Freeze-drying of poly((2-dimethylamino)ethyl methacrylate)-based gene delivery systems. Pharm Res. 1997;14:1838–41.

    Google Scholar 

  89. Miyata K, Kakizawa Y, Nishiyama N, Yamasaki Y, Watanabe T, Kohara M, Kataoka K. Freeze-dried formulations for in vivo gene delivery of PEGylated polyplex micelles with disulfide crosslinked cores to the liver. J Control Release. 2005;109:15–23.

    Google Scholar 

  90. Talsma H, Cherng JY, Lehrmann H, Kursa M, Ogris W, Hennink WE, Cotten M, Wagner E. Stabilization of gene delivery systems by freeze-drying. Int J Pharm. 1997;157:233–8.

    Google Scholar 

  91. Poxon SW, Hughes JA. The effect of lyophilization on plasmid DNA activity. Pharm Dev Technol. 2000;5:115–22.

    Google Scholar 

  92. Arakawa T, Timasheff SN. Stabilization of protein structure by sugars. BioChemistry. 1982;21:6536–44.

    Google Scholar 

  93. Carpenter JF, Prestrelski SJ, Anchordoquy TJ, Arakawa T. Interactions of stabilizers with proteins during freezing and drying. ACS Sym Series. 1994;567:134–47.

    Google Scholar 

  94. Pikal MJ. Freeze-drying of proteins. ACS Symp Ser. 1994;567:120–33.

    Google Scholar 

  95. Li B, Li S, Tan Y, Stolz DB, Watkins SC, Block LH, Huang L. Lyophilization of cationic lipid-protamine-DNA (LPD) complexes. J Pharm Sci. 2000;89:355–64.

    Google Scholar 

  96. Ando S, Putnam D, Pack DW, Langer R. PLGA microspheres containing plasmid DNA: preservation of supercoiled DNA via cryopreparation and carbohydrate stabilization. J Pharm Sci. 1999;88:126–30.

    Google Scholar 

  97. Crowe JH, Crowe LM, Carpenter JF, Wistrom CA. Stabilization of dry phospholipid bilayers and proteins by sugars. Biochem J. 1987;242:1–10.

    Google Scholar 

  98. Armstrong TK, Girouard LG, Anchordoquy TJ. PEGylation does not preserve cationic lipid/DNA complexes during freeze-thawing and lyophilization. J Pharm Sci. 2002;91:2549–58.

    Google Scholar 

  99. Cherng J-Y, Wetering Pvd, Talsma H, Crommelin DJA, Hennik WE. Stabilization of polymer-based gene delivery systems. Int J Pharm. 1999;183:25–8.

    Google Scholar 

  100. Franks F, Hatley RHM, Mathias SF. Materials science and the production of shelf-stable biologicals. Pharm Technol Internat. 1991;3:40–4.

    Google Scholar 

  101. Levine H, Slade L. Another view of trehalose for drying and stabilizing biological materials. Biopharm. 1992;5:36–40.

    Google Scholar 

  102. Allison SD, Molina MdC, Anchordoquy TJ. Stabilization of lipid/DNA complexes during the freezing step of the lyophilization process: the particle isolation hypothesis. Biochim Biophys Acta. 2000;1468:127–38.

    Google Scholar 

  103. Molina MdC, Allison DS, Anchordoquy TJ. Maintenance of particle size during the freezing step of the lyophilization process is insufficient for preservation of activity: insight from other structural indicators. J Pharm Sci. 2001;90:1445–55.

    Google Scholar 

  104. Armstrong TK, Anchordoquy TJ. Immobilization of nonviral vectors during the freezing step of lyophilization. J Pharm Sci. 2004;93:2698–709.

    Google Scholar 

  105. Kasper JC, Pikal MJ, Friess W. Investigations on polyplex stability during the freezing step of lyophilization using controlled ice nucleation–the importance of residence time in the low-viscosity fluid state. J Pharm Sci. 2013;102:929–46.

    Google Scholar 

  106. Crowe LM, Crowe, JH, Rudolph A, Womersley C, Appel L. Preservation of freeze-dried liposomes by trehalose. Arch Biochem Biophys. 1985;242:240–7.

    Google Scholar 

  107. Crowe LM, Womersley C, Crowe JH, Reid D, Appel L, Rudolph A. Prevention of fusion and leakage in freeze-dried liposomes by carbohydrates. Biochim Biophys Acta. 1986;861:131–40.

    Google Scholar 

  108. Sharma VK, Klibanov AM. Moisture-induced aggregation of lyophilized DNA and its prevention. Pharm Res. 2007;24:168–75.

    Google Scholar 

  109. Kwok KY, Adami RC, Hester KC, Park Y, Thomas S, Rice KG. Strategies for maintaining the particle size of peptide DNA condensates following freeze-drying. Int J Pharm. 2000;203:81–8.

    Google Scholar 

  110. Betker J, Smyth T, Wang W, Anchordoquy TJ. Application of a ultra performance liquid chromatography method in the determination of DNA quality and stability. J Pharm Sci. 2012;101:987–97.

    Google Scholar 

  111. Colotte M, Coudy D, Tuffet S, Bonnet J. Adverse effect of air exposure on the stability of DNA stored at room temperature. Biopreserv Biobanking. 2011;9:47–50.

    Google Scholar 

  112. vd Heijden I, Beijnen JH, Nuijen B. Long term stability of lyophilized plasmid DNA pDERMATT. Int J Pharm. 2013;453:648–50.

    Google Scholar 

  113. Jameel F, Amsberry KL, Pikal MJ. Freeze drying properties of some oligonucleotides. Pharm Dev Technol. 2001;6:151–7.

    Google Scholar 

  114. Leboeuf C, Ratajczak P, Zhao W-L, Plassa LF, Court M, Pisonero H, Murata H, Cayuela J-M, Ameisen J-C, Garin J, Janin A. Long-term preservation at room temperature of freeze-dried human tumor samples dedicated to nucleic acids analyses. Cell Preserv Technol. 2008;6:191–8.

