Nanoparticle-based drug delivery to the vagina: a review

Abstract

Vaginal drug administration can improve prophylaxis and treatment of many conditions affecting the female reproductive tract, including sexually transmitted diseases, fungal and bacterial infections, and cancer. However, achieving sustained local drug concentrations in the vagina can be challenging, due to the high permeability of the vaginal epithelium and expulsion of conventional soluble drug dosage forms. Nanoparticle-based drug delivery platforms have received considerable attention for vaginal drug delivery, as nanoparticles can provide sustained release, cellular targeting, and even intrinsic antimicrobial or adjuvant properties that can improve the potency and/or efficacy of prophylactic and therapeutic modalities. Here, we review the use of polymeric nanoparticles, liposomes, dendrimers, and inorganic nanoparticles for vaginal drug delivery. Although most of the work toward nanoparticle-based drug delivery in the vagina has been focused on HIV prevention, strategies for treatment and prevention of other sexually transmitted infections, treatment for reproductive tract cancer, and treatment of fungal and bacterial infections are also highlighted.

Keywords: Cervical cancer; HIV PrEP; Microbicides; Mucosal vaccines; Sexually transmitted infections.

Figure 1

Distribution of Langerhan’s cells (LC) in the vaginal epithelium in (a) diestrus and (b) estrus phase mouse vaginal tissue. Antibodies against MHC class II (red) and CD11c (green) denote LC. The white line indicates the luminal edge of the epithelium, whereas the yellow line indicates the basement membrane. The images were obtained at 20x magnification. L denotes the lumen. Note the thick tissue barrier between the LC and the lumen space in the estrus phase mouse vagina. Reprinted with permission from [38].

Figure 2

Hemotoxylin and eosin stained tissue sections from (a) an untreated mouse in the estrus phase (x120), (b) a progestin-treated mouse (x120), (c) normal human vaginal epithelium (x50), and (d) normal human cervix (x160). Note the similarities between the thin, columnar, progestin-treated murine vaginal epithelium and the columnar, human ectocervical epithelium. In contrast, the murine estrus phase vaginal epithelium and the human vaginal epithelium are thick, squamous cell layers. Reprinted with permission from (58).

Figure 3

Distribution in the estrus phase mouse vagina of red fluorescent CP and MPP 10 min after administration (top panel), and green fluorescent fluorescein isothiocyanate (FITC) 24 h after administration in a conventional vaginal gel (FITC/gel) or encapsulated within biodegradable MPP (FITC/MPP). Modified with permission from (20).

Figure 4

Penetration of siRNA-loaded PLGA nanoparticles (green) into the vagina and uterine tissue of mice 24 h after vaginal administration. Multiphoton microscopy was used to obtain deep tissue images. Image dimensions are 400 μm x 400 μm x 75 μm. Tissue is stained blue with Hoescht dye. Modified with permission from (74).

Figure 5

Transverse sections of the mouse reproductive tract with TC-1 cervical tumors expressing green fluorescent protein (GFP, green). The epithelium is outlined in white to help distinguish the tissue surface. (a) Arrows indicate large mucoadhesive particle (CP) aggregates. (b) Arrows indicate well-dispersed mucus-penetrating particles (MPP) in close proximity to the tumor at the epithelial surface. Reprinted with permission from (21).

Figure 6

Vaginal delivery of lipoplexes in the estrus phase mouse vagina (Untreated), which is more reminiscent of the structure of the human vagina, was minimal and restricted to tissue debris in the lumen, unless the epithelium was pretreated with 5% citric acid (Treated). The scale bars present 200 μm in the top three panels and 20 μm in the bottom panel. Propidium idodide (PI) was used to stain the epithelium. Adapted with permission from (62).

Figure 7

SEM images of E. Coli either (A) untreated, or (B) after 8 h exposure to carboxyl-terminated PAMAM dendrimers. Magnification 20,000x. The treatment with dendrimers shows damage to the bacterial cell wall. Adapted with permission from (135).

Figure 8

Confocal images of the cervical region of pregnant guinea pigs treated with hydrogels for 72 h. The hydrogel (green) is seen on the surface of the mucosal layer (red), separated by the mucus coating the epithelium (unlabeled). The nuclei are stained blue with DAPI. SE = subepithelial layer, ML = mucified epithelial layer. The right panel is a higher magnification image of the indicated region of the left panel to further illustrate the mucus layer separating the gel from the epithelium. Adapted with permission from [136].