Zinc-Silicate Glasses for Transarterial Chemoembolization of Hepatocellular Carcinoma

Abstract

Drug eluting bead transarterial chemoembolization (DEB-TACE) has emerged as the gold standard therapy for patients diagnosed with hepatocellular carcinoma, the second leading cause of cancer-related deaths worldwide. Presently, DEB-TACE procedures are limited by two factors: (i) particles are radiolucent, making it impossible to determine spatial-temporal distribution within target tissues thus limiting optimum therapy, and (ii) conventional bead technologies require drug pre-loading, which is logistically challenging.

The research presented herein examines these material limitations through two different approaches. The first approach is based on the idea that systems can be optimized for an application by combining multiple components, where each component fulfills a specific role. Towards this end, drug preloaded radiopaque composite embolic microspheres were prepared from polylactic-co-glycolic acid, radiopaque zinc-silicate glass and doxorubicin. Using a design of experiments approach the composition was optimized to provide for maximum radiopacity while drug release was controlled over seven days.

The second approach is one of simplicity and reflects the emerging biomaterial design paradigm that seeks to elicit desired host responses. In this sense therapeutic inorganic ions (TII) released from biomedical glasses are known to promote hard tissue repair and regeneration by triggering angiogenesis and osteogenesis. In DEB-TACE, the desired host response is cell death. Within this framework, two zinc-silicate systems were prepared containing lanthanum and vanadium since these elements are known to have anticancer behavior. The composition-structure-property-function relationships were evaluated based on substitution of lanthanum or vanadium into the glass network. Critically, the ion release capabilities were evaluated in simulated physiological conditions. Increased lanthanum did not dramatically alter the structure of the glass but it did increase the hydrolytic stability of the glasses. Increased vanadium caused polymerization of the Si-network and simultaneously decreased its hydrolytic stability resulting in significant amounts of vanadium release. Exposure of HepG2 cells to vanadium containing extracts resulted in concentration dependent apoptotic cell death.

Biomedical glasses have potential in applications beyond hard tissue repair and regeneration, providing a radiopaque, drug preloaded alternative to existing DEB-TACE materials and a simple means for vectored delivery of TII.