    Google Scholar 

  115. Molina M, Anchordoquy TJ. Metal contaminants promote degradation of lipid/DNA complexes during lyophilization. Biochim Biophys Acta. 2007;1768:669–77.

    Google Scholar 

  116. Yadava P, Gibbs M, Castro C, Hughed JA. Effect of lyophilization and freeze-thawing on the stability of siRNA-liposome complexes. AAPS Pharm Sci Tech. 2008;9:335–41.

    Google Scholar 

  117. Yu J, Anchordoquy TJ. Synergistic effects of surfactants and sugars on lipoplex stability during freeze-drying and rehydration. J Pharm Sci. 2009;98:3319–28.

    Google Scholar 

  118. Andersen MO, Howard KA, Paludan SR, Besenbacher F, Kjems J. Delivery of siRNA from lyophilized polymeric surfaces. Biomaterials. 2008;29:506–12.

    Google Scholar 

  119. Hagiwara K, Kishimoto S, Ishihara M, Koyama Y, Mazda O, Sato T. In vivo gene transfer using pDNA/chitosan/chondroitin sulfate ternary complexes: influence of chondroitin sulfate on the stability of freeze-dried complexes and transgene expression in vivo. J Gene Med. 2013;15:83–92.

    Google Scholar 

  120. Seville PC, Kellaway IW, Birchall JC. Preparation of dry powder dispersions for non-viral gene delivery by freeze-drying and spray-drying. J Gene Med. 2002;4:428–37.

    Google Scholar 

  121. Quaak SG, Haanen JB, Beijnen JH, Nuijen B. Naked plasmid DNA formulation: effect of different disaccharides on stability after lyophilisation. AAPS PharmSciTech. 2010;11:344–50.

    Google Scholar 

  122. Quaak SG, van den BJH, Toebes M, Schumacher TN, Haanen JB, Beijnen JH, Nuijen B. GMP production of pDERMATT for vaccination against melanoma in a phase I clinical trial. Eur J Pharm Biopharm. 2008;70:429–38.

    Google Scholar 

  123. Lee SB, Clabaugh KC, Silva B, Odigie KO, Coble MD, Loreille O, Scheible M, Fourney RM, Stevens J, Carmody GR, Parsons TJ, Pozder A, Eisenberg, AJ, Budowle B, Ahmad T, Miller RW, Crouse CA. Assessing a novel room temperature DNA storage medium for forensic biological samples. Forensic Sci Int Genet. 2012;6:31–40.

    Google Scholar 

  124. Podivinsky E, Love JL, van der Colff L, Samuel L. Effect of storage regime on the stability of DNA used as a calibration standard for real-time polymerase chain reaction. Anal Biochem. 2009;394:132–4.

    Google Scholar 

  125. Baust JG. Strategies for the Storage of DNA. Biopreserv Biobank. 2008;6:251–2.

    Google Scholar 

  126. Mareninov S, De Jesus J, Sanchez DE, Kay AB, Wilson RW, Babic I, Chen W, Telesca D, Lou JJ, Mirsadraei L, Gardner TP, Khanlou N, Vinters HV, Shafa BB, Lai A, Liau LM, Mischel PS, Cloughesy TF, Yong WH. Lyophilized brain tumor specimens can be used for histologic, nucleic acid, and protein analyses after 1 year of room temperature storage. J Neurooncol. 2013;113:365–73.

    Google Scholar 

  127. Hancock BC, Shamblin SL, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res. 1995;12:799–806.

    Google Scholar 

  128. Shapiro R, Danzig M. Acidic hydrolysis of deoxycytidine and deoxyuridine derivatives. The general mechanism of deoxyribonucleoside hydrolysis. BioChemistry. 1972;11:23–9.

    Google Scholar 

  129. Adam RE, Zimm BH. Shear degradation of DNA. Nucleic Acids Res. 1977;4:1513–37.

    Google Scholar 

  130. Bowman RD, Davidson N. Hydrodynamic shear breakage of DNA. Biopolymers. 1972;11:2601–24.

    Google Scholar 

  131. Lengsfeld CS, Anchordoquy TJ. Shear-induced degradation of plasmid DNA. J Pharm Sci. 2002;91:1581–9.

    Google Scholar 

  132. Pyeritz RE, Schlegel RA, Thomas CA Jr. Hydrodynamic shear breakage of DNA may produce single-chained terminals. Biochim Biophys Acta. 1972;272:504–9.

    Google Scholar 

  133. Lentz YK, Anchordoquy TJ, Lengsfeld CS. Rationale for the selection of an aerosol delivery system for gene delivery. J Aerosol Med. 2006;19:372–84.

    Google Scholar 

  134. Lentz YK, Worden LR, Anchordoquy TJ, Lengsfeld CS. Effect of jet nebulization on DNA: identifying the dominant degradation mechanism and mitigation methods. J Aerosol Sci. 2005;36:973–90.

    Google Scholar 

  135. Levy MS, Collins IJ, Yim SS, Ward JM, Titchener-Hooker N, Ayazi Shamlou P, Dunnill P. Effect of shear on plasmid DNA in solution. Bioprocess Eng. 1999;20:7–13.

    Google Scholar 

  136. Prazeres DMF, Ferreira GNM, Monteiro GA, Cooney CL, Cabral JMS. Large-scale production of pharmaceutical-grade plasmid DNA for gene therapy: problems and bottlenecks. Trends Biotechnol. 1999;17:169–74.

    Google Scholar 

  137. Stadler J, Lemmens R, Nyhammar T. Plasmid DNA purification. J Gene Med. 2004;6(Suppl 1):54–66

    Google Scholar 

  138. Lindahl T. Instability and decay of the primary structure of DNA. Nature. 1993;362:709–15.

    Google Scholar 

  139. Lindahl T, Andersson A. Rate of chain breakage at apurinic sites in double-stranded deoxyribonucleic acid. BioChemistry. 1972;11:3618–23.

    Google Scholar 

  140. Przybylowski M, Bartido S, Borquez-Ojeda O, Sadelain M, Riviere I. Production of clinical-grade plasmid DNA for human Phase I clinical trials and large animal clinical studies. Vaccine. 2007;25:5013–24.

