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. We describe a bipartite drug-delivery system that exploits (i) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (ii) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an ␣-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of ␣-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzymeactivated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model.

Background/aims-Carbomers are widely used in products for the treatment of dry eye; however, the polymer gel thins on addition of probes (for example, fluorescein salt) confounding the comparison of products by objective clinical tests such as spectrophotofluorimetry or scintigraphy. A novel method of radiolabelling carbomer gels, with minimum change to their rheology, has permitted the noninvasive evaluation of precorneal residence of the gel in volunteers using gamma scintigraphy. Tc-DTPA labelled saline in 12 volunteers. Results-The addition of the low sodium radiopharmaceutical produced insignificant rheological changes in the gel compared with conventional 99m Tc-DTPA labelling. The residence times on the eye of the gel formulations were significantly greater than that of the saline control. At 8 minutes postdosing, the label levels retained (mean (SD)) on the ocular surface were: saline, 7% (7%); 99m Tc-DTPA gel, 42% (27%); and 99m Tccarbon gel, 42% (20%) of administered dose. There was no diVerence observed in the precorneal distribution between 99m Tc-DTPA solution and particulate markers.Conclusions-These data demonstrate that carbomer based gels significantly extend contact of solutes or suspended solids with the corneal surface. The method of labelling does not significantly change the initial viscosity and is superior to previous methods which have used sodium salts (for example, sodium fluorescein) and therefore underestimate contact time. (Br J Ophthalmol 1998;82:1131-1134 Studies in humans have shown that polymer excipients are eVective in the treatment of dry eye syndrome. The role of the polymer is thought to relate to the ability to moisten the epithelial surface and to provide structure for the aqueous phase of the tear film in a manner analogous to natural mucins. High molecular weight polymers, such as hyaluronic acid, have been shown to slow the turnover of the preocular film.1 2 Application of hyaluronate at 0.3% w/v concentrations caused an increase in tear film thickness within a few seconds of application which was maintained above baseline for over 30 minutes. Until recently, this material has been regarded as being too expensive for commercial development as an artificial tear product, especially as cheaper alternatives exist.Marquardt and Christ compared the residence of a polyacrylic acid (carbomer) based gel with a polyvinyl alcohol based preparation, measuring the fluorescence of the precorneal tear film in healthy volunteers after instillation of the polymer containing sodium fluorescein as a marker. The authors measured tear break up times and conducted Schirmer tests in a small group of patients. Data were obtained which suggested a positive pharmacodynamic eVect up to 6 hours post-dose. 3 However, in the presence of cations, especially sodium or calcium, the viscosity of carbomer gels changes markedly. Unlu and coworkers reported significant rheological changes on incorporation of 0.05% w/v sodium fluorescein (0.05%) and 0.01% w/v disodium edetate. 4 This suggests that...

This study indicates a promising method for the treatment of superficial bladder cancer. Although the mean initial tumor uptake was high, effective therapy of bladder tumors will require an increased retention of the cytotoxic radionuclide in tumor tissue.

The nasal cycle is a well-recognised physiological phenomenon where each side of the nose alternates through phases of congestion and decongestion. Although many physiological properties of the nose alternate with the nasal cycle whether this has any effect on the nasal mucociliary clearance is less clear. As the nose is a potential site for the administration of pharmaceuticals, it is essential that any factors that could affect clearance (and hence absorption) are identified. This study set out to investigate if mucociliary clearance rates differed between the clear and obstructed airway at a morning peak of the nasal cycle in five healthy volunteers with normal nasal anatomy using a dual-radioisotope labelling procedure that allows both sides of the nose to be assessed simultaneously. The clearance of the radiopharmaceutical formulations from the nasal cavity was monitored using gamma scintigraphy and decay-adjusted 50%-clearance times were calculated for each nostril. The ratios of clearance times from the patent nostril when compared to the obstructed nostril were statistically significant (two-tailed t-test; P = 0.039), the mean ratio being 2.5 : 1 (SEM +/- 0.5). It can be concluded that the nasal cycle has a marked effect on the mucociliary clearance patterns of the nose. This may have both theoretical and practical implications for the nasal delivery of drugs.

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