Vaginal Delivery of Biopharmaceuticals



The vagina may be an interesting alternative route for the delivery of biopharmaceuticals, particularly for the management of local conditions or the prevention of infection. The field of anti-HIV microbicides has been particularly prolific in the development of different active peptide/protein-based molecules, as well as of therapeutic genetic material, intended for vaginal administration. Alongside, vaginal vaccination has attracted considerable interest. However, the inherent features of the vaginal tract provide important hurdles to the optimized performance of active biomolecules and require rationale approaches toward the development of suitable products. This chapter provides an overview on such challenges and strategies adopted for the vaginal delivery of biopharmaceuticals.


Vaginal drug delivery Microbicides siRNA Peptides Proteins Permeation enhancers Enzymatic inhibitors Nanocarriers Engineered microbiota 



This work was supported by Fundação para a Ciência e a Tecnologia, Portugal (grant VIH/SAU/0021/2011).


  1. 1.
    Alexander NJ, Baker E, Kaptein M, Karck U, Miller L, Zampaglione E. Why consider vaginal drug administration? Fertil Steril. 2004;82(1):1–12.PubMedGoogle Scholar
  2. 2.
    Bartusevicius A, Barcaite E, Nadisauskiene R. Oral, vaginal and sublingual misoprostol for induction of labor. Int J Gynaecol Obstet. 2005;91(1):2–9.PubMedGoogle Scholar
  3. 3.
    Nurbhai M, Grimshaw J, Watson M, Bond C, Mollison J, Ludbrook A. Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush). Cochrane Database Syst Rev. 2007;(4):CD002845.Google Scholar
  4. 4.
    Roumen FJ. The contraceptive vaginal ring compared with the combined oral contraceptive pill: a comprehensive review of randomized controlled trials. Contraception. 2007;75(6):420–9.PubMedGoogle Scholar
  5. 5.
    Benziger DP, Edelson J. Absorption from the vagina. Drug Metab Rev. 1983;14(2):137–68.PubMedGoogle Scholar
  6. 6.
    Hussain A, Ahsan F. The vagina as a route for systemic drug delivery. J Control Release. 2005;103(2):301–13.PubMedGoogle Scholar
  7. 7.
    Katz DF, Henderson MH, Owen DH, Plenys AM, Walmer DK. What is needed to advance vaginal formulation technology? In: Rencher WF, editor. Vaginal microbicide formulations workshop. Philadelphia: Lippincott-Raven Publishers; 1998. pp. 90–9.Google Scholar
  8. 8.
    Cone RA. Barrier properties of mucus. Adv Drug Deliv Rev. 2009;61(2):75–85.PubMedGoogle Scholar
  9. 9.
    Boskey ER, Cone RA, Whaley KJ, Moench TR. Origins of vaginal acidity: high D/L lactate ratio is consistent with bacteria being the primary source. Hum Reprod. 2001;16(9):1809–13.PubMedGoogle Scholar
  10. 10.
    Caillouette JC, Sharp CF, Jr., Zimmerman GJ, Roy S. Vaginal pH as a marker for bacterial pathogens and menopausal status. Am J Obstet Gynecol. 1997;176(6):1270–75.PubMedGoogle Scholar
  11. 11.
    Acartürk F, Parlatan ZI, Saracoglu OF. Comparison of vaginal aminopeptidase enzymatic activities in various animals and in humans. J Pharm Pharmacol. 2001;53(11):1499–504.PubMedGoogle Scholar
  12. 12.
    das Neves J, Amaral MH, Bahia MF. Vaginal drug delivery. In: Gad SC, editor. Pharmaceutical Manufacturing Handbook: Production and Processes. Hoboken: Wiley; 2008. pp. 809–78.Google Scholar
  13. 13.
    das Neves J, Palmeira-de-Oliveira R, Palmeira-de-Oliveira A, Rodrigues F, Sarmento B. Vaginal mucosa and drug delivery. In: Khutoryanskiy VV, editor. Mucoadhesive Materials and Drug Delivery Systems. Chichester: Wiley; 2014. (In press).Google Scholar
  14. 14.
    Vermani K, Garg S. The scope and potential of vaginal drug delivery. Pharm Sci Technol Today. 2000;3(10):359–64.PubMedGoogle Scholar
  15. 15.
