Doxorubicin-loaded silk films: Drug-silk interactions and in vivo performance in human orthotopic breast cancer

Abstract

Breast cancer is the most common of all malignant diseases in women. Systemic chemotherapy provides low clinical benefit for locoregional control of the disease, while localised chemotherapy may provide a therapeutic advantage. In this study, doxorubicin-loaded silk films were directly applied to tumours. Affinity binding studies demonstrated that the adsorption of doxorubicin onto silk was partially dependent on crystallinity. By manipulating silk crystallinity, or β-sheet content, the doxorubicin release rate could be controlled ranging from immediate release to prolonged release over >4 weeks. Following successful in vitro studies, the therapeutic impact of doxorubicin-loaded silk films on primary tumour growth and metastasis was assessed in mice using a humanised orthotopic breast cancer model (adenocarcinoma). Both soluble and stabilised silk films loaded with doxorubicin had a significantly greater primary tumour response than the equivalent dose of doxorubicin administered intravenously in the absence of the silk film carrier. In addition to reducing primary tumour growth, stabilised silk films loaded with doxorubicin also reduced metastatic spread and autopsy indicated that these films were not associated with any local or systemic toxicities. Collectively, these results suggest that the future use of this approach for localised chemotherapy is promising.

Silk for Drug Delivery Applications: Opportunities and Challenges

“…For example, when casting a thin silk film, the dried fibroin (known as silk I) is completely water soluble; therefore, the drug payload is released in accordance with the solubilization characteristics of the film in an aqueous environment (see supplementary video in reference [37]). When working with thin films, silk I is readily soluble in water and thus releases its payload within seconds.…”

“…[40] In a separate study, the b-sheet content of the silk was used to control doxorubicin release (Figure 2). [37] While these examples describe common strategies for fabricating drug-loaded silks, "in situ" loading has also been attempted. The effort to load silk fibroin with low molecular weight chemicals during sericulture dates back to the early 1920s and attempts to yield intrinsically dyed silk.…”

“…The ability of native silk to strongly absorb the low molecular weight chemotherapeutic agent doxorubicin has recently been exploited to load silk films [37] and silk nanoparticles [40] after carrier fabrication. Systematic studies have shown that the overall loading efficiency correlates with the distribution coefficient (logD) of small molecules of weak alkaline nature; [41] i.e., low molecular weight drugs with a positive net charge can diffuse into silk particles (or films) and this is facilitated by electrostatic interaction with the negatively charged side chains of the hydrophilic spacers of its heavy chain.…”

Doxorubicin loaded nanodiamond-silk spheres for fluorescence tracking and controlled drug release

“…The factor was used to convert the diameters of individual particles to nm. A number of particles (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) were selected for each sample and the size distribution was determined.…”

“…Fluorescence was detected at the peak emission of DoX at 570 nm. A calibration curve was plotted to relate the fluorescence intensities to the known amounts of DoX through curve fitting parameters [39,40]. The parameters from the calibration curve were used to find the unknown concentrations of released DoX in the supernatant corresponding to the fluorescence intensity in the supernatant after every 24 hours.…”