    Google Scholar 

  141. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953;171:737–8.

    Google Scholar 

  142. Tamm C, Shapiro HS, Chargaff E. Correlation between the action of pancreatic desoxyribonuclease and the nature of its substrates. J Biol Chem. 1952;199:313–27.

    Google Scholar 

  143. Richards OC, Boyer PD. Chemical mechanism of sonic, acid, alkaline and enzymic degradation of DNA. J Mol Biol. 1965;11:327–40.

    Google Scholar 

  144. Gedik CM, Wood SG, Collins AR. Measuring oxidative damage to DNA; HPLC and the comet assay compared. Free Rad Res. 1998;29:609–15.

    Google Scholar 

  145. Tamm C, Shapiro HS, Lipshitz R, Chargaff E. Distribution density of nucleotides within a desoxyribonucleic acid chain. J Biol Chem. 1953;203:673–88.

    Google Scholar 

  146. Levy MS, O’Kennedy RD, Ayazi-Shamlou P, Dunnill P. Biochemical engineering approaches to the challenges of producing pure plasmid DNA. Trends Biotechnol. 2000;18:296–305.

    Google Scholar 

  147. Tan SC, Yiap BCDNA. RNA, and protein extraction: the past and the present. J Biomed Biotechnol. 2009;2009:574398.

    Google Scholar 

  148. Voss C. Production of plasmid DNA for pharmaceutical use. Biotechnol Annu Rev. 2007;13:201–22.

    Google Scholar 

  149. Wiendahl M, Oelmeier SA, Dismer F, Hubbuch J. High-throughput screening-based selection and scale-up of aqueous two-phase systems for pDNA purification. J Sep Sci. 2012;35:3197–207.

    Google Scholar 

  150. De la Vega J, ter Braak B, Azzoni AR, Monteiro GA, Prazeres DM. Impact of plasmid quality in lipoplex-mediated transfection. J Pharm Sci. 2013;102:3931–41.

    Google Scholar 

  151. Franklin RE, Gosling RG. Molecular configuration in sodium thymonucleate. Nature. 1953;171:740–1.

    Google Scholar 

  152. Fuller W, Forsyth T, Mahendrasingam A. Water-DNA interactions as studied by X-ray and neutron fibre diffraction. Philos Trans R Soc Lond B Biol Sci. 2004;359;1237–47 (discussion 1247–8).

    Google Scholar 

  153. Egli M, Tereshko V, Teplova M, Minasov G, Joachimiak A, Sanishvili R, Weeks CM, Miller R, Maier MA, An H, Dan Cook P, Manoharan M. X-ray crystallographic analysis of the hydration of A- and B-form DNA at atomic resolution. Biopolymers. 1998;48:234–52.

    Google Scholar 

  154. Walsh M, Tangney M, O’Neill MJ, Larkin JO, Soden DM, McKenna SL, Darcy R, O’Sullivan GC, O’Driscoll CM. Evaluation of cellular uptake and gene transfer efficiency of pegylated poly-L-lysine compacted DNA: implications for cancer gene therapy. Mol Pharm. 2006;3:644–53.

    Google Scholar 

  155. Watson JD, Baker T, Bell SP, Gann A, Levine M, Losick R. Molecular biology of the gene. San Francisco: Cold Spring Harbor Laboratory Press; 2004.

    Google Scholar 

  156. Pohle W, Gauger DR, Dornberger U, Birch-Hirschfeld E, Selle C, Rupprecht A, Bohl M. Hydration of biological molecules: lipids versus nucleic acids. Biopolymers. 2002;67:499–503.

    Google Scholar 

  157. Zhu B, Furuki T, Okuda T, Sakurai M. Natural DNA mixed with trehalose persists in B-form double-stranding even in the dry state. J Phys Chem B. 2007;111:5542–4.

    Google Scholar 

  158. Lentz YK, Anchordoquy TJ. Trehalose mantains dried plasmid DNA in its native B-conformation. Unpublished raw data. 2014.

    Google Scholar 

  159. FDA. Guidance for industry: guidance for human somatic cell therapy and gene therapy. Rockville: Center for Biologics Evaluation and Research; 1998.

    Google Scholar 

  160. FDA. Guidance for industry: considerations for plasmid DNA vaccines for infectious disease indications. Rockville: Center for Biologics Evaluation and Research; 2007.

    Google Scholar 

  161. Ferreira GN, Monteiro GA, Prazeres DM, Cabral JM. Downstream processing of plasmid DNA for gene therapy and DNA vaccine applications. Trends Biotechnol. 2000;18:380–8.

    Google Scholar 

  162. Tejeda-Mansir A, Montesinos RM. Upstream processing of plasmid DNA for vaccine and gene therapy applications. Recent Pat Biotechnol. 2008;2:156–72.

    Google Scholar 

  163. Williams JA, Carnes AE, Hodgson CP. Plasmid DNA vaccine vector design: impact on efficacy, safety and upstream production. Biotechnol Adv. 2009;27:353–70.

    Google Scholar 

  164. Bussey LB, Adamson R, Atchley A. WO/1998/005673: methods for purifying nucleic acids MEGABIOS CORPORATION. 1998.

    Google Scholar 

  165. Eastman EM, Durland RH. Manufacturing and quality control of plasmid-based gene expression systems. Adv Drug Deliv Rev. 1998;30:33–48.

    Google Scholar 

  166. Lahijani R, Hulley G, Soriano G, Horn NA, Marquet M. High-yield production of pBR322-derived plasmids intended for human gene therapy by employing a temperature-controllable point mutation. Hum Gene Ther. 1996;7:1971–80.

    Google Scholar 

  167. McNeilly D, inventor; Genzyme Corporation, assignee. Method for purifying plasmid DNA and plasmid DNA substantially free of genomic DNA. United States patent US 6214586 B1. 2001, April 10.

    Google Scholar 

  168. Olson TC, Marquet M, Horn NA, inventors; Vical Inc., assignee. Optimized high-yield production of plasmid DNA. WO1996040905 A1. 1996, December 19.