    Woolfson AD, Malcolm RK, Gallagher R. Drug delivery by the intravaginal route. Crit Rev Ther Drug Carrier Syst. 2000;17(5):509–55.PubMedGoogle Scholar
  16. 16.
    Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev. 2003;(1):CD000941.Google Scholar
  17. 17.
    Johansson ED, Sitruk-Ware R. New delivery systems in contraception: vaginal rings. Am J Obstet Gynecol. 2004;190(4 Suppl 1): S54–9.PubMedGoogle Scholar
  18. 18.
    Vollebregt A, van’t Hof DB, Exalto N. Prepidil compared to propess for cervical ripening. Eur J Obstet Gynecol Reprod Biol. 2002;104(2):116–9.PubMedGoogle Scholar
  19. 19.
    Ariën KK, Jespers V, Vanham G. HIV sexual transmission and microbicides. Rev Med Virol. 2011;21(2):110–33.Google Scholar
  20. 20.
    Shattock RJ, Rosenberg Z. Microbicides: topical prevention against HIV. Cold Spring Harb Perspect Med. 2012;2(2):a007385.PubMedGoogle Scholar
  21. 21.
    Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany AB, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168–74.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Obiero J, Mwethera PG, Wiysonge CS. Topical microbicides for prevention of sexually transmitted infections. Cochrane Database Syst Rev. 2012;6:CD007961.PubMedGoogle Scholar
  23. 23.
    Braunstein S, van de Wijgert J. Preferences and practices related to vaginal lubrication: implications for microbicide acceptability and clinical testing. J Womens Health. 2005;14(5):424–33.Google Scholar
  24. 24.
    Emau P, Tian B, O’Keefe BR, Mori T, McMahon JB, Palmer KE, Jiang Y, Bekele G, Tsai CC. Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide. J Med Primatol. 2007;36(4–5):244–53.PubMedGoogle Scholar
  25. 25.
    Welch BD, Francis JN, Redman JS, Paul S, Weinstock MT, Reeves JD, Lie YS, Whitby FG, Eckert DM, Hill CP, Root MJ, Kay MS. Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance. J Virol. 2010;84(21):11235–44.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Eade CR, Wood MP, Cole AM. Mechanisms and modifications of naturally occurring host defense peptides for anti-HIV microbicide development. Curr HIV Res. 2012;10(1):61–72.PubMedGoogle Scholar
  27. 27.
    Hooven TA, Randis TM, Hymes SR, Rampersaud R, Ratner AJ. Retrocyclin inhibits Gardnerella vaginalis biofilm formation and toxin activity. J Antimicrob Chemother. 2012;67(12):2870–2.PubMedGoogle Scholar
  28. 28.
    Veselinovic M, Neff CP, Mulder LR, Akkina R. Topical gel formulation of broadly neutralizing anti-HIV-1 monoclonal antibody VRC01 confers protection against HIV-1 vaginal challenge in a humanized mouse model. Virology. 2012;432(2):505–10.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Morellato-Castillo L, Acharya P, Combes O, Michiels J, Descours A, Ramos OH, Yang Y, Vanham G, Arien KK, Kwong PD, Martin L, Kessler P. Interfacial cavity filling to optimize CD4-mimetic miniprotein interactions with HIV-1 surface glycoprotein. J Med Chem. 2013;56(12):5033–47.Google Scholar
  30. 30.
    Bogers WM, Bergmeier LA, Ma J, Oostermeijer H, Wang Y, Kelly CG, P. Ten Haaft, Singh M, Heeney JL, Lehner T. A novel HIV-CCR5 receptor vaccine strategy in the control of mucosal SIV/HIV infection. AIDS. 2004;18(1):25–36.PubMedGoogle Scholar
  31. 31.
    Kanazawa T, Takashima Y, Okada H. Vaginal DNA vaccination against infectious diseases transmitted through the vagina. Front Biosci (Elite Ed.). 2012;4:2340–53.Google Scholar
  32. 32.
    Shin H, Iwasaki A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature. 2012;491(7424):463–7.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Magliani W, Conti S, Cassone A, De Bernardis F, Polonelli L. New immunotherapeutic strategies to control vaginal candidiasis. Trends Mol Med. 2002;8(3):121–6.PubMedGoogle Scholar
  34. 34.
    Yang S, Chen Y, Ahmadie R, Ho EA. Advancements in the field of intravaginal siRNA delivery. J Control Release. 2013;167(1):29–39.PubMedGoogle Scholar
  35. 35.
