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. 2015 Sep 28:10:6027-37.
doi: 10.2147/IJN.S90347. eCollection 2015.

Positively charged micelles based on a triblock copolymer demonstrate enhanced corneal penetration

Jingguo Li  1 , Zhanrong Li  1 , Tianyang Zhou  1 , Junjie Zhang  1 , Huiyun Xia  1 , Heng Li  1 , Jijun He  1 , Siyu He  1 , Liya Wang  1
Affiliations

Positively charged micelles based on a triblock copolymer demonstrate enhanced corneal penetration

Jingguo Li et al. Int J Nanomedicine. .

Abstract

Purpose: The cornea is a main barrier to drug penetration after topical application. The aim of this study was to evaluate the abilities of micelles generated from a positively charged triblock copolymer to penetrate the cornea after topical application.

Methods: The triblock copolymer poly(ethylene glycol)-poly(ε-caprolactone)-g-polyethyleneimine was synthesized, and the physicochemical properties of the self-assembled polymeric micelles were investigated, including hydrodynamic size, zeta potential, morphology, drug-loading content, drug-loading efficiency, and in vitro drug release. Using fluorescein diacetate as a model drug, the penetration capabilities of the polymeric micelles were monitored in vivo using a two-photon scanning fluorescence microscopy on murine corneas after topical application.

Results: The polymer was successfully synthesized and confirmed using nuclear magnetic resonance and Fourier transform infrared. The polymeric micelles had an average particle size of 28 nm, a zeta potential of approximately +12 mV, and a spherical morphology. The drug-loading efficiency and drug-loading content were 75.37% and 3.47%, respectively, which indicates that the polymeric micelles possess a high drug-loading capacity. The polymeric micelles also exhibited controlled-release behavior in vitro. Compared to the control, the positively charged polymeric micelles significantly penetrated through the cornea.

Conclusion: Positively charged micelles generated from a triblock copolymer are a promising vehicle for the topical delivery of hydrophobic agents in ocular applications.

Keywords: controlled release; corneal barriers; corneal penetration; polymeric micelles; topical administration.

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Figures

Figure 1
Figure 1
Synthetic route of the copolymer. Abbreviations: ε-CL, ε-caprolactone; PEI, polyethyleneimine; DCC, dicyclohexylcarbodiimide; NHS, N-hydroxy-succinimide; PEG-PCL-g-PEI, poly(ethylene glycol)-poly (ε-caprolactone)-g-polyethyleneimine.
Figure 2
Figure 2
1H NMR spectra of PEG-OH, PEG-PCL-OH, PEG-PCL-COOH in chloroform-d1 and PEG-PCL-g-PEI in methanol-d4 recorded on a Varian Unity 300 MHz spectrometer. Abbreviations: NMR, nuclear magnetic resonance; PEG, poly(ethylene glycol); PCL, poly(ε-caprolactone); PEI, polyethyleneimine.
Figure 3
Figure 3
FTIR spectra of the diblock intermediates PEG-PCL-COOH (A) and PCI (B). Abbreviations: PEG, poly(ethylene glycol); PCL, poly(ε-caprolactone); PCI, poly (ethylene glycol)-poly(ε-caprolactone)-g-polyethyleneimine; FTIR, Fourier transform infrared spectroscopy.
Figure 4
Figure 4
Schematic illustration of the formation of drug-loaded polymeric micelles. Abbreviations: PEG, poly(ethylene glycol); PCL, poly(ε-caprolactone); PEI, polyethyleneimine.
Figure 5
Figure 5
The morphology and drug release behavior of micelles. Notes: (A) Morphology of polymeric micelles determined by scanning electron microscopy (SEM). Scale bar represents 200 nm. (B) In vitro-release profile of CyA-loaded micelles at pH 7.2. Abbreviations: CyA, cyclosporine; h, hours.
Figure 6
Figure 6
Representative in vivo two-photon microscopy images of corneal cross-sections at 15 min, 30 min, and 60 min after administration of different types of eye drops in C57BL/6 mice. Notes: The administered eye drops were (A) FDA-loaded PCI micelles, (B) FDA nanoparticles, (C) FDA microparticles, and (D) FDA-loaded PEG-PCL micelles (magnification, 100×). Abbreviations: min, minutes; FDA, fluorescein diacetate; PCI, poly(ethylene glycol)-poly(ε-caprolactone)-g-polyethyleneimine; PEG, poly(ethylene glycol); PCL, poly(ε-caprolactone).
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