Degradative-release as a function of drug structure from LDI-glycerol polyurethanes

Abstract

Naphthalene analogs with differing hydroxyl and amine functionality were incorporated into degradable polyurethane foams synthesized from lysine diisocyanate and glycerol to determine if chemical structure can be used in controlled release systems. Excitation and emission spectra of the various naphthalene analogs in aqueous solution were collected to ensure they were capable of being quantitatively detected in aqueous solution at low concentrations. The fluorescence stability of the compounds was assessed over a 2-week period at 70 • C; the analogs were all found to exhibit signal decay to varying degrees. Polyurethane foam materials containing the naphthalene analogs were synthesized and examined via scanning electron microscopy; incorporating naphthalene ligands did not grossly alter the polyurethane morphology. The analog distribution was then assessed via fluorescence microscopy, and the naphthalene analogs were found evenly dispersed throughout the polyurethane materials. Foam samples containing various analogs were then incubated in PBS buffer solution (pH 7.4) at 4, 22, 37 and 70 • C for 11-weeks. Temperature dependent release of naphthalene analogs from the polyurethane foams was found to depend upon the functional groups present on the naphthalene analog. These results suggest that the chemical structure of a drug plays a unique role in controlling release from hydrolytically degradable drug delivery systems.

Injectable foams for regenerative medicine

“…While biodegradable PUR foams have been synthesized from aliphatic polyisocyanates, 85 lysine-derived polyisocyanates have shown the greatest promise for injectable and settable systems. 78,79,81,83,[86][87][88][89] Reactive PUR scaffolds prepared from lysine-derived polyisocyanates, including lysine methyl ester diisocyanate (LDI) and lysine triisocyanate (LTI), and tertiary amine catalysts, have been reported to induce a minimal inflammatory response on host tissue in both cutaneous and bone defects in vivo. 79,83,86,89 Furthermore, in vitro cytotoxicity testing of the leachates from the reactive PUR has shown that the reactive PUR components are nontoxic.…”

“…The diffusion- and degradation-controlled drug delivery strategies are summarized in Figure 10. Fluorescent images obtained using a DAPI filter (Figure 10A) show uniform distribution of naphthalene compounds in an LDI-glycerol PUR foam, as evidenced by the consistent blue color throughout the material 88 . In contrast, SEM (Figure 10B) and confocal (Figure 10C) images of an LTI-polyester foam augmented with FITC-labeled BSA as a labile powder show discrete BSA-FITC particles distributed throughout the scaffold.…”

“…Injectable lysine-derived PUR scaffolds have also been investigated as drug delivery systems to support both diffusion-controlled release of biologics added as labile powders 95-98 as well as degradation-controlled release of drugs covalently bound to the polymer 87, 88, 99-101 . The diffusion- and degradation-controlled drug delivery strategies are summarized in Figure 10.…”

“…Release of other biologics, such as nanoparticles delivering siRNA 98 , added to injectable PUR bone grafts as a labile powder has also been reported to be diffusion-controlled, with sustained release for up to 3 – 8 weeks. In an alternative approach, drugs with active hydrogen groups (e.g., primary hydroxyl groups and amines), such as ascorbic acid 103 , naphthalene compounds 88 , and the anti-tumor drug 7- tert -butyldimethylsilyl-10-hydroxy-camptothecin (DB-67) 101 , were dissolved in the reactive PUR prior to injection and subsequently released in biologically active form by degradation of the polymer. Recent studies have reported that the release kinetics can be controlled by the composition of the drug 88 , the choice of catalyst 87 , or the addition of ionic ligands 99 , which offer greater tunability compared to diffusion-controlled release.…”

“…In an alternative approach, drugs with active hydrogen groups (e.g., primary hydroxyl groups and amines), such as ascorbic acid 103 , naphthalene compounds 88 , and the anti-tumor drug 7- tert -butyldimethylsilyl-10-hydroxy-camptothecin (DB-67) 101 , were dissolved in the reactive PUR prior to injection and subsequently released in biologically active form by degradation of the polymer. Recent studies have reported that the release kinetics can be controlled by the composition of the drug 88 , the choice of catalyst 87 , or the addition of ionic ligands 99 , which offer greater tunability compared to diffusion-controlled release. Potential advantages of covalently binding drugs to PUR scaffolds include the ability to increase drug loading and control release to achieve therapeutically relevant doses.…”