Local delivery of hormonal therapy with silastic tubing for prevention and treatment of breast cancer

Abstract

Broad use of germline testing has identified an increasing number of women at risk for breast cancer with a need for effective chemoprevention. We report a novel method to selectively deliver various anti-estrogens at high drug levels to the breast tissue by implanting a device comprised of silastic tubing. Optimized tubing properties allow elution of otherwise poorly bioavailable anti-estrogens, such as fulvestrant, into mammary tissue in vitro and in vivo with levels sufficient to inhibit estrogen receptor activation and tumor cell proliferation. Implantable silastic tubing delivers fulvestrant selectively to mouse mammary fat tissue for one year with anti-tumor effects similar to those achieved with systemic fulvestrant exposure. Furthermore, local delivery of fulvestrant significantly decreases cell proliferation, as assessed by Ki67 expression, most effectively in tumor sections adjacent to tubing. This approach may thereby introduce a potential paradigm shift and offer a promising alternative to systemic therapy for prevention and early interception of breast cancer.

A long-term fulvestrant eluting implant is safe, non-toxic, and reduces the risk of breast cancer in in vivo models.

“…Together, these findings suggest that an implant reformulated to deliver greater rates of fulvestrant for a longer duration could provide comparable risk reduction to systemic therapy. This and previous studies with silicone-based tubing implants demonstrate fulvestrant is released with zero order kinetics (DNS and Park et al 21 ). Increasing the amount of fulvestrant in an implant extends the duration of release, while decreasing tubing wall thickness increases the release rate.…”

“…Fulvestrant was chosen as the active agent to be delivered due to its proven efficacy in patients, relative potency against the estrogen receptor, high lipophilicity, not requiring metabolism, unlike tamoxifen, to be fully active, as well as its long-established safety history 20 . This proof of principle study demonstrated that when sealed within the lumen of silicone tubing, fulvestrant exhibited zero order elution by passive diffusion for an estimated duration exceeding five years, remaining stable and active 21 . In vivo murine experiments showed eluted fulvestrant maintained preferential on target (e.g.…”

“…This therapeutic approach to breast cancer prevention is, however, limited by adverse effects that result in diminished patient compliance. In a previous study, we demonstrated that locally delivered fulvestrant using a silicone-based passive diffusion drug eluting implant could inhibit tumor growth in mice, while minimizing systemic exposure 21 . In this study, we sought to determine whether this approach could prevent breast cancer from developing while maintaining minimal off target exposure in a well-established rat breast cancer prevention model and in sheep using a localized delivery implant scaled for the breast.…”

“…These implants consisted of silastic silicone tubing, 1.6 to 2 cm in length, filled with powdered fulvestrant and sealed on both ends with silicone adhesive. Fulvestrant eluted from these implants by passive diffusion exhibiting zero order kinetics, with tubing wall thickness governing the release rate 21 . To assess larger implant and form factor designs to cover a larger area of breast tissue with ensured drug content uniformity, an alternate formulation of silicone and fulvestrant was created.…”

“…The kidney and liver are the primary organs of fulvestrant metabolism and clearance and exhibit highest tissue concentrations across animal models and humans 21 . In animals systemically treated, both kidney (298.1 ng/g, Fig.…”