Multifunctional drug delivery devices are highly sought after since the restoration of function to diseased tissue often requires varied and sometimes conflicting design requirements. This is notably true for designing devices intended to prevent lung tumor recurrence following surgical resection. Lung cancer is the leading cause of cancer deaths among men and women in the United States with over 160,000 deaths per year. Even in the setting of complete surgical resection, nearly 40% of patients with early lung cancer will develop recurrent disease at a local or distant site. Even when recurrence is local, the majority of patients are not candidates for repeat surgical resection with a resultant 2-year survival of only 18-24%.
We have synthesized new poly(carbonate-co-ester) copolymers based on glycerol and ε-caprolactone (Figure), which are ideal for this specific drug delivery application for the following reasons: 1) moldable films are easily applied to a flexible, deformable tissue surface such as the lung which actively moves as it expands and contracts during respiration; 2) the copolymer features reactive side groups that can be modified to afford a wide range of physical properties that control drug release kinetics and material properties; 3) the films can be combined with standard buttressing materials to provide an air-tight seal; 4) films can be stapled and secured to lung tissue; and 5) therapeutic agents can be loaded into the copolymer at varying concentrations and released locally over months, thereby maximizing drug exposure to the local cells, and minimizing systemic toxicity associated with direct intravenous bolus injections of therapeutic agents.
As shown in the figure, caprolactone was copolymerized with 5-benzyloxy-1,3-dioxan-2-one to form a copolymer, which, after the removal of the benzyl side chains from the glycerol carbonate units via a mild hydrogenolysis reaction afforded secondary hydroxyl pendant side groups for subsequent functionalization. We have prepared a number of derivatives including those containing fatty acids.
We next evlauated the paclitaxel-loaded poly(glycerol monostearate-co-ε-caprolactone film formulation for the prevention of lung tumor recurrence after surgical resection. Mice received a subcutaneous injection of LLC cells followed by surgical resection when the primary tumor size reached an average of 500 square mm. The mice were randomized in a blinded fashion to receive one of four treatments at the time of surgery: 1) implantation of paclitaxel-loaded films containing a total paclitaxel dose of 300 μg at the surgical site; 2) intraperitoneal administration of a single 300 μg paclitaxel dose as systemic therapy; 3) local administration of 300 μg of paclitaxel at the surgical site; or 4) implantation of unloaded films at the surgical resection site. None of the 12 mice treated with paclitaxel-loaded films at the site of subcutaneous tumor resection developed local recurrence directly at the site of the film and only 2 recipients developed locoregional recurrence over a 90-day follow-up. The overall freedom from recurrence was 83.3%. In marked contrast, freedom from recurrence at 30 days in mice given unloaded films, or paclitaxel administered intraperitoneally or locally at the surgical site, was 12.5%, 22.2%, and 0% in these respective groups. Median time to recurrence was 9, 8, and 11 days, respectively.