Prevention of lung tumor recurrence through localized drug delivery via paclitaxel-eluting glycerol-based polymeric films

A majority of the projected 1,437,180 new cancer cases in 2008 will be diagnosed at a locoregional stage, where surgical resection is the preferred treatment. However, the benefit of removing cancerous tissue must be balanced against the resulting morbidity to the patient, and frequently, despite a complete surgical resection, undetected microscopic disease can remain leading to tumor recurrence. Consequently, an important area of research has focused on harnessing local drug delivery via controlled release polymer systems to prevent local recurrence and to avoid the often-severe side effects associated with the systemic administration of chemotherapy.;New poly(glycerol-co-caprolactone) copolymers comprised of glycerol and 6-hydroxycaproic acid repeating units were synthesized via a ring-opening polymerization and characterized. Poly(glycerol-co-caprolactone) copolymers were then conjugated to various hydrophobic biocompatible side chains for evaluation as polymer matrices for controlled release of a chemotherapeutic agent. The choice of side chain profoundly affected the resulting polymer properties including thermal transitions, relative crystallinity, and hydrophobicity. Drug-loaded films cast from solutions of polymer and 10-hydroxycamptothecin (HCPT) demonstrated prolonged release from four to over seven weeks without initial burst release behavior depending upon side chain structure. Drug-loaded stearic acid-conjugated poly(glycerol-co-caprolactone) films led to substantial anti-cancer activity in vitro for at least for 50 days when exposed to fresh cultures of Lewis lung carcinoma cells (LLC).;HCPT-loaded films adhered to pericardial substrates were implanted subcutaneously into mice, and LLC cells were injected overtop the films to approximate microscopic malignant disease. No local tumor growth was observed for the mice with drug-loaded films, while in stark contrast 78% of mice with unloaded films developed tumor at the surface of the films. Following these results, a true recurrence animal model was designed and evaluated using paclitaxel-loaded films. Paclitaxel-loaded films were found to prevent locally recurrent disease when implanted following resection of the primary tumor in vivo, without impairment of wound healing. Successful clinical use of this drug-eluting film would alter the definition of surgically resectable lung cancer, shift the risk-benefit ratio towards prophylactic treatment of "close" surgical margins, and potentially eliminate local recurrence as the leading cause of death among patients following "curative" surgical resection.