    Castle PE, Whaley KJ, Hoen TE, Moench TR, Cone RA. Contraceptive effect of sperm-agglutinating monoclonal antibodies in rabbits. Biol Reprod. 1997;56(1):153–9.PubMedGoogle Scholar
  36. 36.
    Norton EJ, Diekman AB, Westbrook VA, Flickinger CJ, Herr JC. RASA, a recombinant single-chain variable fragment (scFv) antibody directed against the human sperm surface: implications for novel contraceptives. Hum Reprod. 2001;16(9):1854–60.PubMedGoogle Scholar
  37. 37.
    Corbo DC, Liu JC, Chien YW. Characterization of the barrier properties of mucosal membranes. J Pharm Sci. 1990;79(3):202–6.PubMedGoogle Scholar
  38. 38.
    van der Bijl P, van Eyk AD. Human vaginal mucosa as a model of buccal mucosa for in vitro permeability studies: an overview. Curr Drug Deliv. 2004;1(2):129–35.Google Scholar
  39. 39.
    van der Bijl P, van Eyk AD, Thompson IO. Permeation of 17beta-estradiol through human vaginal and buccal mucosa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85(4):393–8.Google Scholar
  40. 40.
    van der Bijl P, van Eyk AD, Thompson IO, Stander IA. Diffusion rates of vasopressin through human vaginal and buccal mucosa. Eur J Oral Sci. 1998;106(5):958–62.Google Scholar
  41. 41.
    van der Bijl P, Penkler L, van Eyk AD. Permeation of sumatriptan through human vaginal and buccal mucosa. Headache. 2000;40(2):137–41.Google Scholar
  42. 42.
    van der Bijl P, van Eyk AD. Comparative in vitro permeability of human vaginal, small intestinal and colonic mucosa. Int J Pharm. 2003;261(1–2):147–52.Google Scholar
  43. 43.
    Chan RL, Henzl MR, LePage ME, LaFargue J, Nerenberg CA, Anik S, Chaplin MD. Absorption and metabolism of nafarelin, a potent agonist of gonadotropin-releasing hormone. Clin Pharmacol Ther. 1988;44(3):275–82.PubMedGoogle Scholar
  44. 44.
    Cole AL, Herasimtschuk A, Gupta P, Waring AJ, Lehrer RI, Cole AM. The retrocyclin analogue RC-101 prevents human immunodeficiency virus type 1 infection of a model human cervicovaginal tissue construct. Immunology. 2007;121(1):140–5.PubMedGoogle Scholar
  45. 45.
    Yamamoto A, Hayakawa E, Lee VH. Insulin and proinsulin proteolysis in mucosal homogenates of the albino rabbit: implications in peptide delivery from nonoral routes. Life Sci. 1990;47(26):2465–74.PubMedGoogle Scholar
  46. 46.
    Chun IK, Chien YW. Transmucosal delivery of methionine enkephalin. I: solution stability and kinetics of degradation in various rabbit mucosa extracts. J Pharm Sci. 1993;82(4):373–8.PubMedGoogle Scholar
  47. 47.
    Acartürk F, Robinson JR. Vaginal permeability and enzymatic activity studies in normal and ovariectomized rabbits. Pharm Res. 1996;13(5):779–83.PubMedGoogle Scholar
  48. 48.
    Zeitlin L, Olmsted SS, Moench TR, Co MS, Martinell BJ, Paradkar VM, Russell DR, Queen C, Cone RA, Whaley KJ. A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nat Biotechnol. 1998;16(13):1361–4.PubMedGoogle Scholar
  49. 49.
    Castle PE, Karp DA, Zeitlin L, Garcia-Moreno EB, Moench TR, Whaley KJ, Cone RA. Human monoclonal antibody stability and activity at vaginal pH. J Reprod Immunol. 2002;56(1–2):61–76.PubMedGoogle Scholar
  50. 50.
