Biodegradable poly(terephthalate-co-phosphate)s: synthesis, characterization and drug-release properties.

To develop biodegradable polymers with favorable physicochemical and biological properties, we have synthesized a series of poly(terephthalate-co-phosphate)s using a two-step poly-condensation. The diol 1,4-bis(2-hydroxyethyl) terephthalate was first reacted with ethylphosphorodichloridate (EOP), and then chain-extended with terephthaloyl chloride (TC). Incorporation of phosphate into the poly(ethylene terephthalate) backbone rendered the co-polymers soluble in chloroform and biodegradable, lowered the Tg, decreased the crystallinity and increased the hydrophilicity. With an EOP/TC molar feed ratio of 80: 20, the polymer exhibited good film-forming property, yielding at 86.6 +/- 1.6% elongation with an elastic modulus of 13.76 +/- 2.66 MPa. This polymer showed a favorable toxicity profile in vitro and good tissue biocompatibility in the muscular tissue of mice. In vitro the polymer lost 21% of mass in 21 days, but only 20% for up to 4 months in vivo. It showed no deterioration of properties after sterilization by gamma-irradiation at 2.5 Mrad on solid CO2. Release of FITC-BSA from the microspheres was diffusion-controlled and exceeded 80% completion in two days. Release of the hydrophobic cyclosporine-A from microspheres was however much more sustained and near zero-ordered, discharging 60% in 70 days. A limited structure-property relationship has been established for this co-polymer series. The co-polymers became more hydrolytically labile as the phosphate component (EOP) was increased and the side chains were switched from the ethoxy to the methoxy structure. Converting the methoxy group to a sodium salt further increased the degradation rate significantly. The chain rigidity as reflected in the Tg values of the co-polymers decreased according to the following diol structure in the backbone: ethylene glycol > 2-methylpropylene diol > 2,2-dimethylpropylene diol. The wide range of physicochemical properties obtainable from this co-polymer series should help the design of degradable biomaterials for specific biomedical applications.

Anti-tumor effect of combination therapy with intratumoral controlled-release paclitaxel (PACLIMER microspheres) and radiation.

BACKGROUND: Paclitaxel is one of the few chemotherapeutics effective in patients with advanced protstate cancer. Paclitaxel has also been reported to have radiosensitizing effects in prostate cancer. Local delivery of a controlled-release paclitaxel product may allow for increase local concentrations of paclitaxel at the tumor site and, in conjunction with radiation, may enhance cell kill by its radiosensitization mechanism. METHODS: Orthotopic LNCaP tumors were injected with 40% PACLIMER Microspheres (40% loading; w:w) when tumors were 100-200 mm(3). Twenty-eight days post cell injection, mice were sacrificed, tumors weighed, and serum measured for PSA. TSU-xenografts were injected with PACLIMER Microspheres (10% and 40% loaded; w:w) or placebo microspheres when the tumors were approximately 100 mm(3). Half of xenograft tumors were irradiated with a single dose (10 Gy) of radiation. Tumor volume was followed over time. RESULTS: Forty percent PACLIMER Microspheres significantly reduced tumor growth in the LNCaP orthotopic model. PSA was a good indicator of response. Forty percent PACLIMER Microspheres had a significant effect on slowing TSU growth compared to placebo microspheres. Addition of a single acute dose of radiation significantly enhanced the effect of 10% PACLIMER Microspheres (P < 0.05), had minimal effect on 40% PACLIMER Microspheres, and no enhancing effect on tumors treated with placebo microspheres. CONCLUSIONS: A controlled-release formulation of paclitaxel can be very effective in the treatment of prostate cancer. Additionally, PACLIMER Microspheres may be effectively used as a radiosensitizer in genitourinary cancers.

Polilactofate microspheres for Paclitaxel delivery to central nervous system malignancies.

PURPOSE: The purpose of this study was to demonstrate that surgically implanted, controlled-release, biodegradable polilactofate microspheres (Paclimer) can be used safely to bypass the blood-brain barrier and deliver paclitaxel to malignant brain tumors. EXPERIMENTAL DESIGN: The rate of paclitaxel release from Paclimer microspheres submerged in PBS was measured in vitro by high-performance liquid chromatography. In vivo studies of Paclimer were performed as intracranial implants in Fischer 344 rats in the presence or absence of 9L gliosarcoma. Mantel-Cox statistics were used to assess the efficacy of Paclimer at extending survival of tumor-bearing animals compared with control implants. Paclimer implants tagged with [(3)H]paclitaxel were used to measure biodistribution of paclitaxel from the Paclimer implant. RESULTS: Paclimer released paclitaxel at a constant rate for up to 3 months in vitro. In vivo, Paclimer implants placed intracranially in rats released active drug for up to 30 days after implantation and doubled the median survival of rats bearing established 9L gliosarcomas (median survival of paclitaxel-treated animals = 35 days; median survival of control-treated animal = 16 days; P < 0.0001). Active drug was distributed throughout the rat brain based on liquid scintillation counting and TLC. Rats implanted with Paclimer demonstrated no overt signs of neurotoxicity and exhibited local cytopathological changes consistent with exposure to an antimicrotubule agent. CONCLUSIONS: Paclimer extends survival in a rodent model of glioma with minimal morbidity and optimal pharmacokinetics.

In vitro and in vivo degradation studies of a novel linear copolymer of lactide and ethylphosphate.

Poly(lactide-co-ethylphosphate)s, a new class of linear phosphorus-containing copolymers made by chain-extending low-molecular-weight polylactide prepolymers with ethyl dichlorophosphate, were investigated for their in vitro and in vivo degradation mechanism and kinetics. Microspheres made from poly(lactide-co-ethylphosphate) were studied under both accelerated and normal in vitro degradation conditions. Gel permeation chromatography (GPC), 1H- and 31P-NMR, weight loss measurements, and differential scanning calorimetry (DSC) techniques were used to characterize the change of molecular weight (M(w)), chemical composition, and glass transition temperature (T(g)) of the degrading polymers. The results indicated that the copolymers degraded in a two-stage fashion, with cleavage of the phosphate-lactide linkages contributing mostly to the initial more rapid degradation phase and cleavage of the lactide-lactide bonds being responsible for the slower latter stage degradation. The decrease in the copolymer M(w) was accompanied by a continuous mass loss. Results from the accelerated degradation studies confirmed that the copolymers degraded into various monomers of the copolymers, which were non-toxic and biocompatible. A two-stage hydrolysis pathway was thus proposed to explain the degradation behavior of the copolymers. In vivo degradation studies performed in mice demonstrated a good in vitro and in vivo correlation for the degradation rates. In vivo clearance of the polymer was faster and without any lag phase. These copolymers are potentially advantageous for drug delivery and other biomedical applications where rapid clearance of the polymer carrier and repeated dosing capability are essential to the success of the treatment.