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

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.

Porous Paclitaxel Mesh Reduces Local Recurrence in Patient-Derived Xenograft Resection Model.

BACKGROUND: Drug-loaded meshes offer a promising delivery strategy for the prevention of local recurrence. Patient-derived xenograft (PDX) models are representative of individual patient tumors and predictive of clinical outcomes. METHODS: A PDX model was established in NSG (NOD-scid IL2Rgammanull) mice using tumor tissue from a patient with aggressive lung adenocarcinoma. Polyglycolic acid (PGA) meshes loaded with paclitaxel (PGA+PTX) were electrospun. Tumor-bearing mice were randomized into 4 groups after macroscopic complete resection: (1) no treatment (n = 10); (2) intraperitoneal PTX at 20 mg/kg (n = 10); (3) PGA mesh without drug (n = 14); and (4) PGA+PTX mesh at 12 mg/kg (n = 14). A 1-cm2 mesh was placed onto the tumor resection beds. Groups were observed for local recurrence for 120 postoperative days. RESULTS: PDX mice treated with PGA+PTX meshes after resection exhibited a >5-fold increase in recurrence-free survival (P < .0001) compared with systemically treated and untreated control groups. Median recurrence-free survival was 24 days for untreated and intraperitoneal PTX groups, 28 days for unloaded PGA mesh group, and undefined for the PGA+PTX mesh group. CONCLUSIONS: Development of a PDX surgical resection model of non-small cell lung cancer permits robust assessment of postresection local recurrence for preclinical studies of patient-derived tumors. Intraoperative placement of drug-loaded meshes demonstrates superior local disease treatment, suggesting that this approach may improve recurrence-free survival in early-stage non-small cell lung cancer patients undergoing limited resection.

Synthesis and characterization of carbohydrate-based biosurfactant mimetics.

Glycolipid biosurfactants are of interest for various industry sectors. We report the synthesis and characterization of enantiopure poly-amido-saccharides (PASs) containing myristoyl (C14), palmitoyl (C16), or stearoyl (C18) terminal chain lengths as mimetics of glycolipid biosurfactants. These amphiphilic polymers are water soluble, adopt a helical secondary structure, decompose at temperatures greater than 240 °C, are non-cytotoxic, and self-assemble into nanostructures. Polymers containing the shorter hydrophilic chain lengths and the hydrophobic C14 chain exhibit the lowest surface tension among all polymers.

Minimally invasive, sustained-release relaxin-2 microparticles reverse arthrofibrosis.

Substantial advances in biotherapeutics are distinctly lacking for musculoskeletal diseases. Musculoskeletal diseases are biomechanically complex and localized, highlighting the need for novel therapies capable of addressing these issues. All frontline treatment options for arthrofibrosis, a debilitating musculoskeletal disease, fail to treat the disease etiology-the accumulation of fibrotic tissue within the joint space. For millions of patients each year, the lack of modern and effective treatment options necessitates surgery in an attempt to regain joint range of motion (ROM) and escape prolonged pain. Human relaxin-2 (RLX), an endogenous peptide hormone with antifibrotic and antifibrogenic activity, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, RLX has previously faltered through multiple clinical programs because of pharmacokinetic barriers. Here, we describe the design and in vitro characterization of a tailored drug delivery system for the sustained release of RLX. Drug-loaded, polymeric microparticles released RLX over a multiweek time frame without altering peptide structure or bioactivity. In vivo, intraarticular administration of microparticles in rats resulted in prolonged, localized concentrations of RLX with reduced systemic drug exposure. Furthermore, a single injection of RLX-loaded microparticles restored joint ROM and architecture in an atraumatic rat model of arthrofibrosis with clinically derived end points. Finally, confirmation of RLX receptor expression, RXFP1, in multiple human tissues relevant to arthrofibrosis suggests the clinical translational potential of RLX when administered in a sustained and targeted manner.

Doxorubicin-Loaded Polymeric Meshes Prevent Local Recurrence after Sarcoma Resection While Avoiding Cardiotoxicity.

Surgery is the only potentially curative treatment for localized soft-tissue sarcomas. However, for sarcomas arising in the retroperitoneum, locoregional recurrence rates are 35% to 59% despite resection. Doxorubicin (DOX) is the standard first-line systemic chemotherapy for advanced soft-tissue sarcoma, yet its intravenous administration yields limited clinical efficacy and results in dose-limiting cardiotoxicity. We report the fabrication and optimization of a novel electrospun poly(caprolactone) (PCL) surgical mesh coated with layers of a hydrophobic polymer (poly(glycerol monostearate-co-caprolactone), PGC-C18), which delivers DOX directly to the operative bed following sarcoma resection. In xenograft models of liposarcoma and chondrosarcoma, DOX-loaded meshes (DoM) increased overall survival 4-fold compared with systemically administered DOX and prevented local recurrence in all but one animal. Importantly, mice implanted with DoMs exhibited preserved cardiac function, whereas mice receiving an equivalent dose systemically displayed a 23% decrease from baseline in both cardiac output and ejection fraction 20 days after administration. Collectively, this work demonstrates a feasible therapeutic approach to simultaneously prevent post-surgical tumor recurrence and minimize cardiotoxicity in soft-tissue sarcoma. SIGNIFICANCE: A proof-of-principle study in animal models shows that a novel local drug delivery approach can prevent tumor recurrence as well as drug-related adverse events following surgical resection of soft-tissue sarcomas.

Sustained Supratherapeutic Paclitaxel Delivery Enhances Irreversible Sarcoma Cell Death.

Risk of locoregional recurrence after sarcoma resection is high, increasing both morbidity and mortality. Intraoperative implantation of paclitaxel (PTX)-eluting polymer films locally delivers sustained, supratherapeutic PTX concentrations to the tumor bed that are not clinically feasible with systemic therapy, thereby reducing recurrence and improving survival in a murine model of recurrent sarcoma. However, the biology underlying increased efficacy of PTX-eluting films is unknown and provides the impetus for this work. In vitro PTX efficacy is time and dose dependent with prolonged exposure significantly decreasing PTX IC50 values for human chondrosarcoma (CS-1) cells (153.9 nmol/L at 4 hours vs. 14.2 nmol/L at 30 hours, P = 0.0001). High-dose PTX significantly inhibits proliferation with in vivo PTX films delivering a dose >130 µmol/L directly to the tumor thereby irreversibly arresting cell cycle and inducing apoptosis in CS-1 as well as patient-derived liposarcoma (LP6) and leiomyosarcoma (LMS20). Supratherapeutic PTX upregulates the expression of p21 in G2-M arrested cells, and irreversibly induces apoptosis followed by cell death, within 4 hours of exposure. Microarray analyses corroborate the finding of poor DNA integrity commonly observed as a final step of apoptosis in CS-1 cells and tumor. Unlike low PTX concentrations at the tumor bed during systemic delivery, supratherapeutic concentrations achieved with PTX-eluting films markedly decrease sarcoma lethality in vivo and offer an alternative paradigm to prevent recurrence.