    Saltzman WM, Radomsky ML, Whaley KJ, Cone RA. Antibody diffusion in human cervical mucus. Biophys J. 1994;66(2 Pt 1):508–15.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Olmsted SS, Padgett JL, Yudin AI, Whaley KJ, Moench TR, Cone RA. Diffusion of macromolecules and virus-like particles in human cervical mucus. Biophys J. 2001;81(4):1930–7.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Sassi AB, Bunge KE, Hood BL, Conrads TP, Cole AM, Gupta P, Rohan LC. Preformulation and stability in biological fluids of the retrocyclin RC-101, a potential anti-HIV topical microbicide. AIDS Res Ther. 2011;8:27.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Veazey RS, Shattock RJ, Pope M, Kirijan JC, Jones J, Hu Q, Ketas T, Marx PA, Klasse PJ, Burton DR, Moore JP. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med. 2003;9(3):343–6.PubMedGoogle Scholar
  54. 54.
    Lederman MM, Veazey RS, Offord R, Mosier DE, Dufour J, Mefford M, Piatak M Jr., Lifson JD, Salkowitz JR, Rodriguez B, Blauvelt A, Hartley O. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science. 2004;306(5695):485–7.PubMedGoogle Scholar
  55. 55.
    Van Herrewege Y, Morellato L, Descours A, Aerts L, Michiels J, Heyndrickx L, Martin L, Vanham G. CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides. J Antimicrob Chemother. 2008;61(4):818–26.PubMedGoogle Scholar
  56. 56.
    Zeitlin L, Pauly M, Whaley KJ. Second-generation HIV microbicides: continued development of griffithsin. Proc Natl Acad Sci U S A. 2009;106(15):6029–30.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Wheeler LA, Trifonova R, Vrbanac V, Basar E, McKernan S, Xu Z, Seung E, Deruaz M, Dudek T, Einarsson JI, Yang L, Allen TM, Luster AD, Tager AM, Dykxhoorn DM, Lieberman J. Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras. J Clin Invest. 2011;121(6):2401–12.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Ramessar K, Rademacher T, Sack M, Stadlmann J, Platis D, Stiegler G, Labrou N, Altmann F, Ma J, Stoger E, Capell T, Christou P. Cost-effective production of a vaginal protein microbicide to prevent HIV transmission. Proc Natl Acad Sci U S A. 2008;105(10):3727–32.PubMedCentralPubMedGoogle Scholar
  59. 59.
    O’Keefe BR, Vojdani F, Buffa V, Shattock RJ, Montefiori DC, Bakke J, Mirsalis J, d’Andrea AL, Hume SD, Bratcher B, Saucedo CJ, McMahon JB, Pogue GP, Palmer KE. Scaleable manufacture of HIV-1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component. Proc Natl Acad Sci U S A. 2009;106(15):6099–104.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Kramski M, Center RJ, Wheatley AK, Jacobson JC, Alexander MR, Rawlin G, Purcell DF. Hyperimmune bovine colostrum as a low-cost, large-scale source of antibodies with broad neutralizing activity for HIV-1 envelope with potential use in microbicides. Antimicrob Agents Chemother. 2012;56(8):4310–9.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Morimoto K, Takeeda T, Nakamoto Y, Morisaka K. Effective vaginal absorption of insulin in diabetic rats and rabbits using polyacrylic acid aqueous gel bases. Int J Pharm. 1982;12(2–3):107–11.Google Scholar
  62. 62.
    Wang B, Dang K, Agadjanyan MG, Srikantan V, Li F, Ugen KE, Boyer J, Merva M, Williams WV, Weiner DB. Mucosal immunization with a DNA vaccine induces immune responses against HIV-1 at a mucosal site. Vaccine. 1997;15(8):821–5.PubMedGoogle Scholar
  63. 63.
    Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ, Springer MS, Moore JP. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature. 2005;438(7064):99–102.PubMedGoogle Scholar
  64. 64.
    das Neves J, Bahia MF. Gels as vaginal drug delivery systems. Int J Pharm. 2006;318(1–2):1–14.PubMedGoogle Scholar
  65. 65.
