pH-controlled drug loading and release from biodegradable microcapsules

Abstract

Microcapsules made of biopolymers are of both scientific and technological interest and have many potential applications in medicine, including their use as controlled drug delivery devices. The present study makes use of the electrostatic interaction between polycations and polyanions to form a multilayered microcapsule shell and also to control the loading and release of charged drug molecules inside the microcapsule. Micron-sized calcium carbonate (CaCO3) particles were synthesized and integrated with chondroitin sulfate (CS) through a reaction between sodium carbonate and calcium nitrate tetrahydrate solutions suspended with CS macromolecules. Oppositely charged biopolymers were alternately deposited onto the synthesized particles using electrostatic layer-by-layer self-assembly, and glutaraldehyde was introduced to cross-link the multilayered shell structure. Microcapsules integrated with CS inside the multilayered shells were obtained after decomposition of the CaCO3 templates. The integration of a matrix (i.e., CS) permitted the subsequent selective control of drug loading and release. The CS-integrated microcapsules were loaded with a model drug, bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA), and it was shown that pH was an effective means of controlling the loading and release of FITC-BSA. Such CS-integrated microcapsules may be used for controlled localized drug delivery as biodegradable devices, which have advantages in reducing systemic side effects and increasing drug efficacy.

Figure 1

Schematic diagram for the preparation of CS integrated multilayered microcapsules and related loading and release of FITC-BSA. (A→B): preparation of CS integrated CaCO₃ templates, (B→C): self-assembly and crosslinking of multilayered shell on CaCO₃(CS) templates, (C→D): decomposition of the CaCO₃ templates and formation of CS integrated multilayered microcapsules, (D→E): loading of BSA into CS integrated microcapsules at a pH at which BSA has net positive charges, and (E→F): release of BSA from CS integrated microcapsules at neutral pH where BSA has net negative charges. CS, crosslinked multilayered shell, BSA. The net charge of BSA is positive below its pI (pH 5.0) and negative above its pI.

Figure 2

Absorbance of (PLL/CS)₅ multilayers on quartz slides (A) after crosslinking using 0.5% GA as a function of time, and (B) after crosslinking with different concentrations of GA for 24 h.

Figure 3

SEM images of (PLL/CS)₅ microcapsules crosslinked for 24 h using GA at a concentration of (A) 0.05%, (B) 0.1%, (C) 0.5%, (D) 1%, and (E) 5%.

Figure 4

FITC-BSA concentrations in the microcapsule interior as a function of pH of BSA solution.

Figure 5

Loading of FITC-BSA within CS integrated (PLL/CS)₅ microcapsules at pH 3.8. (A) CLSM image, and (B) fluorescence profile of the microcapsule shown in (A).

Figure 6

FITC-BSA cumulative release from CS integrated microcapsules vs. incubation time. (A) Release profiles at pHs 7.4, 5.0, and 1.0. The inset is the release of FITC-BSA at pH 7.4 for up to 5,600 min. (B) Release of FITC-BSA at 30 and 65 min. *Release was significantly different between the pH values tested. Release was conducted at 37 °C at pH 7.4 (○), 5.0 (△), and 1.0 (□) solutions.

Figure 6

FITC-BSA cumulative release from CS integrated microcapsules vs. incubation time. (A) Release profiles at pHs 7.4, 5.0, and 1.0. The inset is the release of FITC-BSA at pH 7.4 for up to 5,600 min. (B) Release of FITC-BSA at 30 and 65 min. *Release was significantly different between the pH values tested. Release was conducted at 37 °C at pH 7.4 (○), 5.0 (△), and 1.0 (□) solutions.