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. 2021 Mar 5:9:635485.
doi: 10.3389/fbioe.2021.635485. eCollection 2021.

Fabrication and Characterization of Chitosan/Poly(Lactic-Co-glycolic Acid) Core-Shell Nanoparticles by Coaxial Electrospray Technology for Dual Delivery of Natamycin and Clotrimazole

Xiaoming Cui  1 , Xiaoli Li  2 , Zhilu Xu  1 , Xiuwen Guan  1   3   4 , Jinlong Ma  1   3   4 , Dejun Ding  1   3   4 , Weifen Zhang  1   3   4
Affiliations

Fabrication and Characterization of Chitosan/Poly(Lactic-Co-glycolic Acid) Core-Shell Nanoparticles by Coaxial Electrospray Technology for Dual Delivery of Natamycin and Clotrimazole

Xiaoming Cui et al. Front Bioeng Biotechnol. .

Abstract

Natamycin (NAT) is the drug of choice for the treatment of fungal keratitis (FK). However, its inherent shortcomings, such as poor solubility, high dosing frequency, and long treatment cycle, need to be urgently addressed by designing a new delivery to widen its clinical utility. Growing research has confirmed that clotrimazole (CLZ) plays a significant role in fungal growth inhibition. Hence, coaxial electrospray (CO-ES) technology is used herein to prepare nano-systems with an average hydrodynamic particle size of 309-406 nm for the co-delivery of NAT and CLZ in chitosan (CTS) and poly(lactic-co-glycolic acid) (PLGA). The resulting NAT/CLZ@CTS/PLGA formulations were characterized by a transmission electron microscope (TEM) and in vitro release test. The results show that the formulations had obvious core-shell structures, uniform particle distribution, and also can sustain the release of drugs over 36 h. Furthermore, in vitro hemolysis, in vivo corneal irritation test, local allergenic test, and antifungal activity analyses are performed to evaluate the safety and efficiency of the formulations. Thus, good biosafety along with a significant anti-candidiasis effect are found in the NAT/CLZ@CTS/PLGA nanoparticles (NPs). Taken together, the results suggest that this design may provide a promising drug delivery system and a new option for the treatment of FK.

Keywords: C. albicans; clotrimazole; coaxial electrospray; core-shell structure; natamycin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic that shows the preparation and function of NAT/CLZ@CTS/PLGA NPs.
FIGURE 2
FIGURE 2
Structure of electro-sprayed NPs. (A) Histogram of hydrodynamic size. (B) Histogram of Zeta potential. (C–F) The morphology using TEM of (C) CTS/PLGA NPs, (D) NAT@CTS/PLGA NPs, (E) CLZ@CTS/PLGA NPs, and (F) NAT/CLZ@CTS/PLGA NPs.
FIGURE 3
FIGURE 3
(A) FT-IR spectra of CTS, PLGA, NAT, and CLZ. (B) FT-IR spectra of electro-sprayed NPs. (C) XRD patterns of CTS, PLGA, NAT, and CLZ. (D) XRD patterns of electro-sprayed NPs. (E) TGA curves of CTS, PLGA, NAT, and CLZ. (F) TGA curves of electro-sprayed NPs.
FIGURE 4
FIGURE 4
In vitro release study (0.2 M PBS, pH 7.4). (A) Profiles for NAT release from various formulations. (B) Profiles for CLZ release from various formulations. (C) Profiles for NAT and CLZ release from NAT/CLZ@CTS/PLGA NPs.
FIGURE 5
FIGURE 5
Hemolysis activity of various core-shell NPs. (A) The photograph of fresh rabbit blood incubated with different concentrations of various core-shell NPs. (B) Hemolysis ratio of different concentrations of various core-shell NPs.
FIGURE 6
FIGURE 6
Antifungal activities against C. albicans. (A) The zone of C. albicans growth inhibition on the cultures of different formulations. (B) The zone of inhibition diameter graph. **P < 0.01, ***P < 0.0001.
FIGURE 7
FIGURE 7
Ophthalmic irritation studies. (A) Ocular observation. (B) Histology analysis (H&E stain). The rats’ eyes were treated with PBS, NAT/CLZ solution, and NAT/CLZ@CTS/PLGA NP formulations for 12 consecutive hours (E, corneal epithelium; ALL, anterior limiting; S, corneal stroma. Scale bar = 50 μm).
FIGURE 8
FIGURE 8
Local allergenic tests. (A) Skin observation. (B) Histology analysis (H&E stain). The skin of the exposed areas was excised from the animals at 72 h for histological studies (SC, stratum corneum; E, epidermis; D, dermis. Scale bar = 50 μm).
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