Vaginal microbicides and their delivery platforms

Expert Opinion on Drug Delivery

Volumn 11, Issue 5, 2014, Pages 723-740

  D'Cruz, Osmond J ^a   Uckun, Fatih M ^a,b  

^a CHILDREN S HOSPITAL LOS ANGELES   (United States)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Antiretroviral; Heterosexual transmission; Human immunodeficiency virus; Intravaginal ring; Live microbicide; Nano microbicides; Reverse transcriptase; Vaginal delivery

Indexed keywords

APTAMER; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; DAPIVIRINE; DENDRIMER; GOLD NANOPARTICLE; HUMAN IMMUNODEFICIENCY VIRUS ANTIBODY; LIPOSOME; MICROBICIDE; NEUTRALIZING ANTIBODY; POLYANION; SILVER NANOPARTICLE; SMALL INTERFERING RNA; STAMPIDINE; TENOFOVIR;

CLINICAL EFFECTIVENESS; DRUG DELIVERY SYSTEM; DRUG DISTRIBUTION; DRUG RESISTANCE; DRUG SOLUBILITY; GENE THERAPY; HETEROSEXUALITY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; LACTOBACILLUS; MICROFLORA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RNA INTERFERENCE; SEXUAL TRANSMISSION; SUSTAINED DRUG RELEASE; VAGINA MUCOSA;

ADMINISTRATION, INTRAVAGINAL; ANTI-RETROVIRAL AGENTS; CHEMISTRY, PHARMACEUTICAL; DRUG DELIVERY SYSTEMS; FEMALE; HIV INFECTIONS; HIV-1; HUMANS; SEXUALLY TRANSMITTED DISEASES, VIRAL;

EID: 84899056265     PISSN: 17425247     EISSN: 17447593     Source Type: Journal    
DOI: 10.1517/17425247.2014.888055     Document Type: Review

References (92)

