Functionalized hydrophobic poly(glycerol-co-ε-caprolactone) depots for controlled drug release.

A limitation to many polymer-based drug delivery systems is the lack of ability to customize a particular polymer composition for tailoring drug release kinetics to a specific clinical application. In this study, we investigated the structure-property effects of conjugating various hydrophobic biocompatible side chains to poly(glycerol-co-caprolactone) copolymers with the goal of achieving prolonged and controlled release of a chemotherapeutic agent. The choice of side chain significantly affected the resulting polymer properties including thermal transitions, relative crystallinity (ΔH(f)), and hydrophobicity. Drug-loaded films cast from solutions of polymer and 10-hydroxycamptothecin demonstrated prolonged release from four to over seven weeks depending upon side chain structure without initial burst release behavior. Use of the stearic acid-conjugated poly(glycerol-co-caprolactone) films afforded substantial anticancer activity in vitro for at least 50 days when exposed to fresh cultures of A549 human lung cancer cells over 24 h intervals, correlating well with the measured drug release kinetics.

Paclitaxel-eluting polymer film reduces locoregional recurrence and improves survival in a recurrent sarcoma model: a novel investigational therapy.

BACKGROUND: Locoregional recurrences occur in up to 50% of patients after macroscopically complete (R0/R1) resections of abdominal, pelvic, and retroperitoneal sarcomas. Efficacy of a drug-eluting polymer film in reducing locoregional recurrence rates was assessed in a murine recurrent sarcoma model. METHODS: Poly(glycerol monostearate-co-caprolactone) polymer films were synthesized with and without 300 µg paclitaxel (Pax-film and unloaded film). Cytotoxicity was assessed against CS-1 (human chondrosarcoma) cells in vitro and in vivo in nude mice. Following R0/R1 resection of primary subcutaneous tumors, mice were blindly randomized to: (1) Pax-film implant, (2) unloaded film implant, (3) paclitaxel 300 µg IV (Pax IV), or (4) no other therapy ("untreated"). Locoregional recurrence, overall survival (OS), and tumor mitotic index were evaluated. RESULTS: Pax-films, but not unloaded films, reduced CS-1 viability in vitro for >50 days (P < 0.001). In vivo, locoregional recurrence was observed in 2 of 12 Pax-film mice (17%), 9 of 13 unloaded film mice (69%), 8 of 9 Pax IV mice (89%), and 7 of 8 untreated mice (88%) (P < 0.01). Median OS was 81, 64, 48, and 56 days, respectively. Paclitaxel levels in local tissues were 50- to 300-fold greater in Pax-film mice compared with Pax IV mice. Tumor mitotic index adjacent to Pax-films was significantly lower than adjacent to unloaded films. CONCLUSIONS: Tumor bed implantation of Pax-films after R0/R1 resection is superior to Pax IV as evidenced by reduced locoregional recurrence and improved OS in a murine recurrent sarcoma model. Continuous local drug exposure via polymer films represents a potentially novel approach for treatment of locally aggressive sarcomas.

Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers.

Polymer-based drug delivery depots have been investigated over the last several decades as a means to improve upon the lack of tumor targeting and severe systemic morbidities associated with intravenous chemotherapy treatments. These localized therapies exist in a variety of form factors designed to facilitate the delivery of drug directly to the site of disease in a controlled manner, sparing off-target tissue toxicities. Many of these depots are biodegradable and designed to maintain therapeutic concentrations of drug at the tumor site for a prolonged period of time. Thus a single implantation procedure is required, sometimes coincident with tumor excision surgery, and thereby biodegrading following complete release of the loaded active agent. Even though localized polymer depot delivery systems have been investigated, a surprisingly small subset of these technologies has demonstrated potentially curative preclinical results for cancer applications, and fewer have progressed toward commercialization. The aims of this article are to review the most well-studied and efficacious local polymer delivery systems from the last two decades, to examine the rationale for utilizing drug-eluting polymer implants in cancer patients, and to identify the patient cohorts that could most benefit from localized therapy. Finally, a discussion of the physiological barriers to localized therapy (i.e. drug penetration, transport), technical hurdles, and future outlook of the field is presented.

Prevention of in vivo lung tumor growth by prolonged local delivery of hydroxycamptothecin using poly(ester-carbonate)-collagen composites.

