High dose, dual-release polymeric films for extended surgical bed paclitaxel delivery

Abstract

While surgery represents a major therapy for most solid organ cancers, local recurrence is clinically problematic for cancers such as sarcoma for which adjuvant radiotherapy and systemic chemotherapy provide minimal local control or survival benefit and are dose-limited due to off-target side effects. We describe an implantable, biodegradable poly(1,2-glycerol carbonate) and poly(caprolactone) film with entrapped and covalently-bound paclitaxel enabling safe, controlled, and extended local delivery of paclitaxel achieving concentrations 10,000× tissue levels compared to systemic administration. Films containing entrapped and covalently-bound paclitaxel implanted in the tumor bed, immediately after resection of human cell line-derived chondrosarcoma and patient-derived xenograft liposarcoma and leiomyosarcoma in mice, improve median 90- or 200-day recurrence-free and overall survival compared to control mice. Furthermore, mice in the experimental film arm show no film-related morbidity. Continuous, extended, high-dose paclitaxel delivery via this unique polymer platform safely improves outcomes in three different sarcoma models and provides a rationale for future incorporation into human trials.

Keywords: Drug delivery; Dual release; Paclitaxel; Resection; Sarcoma.

Figure 1.

a) Schematic for tumor recurrence post-resection with and without film. PC – peritoneal cavity; K – kidney; C – colon; T – tumor. b) Schematic for film coating. Polymer and free PTX solutions in DCM were casted onto PGA buttress by hand via syringe. c) Schematic for paclitaxel conjugation to poly(1,2-glycerol carbonate).

Figure 2.. In vitro characterization of PGC-PTX and PTX+PGC-PTX films.

a) Mechanism of PTX degradation. Hydrolysis can occur at either ester on the succinic acid yielding PTX or PTX-SA. b) Mass-loss of each material in complete DMEM + 10% fetal bovine serum + 1% penicillin/streptomycin media. Degradation rates determined by linear fits for PGA, PCL, PGC-PTX, and PTX+PGC-PTX groups (Y = 4.736*X − 5.723, R²=0.9607; Y = 1.789*X + 3.475, R²=0.7560; Y = 1.466*X − 4.888, R²=0.6294; Y = 1.974*X − 4.172, R²=0.7429). c & d) Cumulative release of PTX and PTX-SA from PGC-PTX and PTX+PGC-PTX meshes into 0.3% w/v SDS in PBS. e) Rate of hydrolysis of PTX-SA in PBS. Scanning electron micrographs of PGA buttresses with f) PCL, g) PGC-PTX+PCL, and h) PTX+PGC-PTX+PCL coatings. i) PGC-PTX+PCL with suture. Scale bar = 100 micron. J) IC₅₀ curves of paclitaxel and paclitaxel-succinic acid. K) Viability of CS-1 cells after 24-hr incubation with each film (n=5). The same set of films are used across every time point and are left in 0.2% w/v SDS in PBS release buffer between time points.

Figure 3.

Tissue extraction of PTX with (a) PTX+PGC-PTX film, (b) PGC-PTX film, and (c) IP PTX drug delivery systems. Local tissue and plasma levels of paclitaxel post treatment determined via high-performance liquid chromatography; n=4 for each time point.

Figure 4.. Overall and recurrence-free survival of mice post-resection.

(top) Recurrence-free survival and (bottom) body weight of mice post-resection of a) CS-1, b) LMS20, and c) LP6 tumors. All groups in each tumor resection model contained n=8 except CS-1 model mice receiving unloaded and PTX+PGC-PTX film, with n=9 and n=10 mice. For mice weight recovery, all groups contained n=8 except mice receiving unloaded and PTX+PGC-PTX film, with n=9 and n=10 mice.