Fluorocopolymer-coated nitinol self-expanding paclitaxel-eluting stent: pharmacokinetics and vascular biology responses in a porcine iliofemoral model.

AIMS: Our aim was to evaluate arterial responses to paclitaxel and a novel fluorocopolymer-coated nitinol low-dose paclitaxel-eluting stent (FP-PES). METHODS AND RESULTS: Human smooth muscle cell (SMC) migration was assessed after exposure to paclitaxel in vitro. For pharmacokinetics and vascular response, FP-PES or bare metal stents (BMS) were implanted in porcine iliofemoral arteries. Paclitaxel significantly inhibited human coronary and femoral artery SMC migration at doses as low as 1 pM. Inhibition was significantly greater for femoral compared with coronary artery SMCs from 1 pM to 1 µM. Pharmacokinetics showed consistent paclitaxel release from FP-PES over the study duration. The peak arterial wall paclitaxel level was 3.7 ng/mg at 10 days, with levels decreasing to 50% of peak at 60 days and 10% at 180 days. Paclitaxel was not detected in blood or remote organs. Arteriogram and histomorphometry analyses showed FP-PES significantly inhibits neointimal proliferation versus BMS at 30 and 90 days. Re-endothelialisation scores were not different between groups. CONCLUSIONS: Paclitaxel affected femoral artery SMC migration at lower concentrations and to a greater degree than it did coronary artery SMCs. The novel FP-PES used in this preclinical study demonstrated a vascular healing response similar to BMS, while significantly inhibiting neointimal formation up to 90 days.

Chemopreventive effect of aerosolized polyphenon E on lung tumorigenesis in A/J mice.

Effective chemoprevention of lung cancer in high-risk patients through the administration of pharmacologic or nutritional agents is urgently needed. Aerosol inhalation can deliver chemopreventive agents directly to the respiratory tract to inhibit the tumorigenic process. In this study, polyphenon E (PolyE) and (-)-epigallocatechin-3-gallate (EGCG) were administered by aerosol delivery to A/J mice beginning 2 weeks after carcinogen treatment and continuing daily by inhalation throughout the remainder of the study (20 weeks). PolyE decreased tumor load by approximately 59%. However, EGCG, both at the same dose and at a higher dose, failed to inhibit lung carcinogenesis. These results indicate that aerosol delivery of PolyE, but not EGCG, may be a useful chemopreventive protocol in subjects at high risk for lung cancer.

Deposition of aerosolized particles in the maxillary sinuses before and after endoscopic sinus surgery.

BACKGROUND: Recent studies suggest that topical therapy is beneficial in many conditions underlying chronic sinusitis. Current literature has documented low aerosolized particle deposition efficiency into the paranasal sinuses. Mathematical modeling suggests that three factors influence the deposition efficiency: particle size, pressure gradient, and size of the sinus ostium. Ostium size is the most dominant factor. Therefore, we sought to determine if maxillary antrostomy and ethmoidectomy would increase the deposition efficiency. METHODS: Five cadavers underwent pre- and postoperative scintigraphy after administration of aerosolized Tc-99M. Images were obtained with a gamma-camera and regions of interest (ROIs) were drawn around the maxillary sinuses. Counts per minute in the pre- and postoperative ROIs were then compared using the paired t-test. RESULTS: Results indicated a significant increase in deposition of radioactivity in the maxillary sinuses in the postoperative state (p < 0.01). CONCLUSION: Topical therapy for chronic sinusitis may be more feasible in the postoperative population.

Pharmacokinetics of 5-fluorouracil in the hamster following inhalation delivery of lipid-coated nanoparticles.

The inhalation delivery of 5-fluorouracil (5-FU) in lipid-coated nanoparticles (LNPs) to hamsters was evaluated to determine the feasibility for use in lung cancer chemotherapy. The inhaled dose, 30 mg LNPs/kg body weight (1.5 mg/kg 5-FU), was delivered over an 8-min interval. Fluorescein isothiocyanate dextran (FITC-dextran) was included within the LNPs to provide an estimate of the particle concentration. The concentration of FITC-dextran and total 5-FU (released and LNP-associated) was determined as a function of time in the lung, trachea, larynx, esophagus, and serum. Concentrations of 5-FU and FITC-dextran were initially high in the trachea, larynx, and esophagus, and lower in the lung. Within 24 h, greater than 99% of the LNPs were cleared from the respiratory tract and total 5-FU concentrations mirrored the LNP concentration. An eight-compartment pharmacokinetic model was used to describe the observed trends in concentrations of LNPs and total 5-FU and to estimate the released 5-FU concentration in the above tissues. From this analysis, effective local targeting as well as sustained efficacious concentrations of 5-FU in the expected tumor sites were demonstrated.

Development of a respirable, sustained release microcarrier for 5-fluorouracil II: In vitro and in vivo optimization of lipid coated nanoparticles.

The release rate of 5-fluorouracil (5-FU) from lipid-coated nanoparticles (LNPs) was determined to develop a respirable delivery system for use as adjuvant (postsurgery) therapy for lung cancer. LNPs were prepared by spray drying, and the in vitro release was measured by microdialysis. The composition of the core and shell affected the release rate. Increasing the core diameter at constant shell thickness and increasing shell thickness at constant core diameter reduced the release rate, suggesting that the lipid shell is the rate limiting step for the release of 5-FU. A model consisting of a sequential zero-order/first-order dependence on time from polydispersed cores within polydispersed shells was developed to describe the release. Based on studies of the effect of geometry of the layered particles, the optimal formulation was identified as a 600-nm diameter 5-FU/poly-(glutamic acid) core with a 200-nm thick tripalmitin/cetyl alcohol shell. This system is readily aerosolized by ultrasonic atomization, which did not change the release properties. Preliminary instillation and inhalation delivery studies to the hamster resulted in lung levels of the particles and 5-FU that were near the desired values. Through this effort, a sustained-release, respirable delivery system for adjuvant therapy of lung cancer in humans may ultimately be realized.

Development of a respirable, sustained release microcarrier for 5-fluorouracil I: In vitro assessment of liposomes, microspheres, and lipid coated nanoparticles.

The release rate of 5-fluorouracil (5-FU) from liposomes, microspheres, and lipid-coated nanoparticles (LNPs) was determined by microdialysis to investigate their use as a respirable delivery system for adjuvant (postsurgery) therapy of lung cancer. 5-FU was incorporated into liposomes using thin film hydration and into microspheres and LNPs by spray drying. Primary particle size distributions were measured by dynamic light scattering. Liposomes released 5-FU in 4-10 h (k(1) = 0.44-2.31/h, first-order release model). Extruded vesicles with diameters less than one micron released 5-FU more quickly than nonextruded vesicles. With poly-(lactide) (PLA) and Poly-(lactide-co-glycolide) (PLGA) microspheres, slower release rates were observed (k(1) = 0.067-0.202/h). Increasing the lactide:glycolide ratio (50:50-100:0) resulted in a progressive decrease in the release rate of 5-FU. poly-(lactide-co-caprolactone) (PLCL) microspheres released 5-FU more rapidly compared to PLGA systems (k(1) = 0.254-0.259/h). LNPs formulated with polymeric core excipients had lower release rates compared to monomeric excipients (k(1) = 0.043-0.105/h vs. k(1) = 0.192-0.345/h). Changing the lipid chain length of the shell lipid components had a relatively minor effect (k(1) = 0.043-0.129/h). Overall, these systems yielded a wide range of delivery durations that may be suitable for use as an inhalation delivery system for adjuvant therapy of lung cancer.