    Li L, Ben Y, Yuan S, Jiang S, Xu J, Zhang X. Efficacy, stability, and biosafety of sifuvirtide gel as a microbicide candidate against HIV-1. PLoS One. 2012;7(5):e37381.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Dereuddre-Bosquet N, Morellato-Castillo L, Brouwers J, Augustijns P, Bouchemal K, Ponchel G, Ramos OHP, Herrera C, Stefanidou M, Shattock R, Heyndrickx L, Vanham G, Kessler P, Le Grand R, Martin L. MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV162P3 in cynomolgus macaques. PLoS Pathog. 2012;8(12):e1003071.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Curran RM, Donnelly L, Morrow RJ, Fraser C, Andrews G, Cranage M, Malcolm RK, Shattock RJ, Woolfson AD. Vaginal delivery of the recombinant HIV-1 clade-C trimeric gp140 envelope protein CN54gp140 within novel rheologically structured vehicles elicits specific immune responses. Vaccine. 2009;27(48):6791–8.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Donnelly L, Curran RM, Tregoning JS, McKay PF, Cole T, Morrow RJ, Kett VL, Andrews GP, Woolfson AD, Malcolm RK, Shattock RJ. Intravaginal immunization using the recombinant HIV-1 clade-C trimeric envelope glycoprotein CN54gp140 formulated within lyophilized solid dosage forms. Vaccine. 2011;29(27):4512–20.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Gupta PN, Pattani A, Curran RM, Kett VL, Andrews GP, Morrow RJ, Woolfson AD, Malcolm RK. Development of liposome gel based formulations for intravaginal delivery of the recombinant HIV-1 envelope protein CN54gp140. Eur J Pharm Sci. 2012;46(5):315–22.PubMedGoogle Scholar
  70. 70.
    Bilensoy E, Rouf MA, Vural I, Sen M, Hincal AA. Mucoadhesive, thermosensitive, prolonged-release vaginal gel for clotrimazole:beta-cyclodextrin complex. AAPS PharmSciTech. 2006;7(2):E38.Google Scholar
  71. 71.
    Date AA, Shibata A, Goede M, Sanford B, La Bruzzo K, Belshan M, Destache CJ. Development and evaluation of a thermosensitive vaginal gel containing raltegravir + efavirenz loaded nanoparticles for HIV prophylaxis. Antiviral Res. 2012;96(3):430–6.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Oh YK, Park JS, Yoon H, Kim CK. Enhanced mucosal and systemic immune responses to a vaginal vaccine coadministered with RANTES-expressing plasmid DNA using in situ-gelling mucoadhesive delivery system. Vaccine. 2003;21(17–18):1980–8.PubMedGoogle Scholar
  73. 73.
    Han IK, Kim YB, Kang HS, Sul D, Jung WW, Cho HJ, Oh YK. Thermosensitive and mucoadhesive delivery systems of mucosal vaccines. Methods. 2006;38(2):106–11.PubMedGoogle Scholar
  74. 74.
    Bouchemal K, Frelichowska J, Martin L, Lievin-Le Moal V, Le Grand R, Dereuddre-Bosquet N, Djabourov M, Aka-Any-Grah A, Koffi A, Ponchel G. Note on the formulation of thermosensitive and mucoadhesive vaginal hydrogels containing the miniCD4 M48U1 as anti-HIV-1 microbicide. Int J Pharm. 2013;454(2):649–52.Google Scholar
  75. 75.
    Gupta KM, Barnes SR, Tangaro RA, Roberts MC, Owen DH, Katz DF, Kiser PF. Temperature and pH sensitive hydrogels: an approach towards smart semen-triggered vaginal microbicidal vehicles. J Pharm Sci. 2007;96(3):670–81.PubMedGoogle Scholar
  76. 76.
    Gunaseelan S, Gallay PA, Bobardt MD, Dezzutti CS, Esch T, Maskiewicz R. Sustained local delivery of structurally diverse HIV-1 microbicides released from sublimation enthalpy controlled matrices. Pharm Res. 2012;29(11):3156–68.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Loehr BI, Rankin R, Pontarollo R, King T, Willson P, Babiuk LA, van Drunen Littel-van den Hurk S. Suppository-mediated DNA immunization induces mucosal immunity against bovine herpesvirus-1 in cattle. Virology. 2001;289(2):327–33.PubMedGoogle Scholar
  78. 78.
    Machado RM, Palmeira-de-Oliveira A, Martinez-de-Oliveira J, Palmeira-de-Oliveira R. Vaginal films for drug delivery. J Pharm Sci. 2013;102(7):2069–81.PubMedGoogle Scholar
  79. 79.
    Sassi AB, Cost MR, Cole AL, Cole AM, Patton DL, Gupta P, Rohan LC. Formulation development of retrocyclin 1 analog RC-101 as an anti-HIV vaginal microbicide product. Antimicrob Agents Chemother. 2011;55(5):2282–9.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Ballagh SA. Vaginal rings for menopausal symptom relief. Drugs Aging. 2004;21(12):757–66.PubMedGoogle Scholar
  81. 81.