1. Global report: UNAIDS report on the global AIDS epidemic 2013. Available from: http://www.unaids.org/en/ resources/campaigns/globalreport2013/
2. Hladik F, McElrath MJ. Setting the stage: host invasion by HIV. Nat Rev Immunol 2008;8:447-57 (Pubitemid 351735878)
3. Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med 2011;62:127-39
4. D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des 2004;10:315-36 (Pubitemid 38072766)
5. Roddy RE, Zekeng L, Ryan KA, et al. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med 1998;339:504-10 (Pubitemid 28384883)
6. Peterson L, Nanda K, Opoku BK, et al. SAVVY (C31G) gel for prevention of HIV infection in women: a phase 3, double-blind, randomized, placebo controlled trial in ghana. PLoS One 2007;2:e1312
7. Feldblum PJ, Adeiga A, Bakare R, et al. SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria. PLoS One 2008;3:e1474
8. Van Damme L, Govinden R, Mirembe F, et al. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med 2008;359:463-72
9. Skoler-Karpoff S, Ramjee G, Ahmed K, et al. Efficacy of carraguard for prevention of HIV infection in women in South Africa: a randomised, doubleblind, placebo-controlled trial. Lancet 2008;372:1977-87
10. Abdool Karim S, Coletti A, Richardson B, et al. HIV prevention trials network (HPTN) 035 study team. safety and effectiveness of vaginal microbicides Buffer Gel and 0.5% PRO 2000/5 gel for the prevention of HIV infection in women: results of the HPTN 035 trial. AIDS 2011;25:957-66
11. D'Cruz OJ, Uckun FM. Recent advances in anogenital antiretroviral microbicides and multimodal delivery systems. J AIDS Clinic Res 2012;3:144
12. Klasse PJ, Shattock R, Moore JP. Antiretroviral drug based microbicides to prevent HIV-1 sexual transmission. Annu Rev Med 2008;59:455-71 (Pubitemid 351287949)
13. Carias AM, McCoombe S, McRaven M, et al. Defining the interaction of HIV-1 with the mucosal barriers of the female reproductive tract. J Virol 2013;87:11388-400
14. Brass AL, Dykxhoorn DM, Benita Y, et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 2008;319:921-6 (Pubitemid 351263756)
15. Zhou H, Xu M, Huang Q, et al. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe 2008;4:495-504
16. D'Cruz OJ, Uckun FM. Novel tight binding PETT, HEPT and DABO-based non-nucleoside inhibitors of HIV-1 reverse transcriptase. J Enzyme Inhib Med Chem 2006;21:329-50 (Pubitemid 44355782)
17. Acartu?rk F. Mucoadhesive vaginal drug delivery systems. Recent Pat Drug Deliv Formul 2009;3:193-205
18. Grabovac V, Guggi D, Bernkop-Schnu?rch A. Comparison of the mucoadhesive properties of various polymers. Adv Drug Deliv Rev 2005;57:1713-23 (Pubitemid 41443475)
19. Subbarao S, Otten RA, Ramos A, et al. Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges. J Infect Dis 2006;194:904-11 (Pubitemid 44454075)
20. Garci'a-Lerma JG, Heneine W. Animal models of antiretroviral prophylaxis for HIV prevention. Curr Opin HIV AIDS 2012;7:505-13
21. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010;329:1168-74.
22. VOICE HIV prevention trial discontinues Tenofovir gel arm. Available from: http://www.fhi360.org/en/ AboutFHI/Media/Releases/ VOICE-discontinues- tenofovir- gel112511.htm [Last updated 25 November 2011]
23. Kohler JJ, Hosseini SH, Hoying-Brandt A, et al. Tenofovir renal toxicity targets mitochondria of renal proximal tubules. Lab Invest 2009;89:513-19
24. Calmy A, Fux CA, Norris R, et al. Low bone mineral density, renal dysfunction, and fracture risk in HIV infection: a crosssectional study. J Infect Dis 2009;200:1746-54
25. Kohler JJ, Hosseini SH, Green E, et al. Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Lab Invest 2011;91:852-8
26. White KL, Chen JM, Margot NA, et al. Molecular mechanisms of tenofovir resistance conferred by human immunodeficiency virus type 1 reverse transcriptase containing a diserine insertion after residue 69 and multiple thymidine analog-associated mutations. Antimicrob Agents Chemother 2004;48:992-1003 (Pubitemid 38280354)
27. Das K, Bandwar RP, White KL, et al. Structural basis for the role of the K65R mutation in HIV-1 reverse transcriptase polymerization, excision antagonism, and tenofovir resistance. J Biol Chem 2009;284:35092-100
28. Hachiya A, Kodama EN, Schuckmann MM, et al. K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism. PLoS One 2011;6:e16242
29. Cahn P, Rolon MJ, Gun AM, et al. Preclinical and first-in-human Phase I clinical evaluation of Stampidine, a potent anti-HIV pharmaceutical drug candidate. J AIDS Clinic Res 2012;3:138.
30. Uckun FM, Pendergrass S, Venkatachalam TK, et al. Stampidine is a potent inhibitor of zidovudine and nucleoside analog reverse transcriptase inhibitor-resistant primary clinical HIV-1 isolates with thymidine analog mutations. Antimicrob Agents Chemother 2002;46:3613-16 (Pubitemid 35192934)
31. Uckun FM, Pendergrass S, Qazi S, Venkatachalam TK. In vitro activity of stampidine against primary clinical HIV isolates. Arzneimittelforschung 2004;54:69-77 (Pubitemid 38147098)
