Early stage release control of an anticancer drug by drug-polymer miscibility in a hydrophobic fiber-based drug delivery system

Abstract

The drug release profiles of doxorubicin-loaded electrospun fiber mats were investigated with regard to drug-polymer miscibility, fiber wettability and degradability. Doxorubicin in hydrophilic form (Dox-HCl) and hydrophobic free base form (Dox-base) was employed as model drugs, and an aliphatic polyester, poly(lactic acid) (PLA), was used as a drug-carrier matrix. When hydrophilic Dox-HCl was directly mixed with PLA solution, drug molecules formed large aggregates on the fiber surface or in the fiber core, due to poor drug-polymer compatibility. Drug aggregates on the fiber surface contributed to the rapid initial release. The hydrophobic form of Dox-base was dispersed better with PLA matrix compared to Dox-HCl. When dimethyl sulfoxide (DMSO) was used as the solvent for Dox-HCl, the miscibility of drug in the polymer matrix was significantly improved, forming a quasi-monolithic solution scheme. The drug release from this monolithic matrix was slowest, and this slow release led to a lower toxicity to hepatocellular carcinoma. When an enzyme was used to promote PLA degradation, the release rates were closely correlated with degradation rates, demonstrating degradation was the dominant release mechanism. The possible drug release mechanisms were speculated based on the release kinetics. The results suggest that manipulation of drug-polymer miscibility and polymer degradability can be an effective means of designing drug release profiles.

Fig. 1. Photographic and microscopic images of doxorubicin-loaded fiber mats. (a) SEM images of drug-loaded PLA fibers; (b) fiber mats producing different colors depending on drug–polymer miscibility; (c) optical images displaying dissolution or aggregation of drug crystals in fiber webs; (d) fluorescence images by the fluoresced doxorubicin.

Fig. 2. Doxorubicin crystal aggregates in PLA–HCl mat observed by an optical microscope (a) and TEM (b). Dox particle is in crystalline phase (1) while PLA fiber was mostly amorphous (2).

Fig. 3. TEM cross-sectional images of Dox-loaded fibers. (a) PLA–HCl; (b) PLA–base; (c) PLA–HCl(DMSO). Note: the magnification of (a) is different, thus the length of 1 μm in (a) appears different.

Fig. 4. In vitro release profiles of doxorubicin from PLA fibrous carriers.

Fig. 5. Accelerated degradation of drug-loaded mats in the presence of proteinase K.

Fig. 6. Drug release profiles with the accelerated degradation. (a) Weight loss (%) of fiber mats for 24 h; (b) cumulative drug release (%) of mats with time; (c) Dox release as a function of weight loss (%).

Fig. 7. Drug release kinetics. (a) Initial stage release (0 to 1 h); (b) later stage release (1 h to 6 days).

Fig. 8. Illustration of doxorubicin drug release mechanisms from a PLA fiber matrix. (a) PLA–HCl; (b) PLA–base; (c) PLA–HCl(DMSO). M1, dissolution of drug molecules; M2, water permeation followed by drug diffusion; M3, polymer degradation followed by drug dissolution/diffusion.

Fig. 9. C3A viability for the positive control with Dox-HCl (a), Dox with PLA samples after 5 h incubation (b), and Dox with PLA samples after 24 h incubation (c). Data represent mean (n = 3) ± S.D. Positive CTRL, Dox-HCl with cells without PLA fiber mats; CTRL, only cells without drug or PLA fiber mats. LC₅₀ approximately 413 μg mL⁻¹.