    Kiser PF, Johnson TJ, Clark JT. State of the art in intravaginal ring technology for topical prophylaxis of HIV infection. AIDS Rev. 2012;14(1):62–77.PubMedGoogle Scholar
  82. 82.
    Malcolm RK, Fetherston SM, McCoy CF, Boyd P, Major I. Vaginal rings for delivery of HIV microbicides. Int J Womens Health. 2012;4:595–605.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Radomsky ML, Whaley KJ, Cone RA, Saltzman WM. Controlled vaginal delivery of antibodies in the mouse. Biol Reprod. 1992;47(1):133–40.PubMedGoogle Scholar
  84. 84.
    Shen H, Goldberg E, Saltzman WM. Gene expression and mucosal immune responses after vaginal DNA immunization in mice using a controlled delivery matrix. J Control Release. 2003;86(2–3):339–48.PubMedGoogle Scholar
  85. 85.
    Kuo-Haller P, Cu Y, Blum J, Appleton JA, Saltzman WM. Vaccine delivery by polymeric vehicles in the mouse reproductive tract induces sustained local and systemic immunity. Mol Pharm. 2010;7(5):1585–95.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Morrow RJ, Woolfson AD, Donnelly L, Curran R, Andrews G, Katinger D, Malcolm RK. Sustained release of proteins from a modified vaginal ring device. Eur J Pharm Biopharm. 2011;77(1):3–10.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Pattani A, Lowry D, Curran RM, McGrath S, Kett VL, Andrews GP, Malcolm RK. Characterisation of protein stability in rod-insert vaginal rings. Int J Pharm. 2012;430(1–2):89–97.PubMedGoogle Scholar
  88. 88.
    Hubert P, Evrard B, Maillard C, Franzen-Detrooz E, Delattre L, Foidart JM, Noel A, Boniver J, Delvenne P. Delivery of granulocyte-macrophage colony-stimulating factor in bioadhesive hydrogel stimulates migration of dendritic cells in models of human papillomavirus-associated (pre)neoplastic epithelial lesions. Antimicrob Agents Chemother. 2004;48(11):4342–8.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Richardson JL, Illum L. (D) Routes of delivery: case studies: (8) the vaginal route of peptide and protein drug delivery. Adv Drug Deliv Rev. 1992;8(2–3):341–66.Google Scholar
  90. 90.
    Sayani AP, Chun IK, Chien YW. Transmucosal delivery of leucine enkephalin: stabilization in rabbit enzyme extracts and enhancement of permeation through mucosae. J Pharm Sci. 1993;82(11):1179–85.PubMedGoogle Scholar
  91. 91.
    Okada H, Yamazaki I, Ogawa Y, Hirai S, Yashiki T, Mima H. Vaginal absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide) in rats I: absorption by various routes and absorption enhancement. J Pharm Sci. 1982;71(12):1367–71.PubMedGoogle Scholar
  92. 92.
    Okada H, Yamazaki I, Yashiki T, Mima H. Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (leuprolide) in rats II: mechanism of absorption enhancement with organic acids. J Pharm Sci. 1983;72(1):75–8.PubMedGoogle Scholar
  93. 93.
    Okada H, Yamazaki I, Yashiki T, Shimamoto T, Mima H. Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (leuprolide) in rats. IV: Evaluation of the vaginal absorption and gonadotropin responses by radioimmunoassay. J Pharm Sci. 1984;73(3):298–302.PubMedGoogle Scholar
  94. 94.
    van der Bijl P, van Eyk AD, Gareis AA, Thompson IO. Enhancement of transmucosal permeation of cyclosporine by benzalkonium chloride. Oral Dis. 2002;8(3):168–72.Google Scholar
  95. 95.
    Gali Y, Delezay O, Brouwers J, Addad N, Augustijns P, Bourlet T, Hamzeh-Cognasse H, Ariën KK, Pozzetto B, Vanham G. In vitro evaluation of viability, integrity and inflammation in genital epithelia upon exposure to pharmaceutical excipients and candidate microbicides. Antimicrob Agents Chemother. 2010;54(12):5105–14.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Değim Z, Değim T, Acartürk F, Erdoğan D, Özoğul C, Köksal M. Rectal and vaginal administration of insulin-chitosan formulations: an experimental study in rabbits. J Drug Target. 2005;13(10):563–72.PubMedGoogle Scholar
  97. 97.