    Google Scholar 

  169. Cattamanchi A, Posavad CM, Wald A, Baine Y, Moses J, Higgins TJ, Ginsberg R, Ciccarelli R, Corey L, Koelle DM. Phase I study of a herpes simplex virus type 2 (HSV-2) DNA vaccine administered to healthy, HSV-2-seronegative adults by a needle-free injection system. Clin Vaccine Immunol. 2008;15:1638–43.

    Google Scholar 

  170. Graham BS, Koup RA, Roederer M, Bailer RT, Enama ME, Moodie Z, Martin JE, McCluskey MM, Chakrabarti BK, Lamoreaux L, Andrews CA, Gomez PL, Mascola JR, Nabel GJ. Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 DNA candidate vaccine. J Infect Dis. 2006;194:1650–60.

    Google Scholar 

  171. Wang S, Kennedy JS, West K, Montefiori DC, Coley S, Lawrence J, Shen S, Green S, Rothman AL, Ennis FA, Arthos J, Pal R, Markham P, Lu S. Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers. Vaccine. 2008;26:1098–110.

    Google Scholar 

  172. Cooke JR, McKie EA, Ward JM, Keshavarz-Moore E. Impact of intrinsic DNA structure on processing of plasmids for gene therapy and DNA vaccines. J Biotechnol. 2004;114:239–54.

    Google Scholar 

  173. Li H, Bo H, Wang J, Shao H, Huang S. Separation of supercoiled from open circular forms of plasmid DNA, and biological activity detection. CytoTechnol. 2011;63:7–12.

    Google Scholar 

  174. Weintraub H, Cheng PF, Conrad K. Expression of transfected DNA depends on DNA topology. Cell. 1986;46:115–22.

    Google Scholar 

  175. Remaut K, Sanders NN, Fayazpour F, Demeester J, De Smedt SC. Influence of plasmid DNA topology on the transfection properties of DOTAP/DOPE lipoplexes. J Control Release. 2006;115:335–43.

    Google Scholar 

  176. Lloyd RS, Haidle CW, Robberson DL. Bleomycin-specific fragmentation of double-stranded DNA. BioChemistry. 1978;17:1890–6.

    Google Scholar 

  177. Volkin DB, Evans RK, Bruner M, inventors; Merck & Co., Inc., assignee. DNA Vaccine Formulations. WO1997040839 A1. 1997, November 6.

    Google Scholar 

  178. Molina MD, Anchordoquy TJ. Formulation strategies to minimize oxidative damage in lyophilized lipid/DNA complexes during storage. J Pharm Sci. 2008;97:5089–105.

    Google Scholar 

  179. Molina MD, Anchordoquy TJ. Degradation of lyophilized lipid/DNA complexes during storage: the role of lipid and reactive oxygen species. Biochim Biophys Acta. 2008;1778:2119–26.

    Google Scholar 

  180. Kolobov AV, Vainberg YP. Stability of the physicochemical parameters of DNA during prolonged keeping. Bull Exp Biol Med. 1976;81:360–3.

    Google Scholar 

  181. Cherng J-Y, Talsma H, Crommelin DJA, Hennink WE. Long term stability of Poly((2-dimethylamino)ethyl methacrylate)-based gene delivery systems. Pharm Res. 1999; 16:1417–23.

    Google Scholar 

  182. Shirkey B, McMaster NJ, Smith SC, Wright DJ, Rodriguez H, Jaruga P, Birincioglu M, Helm RF, Potts M. Genomic DNA of Nostoc commune (Cyanobacteria) becomes covalently modified during long-term (decades) desiccation but is protected from oxidative damage and degradation. Nucleic Acids Res. 2003;31:2995–3005.

    Google Scholar 

  183. Molina MC, Armstrong TK, Zhang Y, Patel MM, Lentz YK, Anchordoquy TJ. The stability of lyophilized lipid/DNA complexes during prolonged storage. J Pharm Sci. 2004;93:2259–73.

    Google Scholar 

  184. Waterman KC, Adami RC, Alsante KM, Hong J, Landis MS, Lombardo F, Roberts CJ. Stabilization of pharmaceuticals to oxidative degradation. Pharm Dev Technol. 2002;7:1–32.

    Google Scholar 

  185. Molina M. Studies on the stabilization of lyophilized lipid/DNA complexes during storage Ph.D. Thesis in Pharmaceutical Sciences. School of Pharmacy, University of Colorado, Denver, CO.; 2007. p. 160.

    Google Scholar 

  186. Qian SY, Buettner GR. Iron and dioxygen chemistry is an important route to initiation of biological free radical oxidations: an electron paramagnetic resonance spin trapping study. Free Radic Biol Med. 1999;26:1447–56.

    Google Scholar 

  187. Schaich KM. Preparation of metal-free solutions for studies of active oxygen species. Methods Enzymol. 1990;186:121–7.

    Google Scholar 

  188. Templeton AC, Han Y-HR, Mahajan R, Chern RT, Reed RA. Rapid headspace oxygen analysis for pharmaceutical packaging applications. Pharm Technol. 2002;7:41–61.

    Google Scholar 

  189. Graf E, Mahoney JR, Bryant RG, Eaton JW. Iron-catalyzed hydroxyl radical formation. Stringent requirement for free iron coordination site. J Biol Chem. 1984;259:3620–4.

    Google Scholar 

  190. Ouameur AA, Arakawa H, Ahmad R, Naoui M, Tajmir-Riahi HA. A comparative study of Fe(II) and Fe(III) interactions with DNA duplex: major and minor grooves bindings. DNA Cell Biol. 2005;24:394–401.

    Google Scholar 

  191. Breen AP, Murphy JA. Reactions of oxyl radicals with DNA. Free Radic Biol Med. 1995;18:1033–77.

    Google Scholar 

  192. Breen AP, Curley JG, Overcashier DE, Hsu CC, Shire SJ. Effect of moisture on the stability of a lyophilized humanized monoclonal antibody formulation. Pharm Res. 2001;18:1345–53.

    Google Scholar 

  193. Croyle MA, Cheng X, Wilson JM. Development of formulations that enhance physical stability of viral vectors for gene therapy. Gene Ther. 2001;8:1281–90.