32. Uckun FM, Qazi S, Venkatachalam TK. In vitro anti-HIV potency of stampidine alone and in combination with standard anti-HIV drugs. Arzneimittelforschung 2005;55:223-31 (Pubitemid 40562613)
33. Uckun FM, Venkatachalam TK, Qazi S. Potency of stampidine against multi-nucleoside reverse transcriptase inhibitor resistant human immunodeficiency viruses. Arzneimittelforschung 2006;56:193-203
34. Uckun FM, DuMez D, Qazi S, et al. Antiretroviral activity of GMP-grade stampidine against genotypically and phenotypically nucleoside reverse transcriptase inhibitor resistant recombinant human immunodeficiency virus. An in vitro study. Arzneimittelforschung 2007;57:112-21 (Pubitemid 46383952)
35. Chen CL, Yu G, Venkatachalam T, Uckun FM. Metabolism of stavudine-5'- [p-bromophenyl methoxy alaninyl phosphate], stampidine, in mice, dogs, and cats. Drug Metab Dispos 2002;30:1523-31
36. Uckun FM, Waurzyniak B, Tibbles H, et al. In vivo pharmacokinetics and toxicity profile of the anti-HIV agent stampidine in dogs and feline immunodeficiency virus-infected cats. Arzneimittelforschung 2006;56:176-92
37. Uckun FM, Qazi S, Pendergrass S, et al. In vivo toxicity, pharmacokinetics, and anti- HIV activity of stavudine-5'- (p-bromo phenyl methoxyalaninyl phosphate) (stampidine) in mice. Antimicrob Agents Chemother 2002;46:3428-36
38. Uckun FM, Chen CL, Samuel P, et al. In vivo antiretroviral activity of stampidine in chronically FIV-infected cats. Antimicrob Agents Chemother 2003;47:1233-40 (Pubitemid 36368580)
39. D'Cruz OJ, Uckun FM. Stampidine is a potential nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide. Fertil Steril 2004;81(Suppl 1):831-41 (Pubitemid 38333068)
40. Uckun FM, Qazi S. Stampidine as a potent epigenetic silencer of host HIV dependency factor genes in HIV-infected cells. J AIDS Clinic Res 2012;4
41. Fletcher P, Harman S, Azijn H, et al. Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother 2009;53:487-95
42. Nel AM, Coplan P, Smythe SC, et al. Pharmacokinetic assessment of dapivirine vaginal microbicide gel in healthy, HIV-negative women. AIDS Res Hum Retroviruses 2010;26:1181-90
43. Romano J, Variano B, Coplan P, et al. Safety and availability of dapivirine (TMC120) delivered from an intravaginal ring. AIDS Res Hum Retroviruses 2009;25:483-8
44. Nel A, Smythe S, Young K, et al. Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Acquir Immune Defic Syndr 2009;51:416-23
45. Schader SM, Oliveira M, Ibanescu RI, et al. In vitro resistance profile of the candidate HIV-1 microbicide drug dapivirine. Antimicrob Agents Chemother 2011;56:751-6
46. Kenney J, Aravantinou M, Singer R, et al. An antiretroviral/zinc combination gel provides 24 hours of complete protection against vaginal SHIV infection in macaques. PLoS One 2011;6:e15835
47. Mao C, Sudbeck EA, Venkatachalam TK, et al. Structure-based drug design of nonnucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase. Biochem Pharmacol 2000;60:1251-65
48. Uckun FM, Qazi S, Venkatachalam T. N'-[2-(2-thiophene) ethyl]-N'-[2- (5-bromopyridyl)] thiourea (HI-443), a rationally designed non-nucleoside reverse transcriptase inhibitor compound with potent anti-HIV activity. Arzneimittelforschung 2007;57:278-85
49. D'Cruz OJ, Qazi S, Yiv S, Uckun FM. A novel vaginal microbicide containing the rationally designed anti-HIV compound HI-443 (N'-[2-(2-thiophene) ethyl]-N'-[2- (5-bromopyridyl)] thiourea]). Expert Opin Investig Drugs 2012;21:265-79
50. D'Cruz OJ, Samuel P, Uckun FM. PHI-443: a novel noncontraceptive broad-spectrum anti-human immunodeficiency virus microbicide. Biol Reprod 2004;71:2037-47 (Pubitemid 39586952)
51. Kilby JM, Eron JJ. Novel therapies based on mechanisms of HIV-1 cell entry. N Engl J Med 2003;348:2228-38 (Pubitemid 36618135)
52. Choe H, Farzan M, Sun Y, et al. The beta chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 1996;85:1135-48 (Pubitemid 26231178)
53. Deng H, Liu R, Ellmeier W, et al. Identification of a major coreceptor for primary isolates of HIV-1. Nature 1996;381:661-6 (Pubitemid 26197679)
54. Cocchi F, DeVico AL, Garzino-Demo A, et al. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV suppressive factors produced by CD8+ T cells. Science 1995;270:1811-15
55. Lederman MM, Veazey RS, Offord R, et al. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 2004;306:485-7 (Pubitemid 39372448)
56. Veazey RS, Ketas TJ, Dufour J, et al. Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor. J Infect Dis 2010;202:739-44
57. Vangelista L, Secchi M, Lusso P. Rational design of novel HIV-1 entry inhibitors by RANTES engineering. Vaccine 2008;26:3008-15
58. Walker LM, Huber M, Doores KJ, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011;477:466-70
59. Hessell AJ, Rakasz EG, Poignard P, et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog 2009;5:e1000433
60. Parren PW, Marx PA, Hessell AJ, et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J Virol 2001;75:8340-7 (Pubitemid 32743706)