Local tumor recurrence has a major impact on long-term patient survival following the surgical treatment of most cancers, and this is especially true with lung cancer. Consequently, methods to deliver chemotherapeutics locally at a lung tumor resection margin would be beneficial since: 1) systemic treatment approaches are ineffective or highly toxic; 2) the incidence of local recurrence does not warrant universal treatment of all patients with a highly morbid systemic therapy; and 3) surgical resection of recurrent disease is not an option and alternative rescue therapies are generally unsuccessful. To begin to meet this clinical need, we have prepared poly(glycerol monostearate-co-epsilon-caprolactone) films as a controlled, prolonged, and low dose delivery matrix for the potent anticancer agent 10-hydroxycamptothecin (HCPT). These drug-loaded films were applied to a collagen-based scaffold clinically indicated for the mechanical buttressing of lung tissue following surgical resection, resulting in a flexible composite that can be secured to the tissue that releases HCPT over seven weeks and thereby prevents the local growth and establishment of Lewis lung carcinoma tumors in vivo (a freedom of local tumor growth of 86%). In comparison, all animals treated with a larger intravenous dose of HCPT or unloaded composites developed rapid local tumors.

Prevention of local tumor recurrence following surgery using low-dose chemotherapeutic polymer films.

AIM: To evaluate the efficacy of a polymer film designed for prolonged paclitaxel release at surgical margins to prevent local recurrence in non-small-cell lung cancer (NSCLC) following complete surgical resection in a murine model. METHODS: Poly(glycerol monostearate co-epsilon-caprolactone) polymer films were prepared with or without 10% (w/w) paclitaxel and characterized for prolonged tumor cytotoxicity in vitro against several NSCLC cell lines including LLC, NCI-H460, and NCI-H292. Films were implanted following complete LLC tumor resection and assessed in vivo for prevention of local tumor recurrence, impact on wound healing, and extent of local drug delivery. Plasma and local tissue concentrations of paclitaxel were compared following systemic administration and film implantation. RESULTS: The flexible polymeric films eluted paclitaxel over several weeks and remained cytotoxic to LLC, NCI-H460, and NCI-H292 cells in vitro for 50 days, while unloaded films did not impair tumor cell growth. Implanted paclitaxel films prevented local tumor recurrence in vivo in 83.3% of animals, compared with unloaded films (12.5%), systemic (22.2%) or locally administered paclitaxel (0%) (P < 0.005). Although minimal paclitaxel remained in either plasma or tissue 10 days after systemic injection, local paclitaxel concentration at the site of surgical resection was significantly greater (3,000-fold) at 10 days when paclitaxel was locally delivered via films (P = 0.024). CONCLUSIONS: Local application of paclitaxel-loaded polymer films following surgical resection can prevent local tumor recurrence without impairing wound healing.

Therapeutic and diagnostic applications of dendrimers for cancer treatment.

Dendrimers are prepared with a level of control not attainable with most linear polymers, leading to nearly monodisperse, globular macromolecules with a large number of peripheral groups. As a consequence, dendrimers are an ideal delivery vehicle candidate for explicit study of the effects of polymer size, charge, composition, and architecture on biologically relevant properties such as lipid bilayer interactions, cytotoxicity, internalization, blood plasma retention time, biodistribution, and tumor uptake. Over the last several years, substantial progress has been made towards the use of dendrimers for therapeutic and diagnostic purposes for the treatment of cancer, including advances in the delivery of anti-neoplastic and contrast agents, neutron capture therapy, photodynamic therapy, and photothermal therapy. The focus of this review is on dendrimer developments from the last four years for oncological applications, with emphasis on distinct architectures and the biological responses these structures elicit.

Crosslinked alpha-elastin biomaterials: towards a processable elastin mimetic scaffold.

Elastin is a critical biochemical and biomechanical component of vascular tissue. However, elastin is also highly insoluble and therefore difficult to process into new biomaterials. We present a simple approach for synthesizing elastin-based materials from two commercially available and water-soluble components: alpha-elastin and a diepoxy crosslinker. Reaction pH was shown to modulate the degree of crosslinking, as demonstrated by materials characterized with a range of swelling ratios (approximately 10-25), enzymatic degradation rates (approximately 8-50% per h in 0.1 u/ml elastase), and elastic moduli (approximately 4-120 kPa). Crosslinking with a combination alkaline and neutral pH process results in materials with the highest degree of crosslinks, as indicated by a swelling ratio of 10, slow degradation rate, and high elastic moduli (approximately 120 kPa). Furthermore, the crosslinked alpha-elastin materials support vascular smooth muscle cell (VSMC) adhesion and a decreased proliferation rate compared to polystyrene controls. The functional outcomes of the crosslinking reaction, including the dependence of structure-function properties on reaction pH, are discussed. Our approach towards 'processable' elastin-based materials is versatile and could be integrated into existing tissue engineering methodologies to enhance biomaterial performance by providing a natural elastomeric and biofunctional component.