Nanomedicines for the prevention/reduction of vaginal transmission of HIV and chlamydia
| dc.contributor.author | Yang, Sidi | |
| dc.contributor.examiningcommittee | Gu, Xiaochen (Pharmacy) Zhong, Wen (Biosystems Engineering) Wu, Xiao Yu (University of Toronto) | en_US |
| dc.contributor.supervisor | Ho, Emmanuel (Pharmacy) | en_US |
| dc.date.accessioned | 2017-08-30T12:27:24Z | |
| dc.date.available | 2017-08-30T12:27:24Z | |
| dc.date.issued | 2013-04-10 | en_US |
| dc.date.issued | 2013-08-08 | en_US |
| dc.degree.discipline | Pharmacy | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | The development of vaginal microbicides could provide women an accessible alternative to protect themselves against sexually transmitted infections (STIs). We developed an intravaginal nanomedicine for the active delivery of saquinavir (SQV) to CD4+ immune cells to prevent/reduce vaginal acquisition of HIV. The nanomedicine was prepared with poly(lactic-co-glycolic acid) (PLGA) and conjugated to anti-CD4 antibody, which could achieve a more than two-fold increase in the intracellular delivery of SQV in vitro without causing any cytotoxicity. In order to better combat vaginal transmission of HIV, we developed a dual-preventive pH-sensitive RNAi-based combination nanomicrobicide for the prevention/reduction of vaginal transmission of HIV by knocking down host factor CCR5 and viral protein Nef simultaneously. The nanomicrobicide possessed a pH-dependent release profile to prevent siRNA from releasing in acidic vaginal environment and release siRNA in neutral intracellular environment. We also proved that knocking down Nef could reactivate Nef-blocked autophagy in vitro and the nanomicrobicide significantly inhibited replication of HIV in vitro. Anti-CD4 antibody conjugation to the nanomicrobicide significantly improved the vaginal distribution and tissue uptake of siRNA, and allowed the nanomicrobicide to achieve targeted gene knockdown in intravaginal CD4+ cells in mice. We further expanded the application of antibody-conjugated nanomedicine in the area of intravaginal delivery of antibody. Herein, we used the system to deliver anti-α4β7 monoclonal antibody (α4β7 Ab) intravaginally as a potential microbicide against HIV. The α4β7 Ab-conjugated nanomedicine decreased the percentage of α4β7high CD4+ T cells and α4β7high CD3+ T cells by half in the vaginal tract of RM 72 hr after a single administration without detectable systemic distribution. In addition, we developed a siRNA-polyethyleneimine (PEI)-based nanomicrobicide with dual preventative activities of reducing bacterial binding and improving host autophagic degradation of bacteria as a potential strategy against vaginal infection of chlamydia trachomatis (C. trachomatis). Platelet derived growth factor-β (PDGFR-β), an irreversible bacterial binding factor on host cells, was knocked down by siRNA and autophagic degradation of C. trachomatis was improved by the introduction of PEI. By working together this dual preventative strategy resulted in 63% decrease of C. trachomatis inclusions in vitro without causing inflammation, apoptosis or reduction in cell viability. | en_US |
| dc.description.note | October 2017 | en_US |
| dc.identifier.citation | Yang, S., et al., Advancements in the field of intravaginal siRNA delivery. J Control Release, 2013. 167(1): p. 29-39. | en_US |
| dc.identifier.citation | Yang, S., et al., Novel intravaginal nanomedicine for the targeted delivery of saquinavir to CD4+ immune cells. Int J Nanomedicine, 2013. 8: p. 2847-58. | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/32393 | |
| dc.language.iso | eng | en_US |
| dc.publisher | ELSEVIER | en_US |
| dc.publisher | DovePress | en_US |
| dc.rights | open access | en_US |
| dc.subject | Microbicide | en_US |
| dc.subject | HIV | en_US |
| dc.subject | Chlamydia | en_US |
| dc.subject | Nanoparticle | en_US |
| dc.subject | Gel | en_US |
| dc.title | Nanomedicines for the prevention/reduction of vaginal transmission of HIV and chlamydia | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | yes | en_US |