61. Klein F, Halper-Stromberg A, Horwitz JA, et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 2012;492:118-22
62. Novina CD, Murray MF, Dykxhoorn DM, et al. siRNA-directed inhibition of HIV-1 infection. Nat Med 2002;8:681-6 (Pubitemid 34778720)
63. Aagaard L, Rossi JJ. RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev 2007;59:75-86 (Pubitemid 46770900)
64. Kumar P, Ban HS, Kim SS, et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 2008;134:577-86
65. De Rosa G, La Rotonda MI. Nano and microtechnologies for the delivery of oligonucleotides with gene silencing properties. Molecules 2009;14:2801-23
66. Khati M, Schu?man M, Ibrahim J, et al. Neutralization of infectivity of diverse R5 clinical isolates of human immunodeficiency virus type 1 by gp120-binding 2'F-NA aptamers. J Virol 2003;77:12692-8 (Pubitemid 37430664)
67. McNamara JO II, Andrechek ER, Wang Y, et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 2006;8:1005-15 (Pubitemid 44215395)
68. Zhou J, Li H, Li S, et al. Novel dual inhibitory function aptamer-siRNA delivery system for HIV-1 therapy. Mol Ther 2008;16:1481-9
69. Neff CP, Zhou J, Remling L, et al. An aptamer siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice. Sci Transl Med 2011;3:66ra6
70. Ham AS, Cost MR, Sassi AB, et al. Targeted delivery of PSC-RANTES for HIV-1 prevention using biodegradable nanoparticles. Pharm Res 2009;26:502-11
71. Bowman MC, Ballard TE, Ackerson CJ, et al. Inhibition of HIV fusion with multivalent gold nanoparticles. J Am Chem Soc 2008;130:6896-7 (Pubitemid 351770109)
72. Bastian AR, Kantharaju McFadden K, et al. Cellfree HIV-1 virucidal action by modified peptide triazole inhibitors of Env gp120. ChemMedChem 2011;6:1335-9
73. Elechiguerra JL, Burt JL, Morones JR, et al. Interaction of silver nanoparticles with HIV-1. J Nanobiotechnology 2005;3:6
74. Lara HH, Ayala-Nunez NV, Ixtepan-Turrent L, et al. Mode of antiviral action of silver nanoparticles against HIV-1. J Nanobiotechnology 2010;8:1
75. Lara HH, Ixtepan-Turrent L, Garza-Trevin?o EN, et al. PVP-coated silver nanoparticles block the transmission of cell-free and cellassociated HIV-1 in human cervical culture. J Nanobiotechnology 2010;8:15
76. Tyssen D, Henderson SA, Johnson A, et al. Structure activity relationship of dendrimer microbicides with dual action antiviral activity. PLoS One 2010;5:e12309
77. Jiang YH, Emau P, Cairns JS, et al. SPL7013 gel as a topical microbicide for prevention of vaginal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses 2005;21:207-13 (Pubitemid 40478228)
78. Cohen CR, Brown J, Moscicki AB, et al. A phase I randomized placebo controlled trial of the safety of 3% SPL7013 Gel (VivaGel-) in healthy young women administered twice daily for 14 days. PLoS One 2011;6:e16258
79. Caron M, Besson G, Etenna SL-D, et al. Protective properties of non-nucleoside reverse transcriptase inhibitor (MC1220) incorporated into liposome against intravaginal challenge of Rhesus Macaques with RT-SHIV. Virology 2010;405:225-33
80. Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev 2000;45:89-121
81. D'Cruz OJ, Uckun FM. Gel-microemulsions as vaginal spermicides and intravaginal drug delivery vehicles. Contraception 2001;64:113-23 (Pubitemid 33042598)
82. D'Cruz OJ, Yiv SH, Uckun FM. GM-144, a novel lipophilic vaginal contraceptive gel-microemulsion. AAPS PharmSciTech 2001;2:E5
83. D'Cruz OJ, Uckun FM. Pre-clinical safety evaluation of novel nucleoside analogue-based dual-function microbicides (WHI-05 and WHI-07). J Antimicrob Chemother 2002;50:793-803 (Pubitemid 36032797)
84. D'Cruz OJ, Samuel P, Uckun FM. Conceival, a novel non-contraceptive vaginal vehicle for lipophilic microbicides. AAPS PharmSciTech 2005;6:E56-64
85. Malcolm K, Woolfson D, Russell J, et al. Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings. J Control Release 2003;90:217-25 (Pubitemid 36694965)
86. Malcolm RK, Edwards KL, Kiser P, et al. Advances in microbicide vaginal rings. Antiviral Res 2010;88:S30-9
87. Singer R, Mawson P, Derby N. An intravaginal ring that releases the NNRTI MIV-150 reduces SHIV transmission in macaques. Sci Transl Med 2012;4:150ra123
88. Teller RS, Srinivasan P, Mesquita PM, et al. Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian- HIV challenges. Proc Natl Acad Sci USA 2013;110:16145-50.
89. Taha TE, Hoover DR, Dallabetta GA, et al. Bacterial vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV. AIDS 1998;12:1699-706 (Pubitemid 28418342)
90. Wells JM, Mercenier A. Mucosal delivery of therapeutic and prophylactic molecules using lactic acid bacteria. Nat Rev Microbiol 2008;6:349-62 (Pubitemid 351552656)
91. Pusch O, Boden D, Hannify S, et al. Bioengineering lactic acid bacteria to secrete the HIV-1 virucide cyanovirin. J Acquir Immune Defic Syndr 2005;40:512-20 (Pubitemid 41669153)
92. Ying T, Chen W, Feng Y, et al. Engineered soluble monomeric IgG1 CH3 domain: generation, mechanisms of function, and implications for design of biological therapeutics. J Biol Chem 2013;288:25154-64