    Fatakdawala H, Uhland SA. Hydrogen peroxide mediated transvaginal drug delivery. Int J Pharm. 2011;409(1–2):121–7.PubMedGoogle Scholar
  98. 98.
    Richardson JL, Illum L, Thomas NW. Vaginal absorption of insulin in the rat: effect of penetration enhancers on insulin uptake and mucosal histology. Pharm Res. 1992;9(7):878–83.PubMedGoogle Scholar
  99. 99.
    Nakada Y, Miyake M, Awata N. Some factors affecting the vaginal absorption of human calcitonin in rats. Int J Pharm. 1993;89(3):169–75.Google Scholar
  100. 100.
    Valenta C, Marschutz M, Egyed C, Bernkop-Schnürch A. Evaluation of the inhibition effect of thiolated poly(acrylates) on vaginal membrane bound aminopeptidase N and release of the model drug LH-RH. J Pharm Pharmacol. 2002;54(5):603–10.PubMedGoogle Scholar
  101. 101.
    Richardson JL, Farraj NF, Illum L. Enhanced vaginal absorption of insulin in sheep using lysophosphatidylcholine and a bioadhesive microsphere delivery system. Int J Pharm. 1992; 88(1–3):319–25.Google Scholar
  102. 102.
    O’Hagan DT, Rafferty D, Wharton S, Illum L. Intravaginal immunization in sheep using a bioadhesive microsphere antigen delivery system. Vaccine. 1993;11(6):660–4.PubMedGoogle Scholar
  103. 103.
    Richardson JL, Ramires PA, Miglietta MR, Rochira M, Bacelle L, Callegaro L, Benedetti L. Novel vaginal delivery systems for calcitonin: I. Evaluation of HYAFF/calcitonin microspheres in rats. Int J Pharm. 1995;115(1):9–15.Google Scholar
  104. 104.
    Rochira M, Miglietta MR, Richardson JL, Ferrari L, Beccaro M, Benedetti L. Novel vaginal delivery systems for calcitonin: II. Preparation and characterization of HYAFF® microspheres containing calcitonin. Int J Pharm. 1996;144(1):19–26.Google Scholar
  105. 105.
    Bonucci E, Ballanti P, Ramires PA, Richardson JL, Benedetti LM. Prevention of ovariectomy osteopenia in rats after vaginal administration of Hyaff 11 microspheres containing salmon calcitonin. Calcif Tissue Int. 1995;56(4):274–9.PubMedGoogle Scholar
  106. 106.
    Kish-Catalone TM, Lu W, Gallo RC, DeVico AL. Preclinical evaluation of synthetic -2 RANTES as a candidate vaginal microbicide to target CCR5. Antimicrob Agents Chemother. 2006;50(4):1497–509.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Kish-Catalone T, Pal R, Parrish J, Rose N, Hocker L, Hudacik L, Reitz M, Gallo R, Devico A. Evaluation of —2 RANTES vaginal microbicide formulations in a nonhuman primate simian/human immunodeficiency virus (SHIV) challenge model. AIDS Res Hum Retroviruses. 2007;23(1):33–42.PubMedGoogle Scholar
  108. 108.
    Ning M, Guo Y, Pan H, Yu H, Gu Z. Niosomes with sorbitan monoester as a carrier for vaginal delivery of insulin: studies in rats. Drug Deliv. 2005;12(6):399–407.PubMedGoogle Scholar
  109. 109.
    Ham AS, Cost MR, Sassi AB, Dezzutti CS, Rohan LC. Targeted delivery of PSC-RANTES for HIV-1 prevention using biodegradable nanoparticles. Pharm Res. 2009;26(3):502–11.PubMedGoogle Scholar
  110. 110.
    Woodrow KA, Cu Y, Booth CJ, Saucier-Sawyer JK, Wood MJ, Saltzman WM. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA. Nat Mater. 2009;8(6):526–33.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Steinbach JM, Weller CE, Booth CJ, Saltzman WM. Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection. J Control Release. 2012;162(1):102–10.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Eszterhas SK, Ilonzo NO, Crozier JE, Celaj S, Howell AL. Nanoparticles containing siRNA to silence CD4 and CCR5 reduce expression of these receptors and inhibit HIV-1 infection in human female reproductive tract tissue explants. Infect Dis Rep. 2011;3(2):e11.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Palliser D, Chowdhury D, Wang QY, Lee SJ, Bronson RT, Knipe DM, Lieberman J. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature. 2006;439(7072):89–94.PubMedGoogle Scholar
  114. 114.
