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. 2020 Dec;27(1):632-641.
doi: 10.1080/10717544.2020.1756985.

PLGA microsphere-based composite hydrogel for dual delivery of ciprofloxacin and ginsenoside Rh2 to treat Staphylococcus aureus-induced skin infections

Minghao Sun  1 , Chune Zhu  2 , Jieyu Long  1 , Chao Lu  1   3 , Xin Pan  1 , Chuanbin Wu  1   3
Affiliations

PLGA microsphere-based composite hydrogel for dual delivery of ciprofloxacin and ginsenoside Rh2 to treat Staphylococcus aureus-induced skin infections

Minghao Sun et al. Drug Deliv. 2020 Dec.

Abstract

When antibiotic-resistant pathogenic bacteria pose a high threat to human health, bacterial multidrug efflux pumps become major contributors to the high-level antibiotic resistance in most microorganisms. Since traditional antibiotics are still indispensable currently, we report a dual drug delivery system to maximize the antibacterial efficacy of antibiotics by inhibiting efflux pumps in bacteria before their exposure to antibiotics. In this research, a microsphere/hydrogel composite was constructed from ciprofloxacin (Cip)-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres and ginsenoside Rh2 (G-Rh2) dispersed thermo-sensitive hydrogel to treat skin infections. In vitro drug release studies indicated that while G-Rh2 in hydrogel presented a faster and short-term release manner to rapidly inhibit the NorA efflux pumps, Cip showed a sustained and long-term release behavior to provide a local high concentration gradient for facilitating drug percutaneous penetration. The combination of Cip and G-Rh2 demonstrated a high degree of synergism against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), hence significantly improving their in vitro antibacterial activity and efficiency. Moreover, the antibacterial performance of the microsphere/hydrogel composite with a sequential release profile is superior to that of other formulations in mouse model of MRSA skin infections, indicating its great potential to treat antibiotic-resistant skin infections.

Keywords: Ciprofloxacin; ginsenoside Rh2; microsphere/hydrogel composite; sequential release; skin infections.

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Figures

Figure 1.
Figure 1.
SEM images of Cip-MS in 8,000× (A) and 18000× (B).
Figure 2.
Figure 2.
Photos of TSG at 20 °C (A) and 33 °C (B), and photos of Cip-MS-G-TSG at 20 °C (C) and 33 °C (D).
Figure 3.
Figure 3.
Rheological properties of TSG. (A) Variation of shear viscosity of TSG and CHG at 20 °C. (B) Variation of shear viscosity of TSG and CHG at 33 °C. (C) Thixotropy profile of TSG and CHG. (D) Variation of G’ and G’’ of TSG with temperature.
Figure 4.
Figure 4.
In vitro cumulative release profiles of Cip-MS-G-TSG (A) and Cip-G-TSG (B) (mean ± SD, n = 3), while the insert picture in (A) was the whole release process of Cip from Cip-MS-G-TSG.
Figure 5.
Figure 5.
MTT assay of Cip-MS-G-TSG on HaCaT cell lines (mean ± SD, n = 6).
Figure 6.
Figure 6.
Time-kill curves of various formulations against MSSA (A) and MRSA (B) (mean ± SD, n = 3). ***p < .001, vs. Cip-MS-G-TSG group.
Figure 7.
Figure 7.
In vivo antibacterial study of Cip-MS-G-TSG. (A) Microbial burden in a murine model of skin infection with various treatments (mean ± SD, n = 6). ***p < .001, vs. Cip-MS-G-TSG group. (B) The mRNA expression levels of TNF-α, IL-6 and IL-1β in the uninfected (Blank) and infected skins (mean ± SD, n = 6). *p < .05, **p < .01, ***p < .001, vs. Blank group. ##p < .01, ###p < .001, vs. Cip-MS-G-TSG group. (C) H&E-stained sections of infected skin with PBS, Cip-G-Solution, Cip-G-TSG and Cip-MS-G-TSG treatments on day 0, 1, 3 and 5, respectively.
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