A tissue-like polymeric drug delivery implant for local cancer therapy

Abstract

Event Abstract Back to Event A tissue-like polymeric drug delivery implant for local cancer therapy Aikaterini Mantzavinou1, 2 and Michael J. Cima2, 3 1 Massachusetts Institute of Technology, Harvard-MIT Division of Health Sciences and Technology, United States 2 Massachusetts Institute of Technology, The David H. Koch Institute for Integrative Cancer Research, United States 3 Massachusetts Institute of Technology, Department of Materials Science, United States Introduction: Polymeric drug delivery implants have been explored for local cancer treatment because of the systemic toxicity and tumor targeting inability associated with intravenous administration[1]. Such implants are often resorbable to avoid removal surgery and minimize the foreign body response. Resorbable implants suffer from poorly controlled drug release and, often, inhibiting form factors[2],[3]. Chemotherapy delivery via nonresorbable polymer matrices has been largely limited to lipophilic drugs[1],[4]. Nonresorbable polymers explored for release of hydrophilic drugs are mechanically ill suited for contact with soft tissue[5]. This study investigated the release of hydrophilic small molecules from a nonresorbable, tissue-like silicone elastomer. Materials and Methods: Ecoflex 00-30 silicone elastomer (EF; Young's modulus 69 kPa, shore hardness 00-30, elongation at break 900%) was chosen for its tissue-like mechanics and biocompatibility to (1) minimize soft tissue irritation and risk of rupture and (2) allow laparoscopic manipulation and removal[6],[7]. Lactose was used as a hydrophilic small molecule for preliminary device fabrication and characterization experiments. Lactose-EF (LEF) devices were prepared by mixing lactose monohydrate powder with uncured EF (10%, 25% or 50% wpowder/wtotal). The mixes were placed in molds in vacuum for 30 min followed by curing for 4 hr at room temperature. Devices of ~1 mm thickness were cut with a 5 mm-diameter punch. For structural analysis, devices were immersed in liquid nitrogen then sectioned laterally in thin slices. Slices were coated with gold-palladium for scanning electron microscopy (SEM) imaging to study the distribution of lactose in the silicone matrix. For in vitro release experiments, each device was weighed, placed in 5 mL of phosphate-buffered saline (PBS) and kept in an oscillating incubator at 37oC and 86 RPM. The device was removed every 24 hr, dried at 100oC for 3 hr, weighed and the PBS replaced. This was repeated daily and the change in mass was averaged (n = 3). Devices containing hydrophilic small molecule chemotherapeutics were prepared and characterized using the same protocols, except high-performance liquid chromatography was used to quantify drug release in PBS (data not shown, studies ongoing). Results and Discussion: LEF devices displayed uniform active agent distribution (Figure 1). The mass of 10% and 25% LEF devices in PBS decreased for 48 hr then plateaued to a constant, lower value. The mass of 50% LEF devices continually decreased after 48 hr at a lower rate that appeared constant (Figure 2). These data represent proof-of-concept release of a hydrophilic small molecule from a lipophilic, tissue-like nonresorbable polymer. Studies characterizing EF devices containing other hydrophilic chemotherapeutics, their in vitro release profile and in vitro tumor cytotoxicity are ongoing. Conclusion: This is, to our knowledge, the first attempt to (1) create a nonresorbable matrix-type controlled-release system based on a supersoft silicone elastomer and (2) use it to deliver hydrophilic small molecules. Controlled delivery of hydrophilic chemotherapeutic agents locally to the tumor from a nonresorbable implant will aid development of fully implantable drug delivery systems for cancer therapy. Such systems hold great promise for better patient outcomes following surgical tumor debulking. This work was funded by the Koch Institute Bridge Project. A.M. received the Ludwig Center for Molecular Oncology Graduate Fellowship from the Ludwig Center for Molecular Oncology Fund.