    Wu SY, Chang HI, Burgess M, McMillan NA. Vaginal delivery of siRNA using a novel PEGylated lipoplex-entrapped alginate scaffold system. J Control Release. 2011;155(3):418–26.PubMedGoogle Scholar
  115. 115.
    Lai SK, O’Hanlon DE, Harrold S, Man ST, Wang YY, Cone R, Hanes J. Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc Natl Acad Sci U S A. 2007;104(5):1482–7.PubMedGoogle Scholar
  116. 116.
    Wang YY, Lai SK, Suk JS, Pace A, Cone R, Hanes J. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angew Chem Int Ed Engl. 2008;47(50):9726–9.Google Scholar
  117. 117.
    Ensign LM, Tang BC, Wang YY, Tse TA, Hoen T, Cone R, Hanes J. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci Transl Med. 2012;4(138):138ra179.Google Scholar
  118. 118.
    Medaglini D, Oggioni MR, Pozzi G. Vaginal immunization with recombinant gram-positive bacteria. Am J Reprod Immunol. 1998;39(3):199–208.PubMedGoogle Scholar
  119. 119.
    Rao S, Hu S, McHugh L, Lueders K, Henry K, Zhao Q, Fekete RA, Kar S, Adhya S, Hamer DH. Toward a live microbial microbicide for HIV: commensal bacteria secreting an HIV fusion inhibitor peptide. Proc Natl Acad Sci USA. 2005;102(34):11993–8.PubMedGoogle Scholar
  120. 120.
    Liu X, Lagenaur LA, Simpson DA, Essenmacher KP, Frazier-Parker CL, Liu Y, Tsai D, Rao SS, Hamer DH, Parks TP, Lee PP, Xu Q. Engineered vaginal lactobacillus strain for mucosal delivery of the human immunodeficiency virus inhibitor cyanovirin-N. Antimicrob Agents Chemother. 2006;50(10):3250–9.PubMedCentralPubMedGoogle Scholar
  121. 121.
    Vangelista L, Secchi M, Liu X, Bachi A, Jia L, Xu Q, Lusso P. Engineering of Lactobacillus jensenii to secrete RANTES and a CCR5 antagonist analogue as live HIV-1 blockers. Antimicrob Agents Chemother. 2010;54(7):2994–3001.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Lagenaur LA, Sanders-Beer BE, Brichacek B, Pal R, Liu X, Liu Y, Yu R, Venzon D, Lee PP, Hamer DH. Prevention of vaginal SHIV transmission in macaques by a live recombinant Lactobacillus. Mucosal Immunol. 2011;4(6):648–57.PubMedCentralPubMedGoogle Scholar
  123. 123.
    Beninati C, Oggioni MR, Boccanera M, Spinosa MR, Maggi T, Conti S, Magliani W, De Bernardis F, Teti G, Cassone A, Pozzi G, Polonelli L. Therapy of mucosal candidiasis by expression of an anti-idiotype in human commensal bacteria. Nat Biotechnol. 2000;18(10):1060–4.PubMedGoogle Scholar
  124. 124.
    Lindgren M, Langel U. Classes and prediction of cell-penetrating peptides. Methods Mol Biol. 2011;683:3–19.PubMedGoogle Scholar
  125. 125.
    Kanazawa T, Takashima Y, Shibata Y, Tsuchiya M, Tamura T, Okada H. Effective vaginal DNA delivery with high transfection efficiency is a good system for induction of higher local vaginal immune responses. J Pharm Pharmacol. 2009;61(11):1457–63.PubMedGoogle Scholar
  126. 126.
    Kanazawa T, Tamura T, Yamazaki M, Takashima Y, Okada H. Needle-free intravaginal DNA vaccination using a stearoyl oligopeptide carrier promotes local gene expression and immune responses. Int J Pharm. 2013;447(1–2):70–4.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.IINFACTS – Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da SaúdeInstituto Superior de Ciências da Saúde-Norte, CESPUGandraPortugal
  2. 2.Faculty of PharmacyUniversity of PortoPortoPortugal

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