    Google Scholar 

  194. Pikal K, Shah S. Moisture transfer from stopper to product and resulting stability implications. Dev Biol Stand. 1991;74:165–79.

    Google Scholar 

  195. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. Oxford: Oxford University Press; 1999.

    Google Scholar 

  196. Scandalios JG. Oxidative stress: molecular perception and transduction of signals triggering antioxidant gene defenses. Braz J Med Biol Res. 2005;38:995–1014.

    Google Scholar 

  197. Chang HI, Yeh MK. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomed. 2012;7:49–60.

    Google Scholar 

  198. Karel M, Labuza TP, Maloney JF. Chemical changes in freeze-dried foods and model systems. Cryobiology. 1967;3:288–96.

    Google Scholar 

  199. Labuza TP, Chou HE. Decrease of linoleate oxidation rate due to water at intermediate water activity. J Food Sci. 1974;39:112–3.

    Google Scholar 

  200. Labuza TP, Heidelbaugh ND, Silver M, Karel M. Oxidation at intermediate moisture contents. J Am Oil Chem Soc. 1971;48:86–90.

    Google Scholar 

  201. Labuza TP, Maloney JF, Karel M. Autoxidation of Methyl Linoleate in freeze-dried model systems. II. Effect of water on cobalt-catalyzed oxidation. J Food Sci. 1966;31:885–91.

    Google Scholar 

  202. Labuza TP, Silver M, Cohn M, Heidelbaugh ND, Karel M. Metal-catalyzed oxidation in the presence of water in foods. J Am Oil Chem Soc. 1971;48:527–31.

    Google Scholar 

  203. Labuza TP, Tannenbaum SR, Karel M. Water content and stability of low-moisture & intermediate-moisture foods. Food Technol. 1970;24:35–42.

    Google Scholar 

  204. Maloney JF, Labuza TP, Wallace DH, Karel M. Autoxidation of Methyl Linoleate in freeze-dried model systems. I. Effect of water on the autocatalyzed oxidation. J Food Sci. 1966;31:878–84.

    Google Scholar 

  205. Frankel EN. Lipid oxidation: mechanisms, products and biological significance. J Amer Oil Chem Soc. 1984;61:1908–17.

    Google Scholar 

  206. Porter N. Mechanisms for the autoxidation of polyunsaturated lipids. Acc Chem Res. 1986;19:262–70.

    Google Scholar 

  207. Wagner BA, Buettner GR, Burns CP. Free radical-mediated lipid peroxidation in cells: oxidizability is a function of cell lipid bis-allylic hydrogen content. BioChemistry. 1994;33:4449–53.

    Google Scholar 

  208. Porter NA, Caldwell SE, Mills KA. Mechanisms of free radical oxidation of unsaturated lipids. Lipids. 1995;30:277–90.

    Google Scholar 

  209. Bruch RC, Thayer WS. Differential effect of lipid peroxidation on membrane fluidity as determined by electron spin resonance probes. Biochim Biophys Acta. 1983;733:216–22.

    Google Scholar 

  210. Kunimoto M, Inoue K, Nojima S. Effect of ferrous ion and ascorbate-induced lipid peroxidation on liposomal membranes. Biochim Biophys Acta. 1981;646:169–78.

    Google Scholar 

  211. Smolen JE, Shohet SB. Permeability changes induced by peroxidation in liposomes prepared from human erythrocyte lipids. J Lipid Res. 1974;15:273–80.

    Google Scholar 

  212. Grit M, Crommelin DJA. The effect of surface charge on the hydrolysis kinetics of partially hydrogenated egg phosphatidylcholine and egg phosphatidylglycerol in aqueous liposome dispersions. Biochim Biophys Acta. 1993;1167:49–55.

    Google Scholar 

  213. Zhang JA, Xuan T, Parmar M, Ma L, Ugwu S, Ali S, Ahmad I. Development and characterization of a novel liposome-based formulation of SN-38. Int J Pharmaceutics. 2004;270:93–107.

    Google Scholar 

  214. Crommelin DJA, van Bommel EMG. Stability of Liposomes on storage: freeze dried, frozen or as an aqueous dispersion. Pharm Res. 1984;1:159–63.

    Google Scholar 

  215. Sun WQ, Leopold AC, Crowe LM, Crowe JH. Stability of dry liposomes in sugar glasses. Biophys J. 1996;70:1769–76.

    Google Scholar 

  216. Minotti G, Aust S. The requirement for iron (III) in the initiation of lipid peroxidation by iron (II) and hydrogen peroxide. J Biol Chem. 1987;262:1098–104.

    Google Scholar 

  217. Yin H, Xu L, Porter NA. Free radical lipid peroxidation: mechanisms and analysis. Chemical Rev. 2011;111:5944–72.

    Google Scholar 

  218. Minotti G, Aust SD. Redox cycling of iron and lipid peroxidation. Lipids. 1992;27:219–26.

    Google Scholar 

  219. Miller DM, Buettner GR, Aust SD. Transition metals as catalysts of “autoxidation” reactions. Free Radic Biol Med. 1990;8:95–108.

    Google Scholar 

  220. Schaich KM. Metals and lipid oxidation. Contemporary issues. Lipids. 1992;27:209–18.

    Google Scholar 

  221. Culbertson SM, Porter NA. Unsymmetrical azo initiators increase efficiency of radical generation in aqueous dispersions, liposomal membranes, and lipoproteins. J Am Chem Soc. 2000;122:4032–8.

    Google Scholar 

  222. Noguchi N, Yamashita H, Gotoh N, Yamamoto Y, Numano R, Niki E. 2,2′-Azobis (4-methoxy-2,4-dimethylvaleronitrile), a new lipid-soluble azo initiator: application to oxidations of lipids and low-density lipoprotein in solution and in aqueous dispersions. Free Radic Biol Med. 1998;24:259–68.

    Google Scholar 

  223. Mowri H, Nojima S, Inoue K. Effect of lipid composition of liposomes on their sensitivity to peroxidation. J Biochem. 1984;95:551–8.

    Google Scholar 

  224. Vossen RC, van Dam-Mieras MC, Hornstra G, Zwaal RF. Continuous monitoring of lipid peroxidation by measuring conjugated diene formation in an aqueous liposome suspension. Lipids. 1993;28:857–61.

    Google Scholar 

  225. Wasungu L, Hoekstra D. Cationic lipids, lipoplexes and intracellular delivery of genes. J Control Release. 2006;116:255–64.

    Google Scholar 

  226. Xu L, Anchordoquy TJ. Cholesterol domains in cationic lipid/DNA complexes improve transfection. Biochim Biophys Acta. 2008;1778:2177–81.

    Google Scholar 

  227. Zidovska A, Evans HM, Ahmad A, Ewert KK, Safinya CR. The role of cholesterol and structurally related molecules in enhancing transfection of cationic liposome-DNA complexes. J Phys Chem B. 2009;113:5208–16.

    Google Scholar 

  228. McLean LR, Hagaman KA. Effect of lipid physical state on the rate of peroxidation of liposomes. Free Radic Biol Med. 1992;12:113–9.

    Google Scholar 

  229. Samuni AM, Lipman A, Barenholz Y. Damage to liposomal lipids: protection by antioxidants and cholesterol-mediated dehydration. Chem Phys Lipids. 2000;105:121–34.

    Google Scholar 

  230. Tirosh O, Kohen R, Katzhendler J, Alon A, Barenholz Y. Oxidative stress effect on the integrity of lipid bilayers is modulated by cholesterol level of bilayers. Chem Phys Lipids. 1997;87:17–22.

    Google Scholar 

  231. Dacaranhe CD, Terao J. A unique antioxidant activity of phosphatidylserine on iron-induced lipid peroxidation of phospholipid bilayers. Lipids. 2001;36:1105–10.

    Google Scholar 

  232. Yoshida K, Terao J, Suzuki T, Takama K. Inhibitory effect of phosphatidylserine on iron-dependent lipid peroxidation. Biochem Biophys Res Commun. 1991;179:1077–81.

    Google Scholar 

  233. Gal S, Pinchuk I, Lichtenberg D. Peroxidation of liposomal palmitoyllinoleoylphosphatidylcholine (PLPC), effects of surface charge on the oxidizability and on the potency of antioxidants. Chem Phys Lipids. 2003;126:95–110.

    Google Scholar 

  234. Mouradian R, Womersley C, Crowe LM, Crowe JH. Degradation of functional integrity during long-term storage of a freeze-dried biological membrane. Cryobiology. 1985;22:119–27.

    Google Scholar 

  235. Payton NM, Wempe MF, Betker JL, Randolph TW, Anchordoquy TJ. Lyophilization of a triply unsaturated phospholipid: effects of trace metal contaminants. Eur J Pharm Biopharm. 2013;85:306–13.

    Google Scholar 

  236. Braughler JM, Chase RL, Pregenzer JF. Stimulation and inhibition of iron-dependent lipid peroxidation by desferrioxamine. Biochem Biophys Res Commun. 1988;153:933–8.

    Google Scholar 

  237. Mei L, McClements DJ, Wu J, Decker EA. Iron-catalyzed lipid oxidation in emulsion as affected by surfactant, pH and NaCl. Food Chem. 1998;61:307–12.

    Google Scholar 

  238. Mozuraityte R, Rustad T, Storrø I. Oxidation of cod phospholipids in liposomes: effects of salts, pH and zeta potential. Eur J Lipid Sci Technol. 2006;108:944–50.

    Google Scholar 

  239. Mozuraityte R, Rustad T, Storrø I. Pro-oxidant activity of Fe2+ in oxidation of cod phospholipids in liposomes. Eur J Lipid Sci Technol. 2006;108:218–26.

    Google Scholar 

  240. Ohyashiki T, Koshino M, Ohta A, Mohri T. The effect of ionic strength on the lipid peroxidation of porcine intestinal brush-border membrane vesicles. Biochim Biophys Acta. 1985;812:84–90.

    Google Scholar 

  241. Fiorentini D, Landi L, Barzanti V, Cabrini L. Buffers can modulate the effect of sonication on egg lecithin liposomes. Free Radic Res Commun. 1989;6:243–50.

    Google Scholar 

  242. Catala A. Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids. 2009;157:1–11.

    Google Scholar 

  243. Yin MC, Faustman C. Influence of temperature, pH, and phospholipid composition upon the stability of myoglobin and phospholipid: a liposome model. J Agric Food Chem. 1993;41:853–7.

    Google Scholar 

  244. Franks F. Freeze-drying. From empiricism to predictability. Cryo Lett. 1990;11:93–110.

    Google Scholar 

  245. Grit M, Zuidam NJ, Underberg WJ, Crommelin DJ. Hydrolysis of partially saturated egg phosphatidylcholine in aqueous liposome dispersions and the effect of cholesterol incorporation on hydrolysis kinetics. J Pharm Pharmacol. 1993;45:490–5.

    Google Scholar 

  246. Vernooij EA, Kettenes-van den Bosch JJ, Underberg WJ, Crommelin DJ. Chemical hydrolysis of DOTAP and DOPE in a liposomal environment. J Control Release. 2002;79:299–303.

    Google Scholar 

  247. Ho RJ, Schmetz M, Deamer DW. Nonenzymatic hydrolysis of phosphatidylcholine prepared as liposomes and mixed micelles. Lipids. 1987;22:156–8.

    Google Scholar 

  248. Kensil CR, Dennis EA. Alkaline hydrolysis of phospholipids in model membranes and the dependence on their state of aggregation. BioChemistry. 1981;20:6079–85.

    Google Scholar 

  249. Aleku M, Schulz P, Keil O, Santel A, Schaeper U, Dieckhoff B, Janke O, Endruschat J, Durieux B, Roder N, Loffler K, Lange C, Fechtner M, Mopert K, Fisch G, Dames S, Arnold W, Jochims K, Giese K, Wiedenmann B, Scholz A, Kaufmann J. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res. 2008;68:9788–98.

    Google Scholar 

  250. Bedikian AY, Richards J, Kharkevitch D, Atkins MB, Whitman E, Gonzalez RA. phase 2 study of high-dose Allovectin-7 in patients with advanced metastatic melanoma. Melanoma Res. 2010;20:218–26.

    Google Scholar 

  251. Felgner PL. Nonviral strategies for gene therapy. Sci Amer. 1997;276:102–6.

    Google Scholar 

  252. Villaret D, Glisson B, Kenady D, Hanna E, Carey M, Gleich L, Yoo GH, Futran N, Hung MC, Anklesaria P, Heald AE. A multicenter phase II study of tgDCC-E1A for the intratumoral treatment of patients with recurrent head and neck squamous cell carcinoma. Head Neck. 2002;24:661–9.

    Google Scholar 

  253. Wheeler JJ, Palmer L, Ossanlou M, MacLachlan I, Graham RW, Zhang YP, Hope MJ, Scherrer P, Cullis PR. Stabilized plasmid-lipid particles: construction and characterization. Gene Ther. 1999;6:271–81.

    Google Scholar 

  254. Zhang YP, Sekirov L, Saravolac EG, Wheeler JJ, Tardi P, Clow K, Leng E, Sun R, Cullis PR, Scherrer P. Stabilized plasmid-lipid particles for regional gene therapy: formulation and transfection properties. Gene Ther. 1999;6:1438–47.

    Google Scholar 

  255. Meidan VM, Cohen JS, Amariglio N, Hirsch-Lerner D, Barenholz Y. Interaction of oligonucleotides with cationic lipids: the relationship between electrostatics, hydration and state of aggregation. Biochim Biophys Acta. 2000;1464:251–61.

    Google Scholar 

  256. Ambegia E, Ansell S, Cullis P, Heyes J, Palmer L, MacLachlan I. Stabilized plasmid-lipid particles containing PEG-diacylglycerols exhibit extended circulation lifetimes and tumor selective gene expression. Biochimica et Biophysica Acta (BBA)—Biomembranes. 2005;1669:155–63.

    Google Scholar 

  257. Morrissey DV, Lockridge JA, Shaw L, Blanchard K, Jensen K, Breen W, Hartsough K, Machemer L, Radka S, Jadhav V, Vaish N, Zinnen S, Vargeese C, Bowman K, Shaffer CS, Jeffs LB, Judge A, MacLachlan I, Polisky B. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol. 2005;23:1002–7.

    Google Scholar 

  258. Semple SC, Akinc A, Chen J, Sandhu AP, Mui BL, Cho CK, Sah DW, Stebbing D, Crosley EJ, Yaworski E, Hafez IM, Dorkin JR, Qin J, Lam K, Rajeev KG, Wong KF, Jeffs LB, Nechev L, Eisenhardt ML, Jayaraman M, Kazem M, Maier MA, Srinivasulu M, Weinstein MJ, Chen Q, Alvarez R, Barros SA, De S, Klimuk SK, Borland T, Kosovrasti V, Cantley WL, Tam YK, Manoharan M, Ciufolini MA, Tracy MA, de Fougerolles A, MacLachlan I, Cullis PR, Madden TD, Hope MJ. Rational design of cationic lipids for siRNA delivery. Nat Biotechnol. 2010;28:172–6.

    Google Scholar 

  259. Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, Harborth J, Heyes JA, Jeffs LB, John M, Judge AD, Lam K, McClintock K, Nechev LV, Palmer LR, Racie T, Rohl I, Seiffert S, Shanmugam S, Sood V, Soutschek J, Toudjarska I, Wheat AJ, Yaworski E, Zedalis W, Koteliansky V, Manoharan M, Vornlocher HP, MacLachlan I. RNAi-mediated gene silencing in non-human primates. Nature. 2006;441:111–4.

    Google Scholar 

  260. Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, Perez J, Chiesa J, Warrington S, Tranter E, Munisamy M, Falzone R, Harrop J, Cehelsky J, Bettencourt BR Geissler M, Butler JS, Sehgal A, Meyers RE, Chen Q, Borland T, Hutabarat RM, Clausen VA, Alvarez R, Fitzgerald K, Gamba-Vitalo C, Nochur SV, Vaishnaw AK, Sah DWY, Gollob JA, Suhr OB. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369:819–29.

    Google Scholar 

  261. Pakunlu RI, Wang Y, Tsao W, Pozharov V, Cook TJ, Minko T. Enhancement of the efficacy of chemotherapy for lung cancer by simultaneous suppression of multidrug resistance and antiapoptotic cellular defense: novel multicomponent delivery system. Cancer Res. 2004;64:6214–24.

    Google Scholar 

  262. Stuart DD, Allen TM. A new liposomal formulation for antisense oligodeoxynucleotides with small size, high incorporation efficiency and good stability. Biochim Biophys Acta. 2000;1463:219–29.

    Google Scholar 

  263. Maurer N, Wong KF, Stark H, Louie L, McIntosh D, Wong T, Scherrer P, Semple SC, Cullis PR. Spontaneous entrapment of polynucleotides upon electrostatic interaction with ethanol-destabilized cationic liposomes. Biophys J. 2001;80:2310–26.

    Google Scholar 

  264. Pastorino F, Brignole C, Marimpietri D, Pagnan G, Morando A, Ribatti D, Semple SC, Gambini C, Allen TM, Ponzoni M. Targeted liposomal c-myc antisense oligodeoxynucleotides induce apoptosis and inhibit tumor growth and metastases in human melanoma models. Clin Cancer Res. 2003;9:4595–605.

    Google Scholar 

  265. Jeffs LB, Palmer LR, Ambegia EG, Giesbrecht C, Ewanick S, MacLachlan I. A scalable, extrusion-free method for efficient liposomal encapsulation of plasmid DNA. Pharm Res. 2005;22:362–72.

    Google Scholar 

  266. Monck MA, Mori A, Lee D, Tam P, Wheeler JJ, Cullis PR, Scherrer P. Stabilized plasmid-lipid particles: pharmacokinetics and plasmid delivery to distal tumors following intravenous injection. J Drug Target. 2000;7:439–52.

    Google Scholar 

  267. Wheeler JJ, Palmer L, Ossanlou M, MacLachlan I, Graham RW, Zhang YP, Hope MJ, Scherrer P, Cullis PR. Stabilized plasmid-lipid particles: construction and characterization. Gene Ther. 1999;6:271–81.

    Google Scholar 

  268. Li C, Deng Y. A novel method for the preparation of liposomes: freeze drying of monophase solutions. J Pharm Sci. 2004;93:1403–14.

    Google Scholar 

  269. Wu SY, Putral LN, Liang M, Chang HI, Davies NM, McMillan NA. Development of a novel method for formulating stable siRNA-loaded lipid particles for in vivo use. Pharm Res. 2009;26:512–22.

    Google Scholar 

  270. Yasuda M, Gan L, Chen B, Kadirvel S, Yu C, Phillips JD, New MI, Liebow A, Fitzgerald K, Querbes W, Desnick RJ. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proc Natl Acad Sci U S A. 2014;111:7777–82.

    Google Scholar 

  271. Imlay JA, Linn S. DNA damage and oxygen radical toxicity. Science. 1988;240:1302–9.

    Google Scholar 

  272. Lloyd DR, Phillips DH. Oxidative DNA damage mediated by copper(II), iron(II) and nickel(II) Fenton reactions: evidence for site-specific mechanisms in the formation of double-strands breaks, 8-hydroxydeoxyguanosine and putative intrastrand cross-links. Mutat Res. 1999;424:23–36.

    Google Scholar 

  273. Ohyashiki T, Kadoya A, Kushida K. The role of Fe+3 on Fe+2-dependent lipid peroxidation in phospholipid liposomes. Chem Pharm Bull. 2002;50:203–7.

    Google Scholar 

  274. Inouye S. Site-specific cleavage of double-strand DNA by hydroperoxide of linoleic acid. FEBS Lett. 1984;172:231–4.

    Google Scholar 

  275. Ueda K, Kobayashi S, Morita J, Komano T. Site-specific DNA damage caused by lipid peroxidation products. Biochim Biophys Acta. 1985;824:341–8.

    Google Scholar 

  276. Yu J, Anchordoquy TJ. Effects of moisture content on the storage stability of dried lipoplex formulations. J Pharm Sci. 2009;98:3378–89.

    Google Scholar 

  277. Allison SD, Anchordoquy TJ, Findeis M, editors. Nonviral vectors for gene therapy. Totowa: Humana; 2001

    Google Scholar 

  278. Armstrong TK, Girouard LG, Anchordoquy TJ. Effects of PEGylation on the preservation of cationic lipid/DNA complexes during freeze-thawing and lyophilization. J Pharm Sci. 2002;91:2549–58.

    Google Scholar 

  279. Mohammed-Saeid W, Michel D, El-Aneed A, Verrall RE, Low NH, Badea I. Development of lyophilized gemini surfactant-based gene delivery systems: influence of lyophilization on the structure, activity and stability of the lipoplexes. J Pharm Pharm Sci. 2012;15:548–67.

    Google Scholar 

  280. Zhong ZR, Zhang ZR, Liu J, Deng Y, Zhang HW Fu Y, Song QG, He Q. Characteristics comparison before and after lyophilization of transferrin modified Procationic-Liposome-Protamine-DNA complexes (Tf-PLPD). Arch Pharm Res. 2007;30:102–8.

    Google Scholar 

  281. Kundu AK, Chandra PK, Hazari S, Ledet G, Pramar YV, Dash S, Mandal TK. Stability of lyophilized siRNA nanosome formulations. Int J Pharm. 2012;423:525–34.

    Google Scholar 

  282. Ray SD, Fariss MW. Role of cellular energy status in tocopheryl hemisuccinate cytoprotection against ethyl methanesulfonate-induced toxicity. Arch Biochem Biophys. 1994;311:180–90.

    Google Scholar 

  283. Tirmenstein MA, Pierce CA, Leraas TL, Fariss MW. A fluorescence plate reader assay for monitoring the susceptibility of biological samples to lipid peroxidation. Anal Biochem. 1998;265:246–52.

    Google Scholar 

  284. Hafez IM, Maurer N, Cullis PR. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 2001;8:1188–96.

    Google Scholar 

  285. Araseki M, Yamamoto K, Miyashita K. Oxidative stability of polyunsaturated fatty acid in phosphatidylcholine liposomes. Biosci Biotechnol Biochem. 2002;66:2573–7.

    Google Scholar 

  286. Samuni AM, Barenholz Y, Crommelin DJA, Zuidam NJ. Irradiation damage to liposomes differing in composition and their protection by nitroxides. Free Rad Biol Med. 1997;23:972–9.

    Google Scholar 

  287. del Pozo-Rodriguez A, Solinis MA, Gascon AR, Pedraz JL. Short- and long-term stability study of lyophilized solid lipid nanoparticles for gene therapy. Eur J Pharm Biopharm. 2009;71:181–9.

    Google Scholar 

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Acknowledgments

This work was supported by NIH grants 1RO1GM093287 and 1R1EB016378 to TJA. The authors also would like to express their sincere thanks to both Dr. Yvonne Lentz and Jamie Betker for their technical support in the DNA-based section.

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Authors and Affiliations

  1. Pharmaceutical Sciences Consultant, 36 Cutler Drive, 01721, Ashland, MA, USA

    Marion dC. Molina Ph.D.

  2. School of Pharmacy, University of Colorado Denver, 80045, Aurora, CO, USA

    Nicole M. Payton & Thomas J. Anchordoquy

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  1. Marion dC. Molina Ph.D.
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Correspondence to Marion dC. Molina Ph.D. .

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  1. Novartis Vaccines and Diagnostics, Holly Springs, North Carolina, USA

    Dushyant Varshney

  2. Novartis Vaccines and Diagnostics, Holly Springs, North Carolina, USA

    Manmohan Singh

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Molina, M., Payton, N., Anchordoquy, T. (2015). Stabilization of Plasmid DNA and Lipid-Based Therapeutics as Dehydrated Formulations. In: Varshney, D., Singh, M. (eds) Lyophilized Biologics and Vaccines. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2383-0_10

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