Synthesis and Characterization of Novel Polyurethane Drug Delivery Systems

Selective delivery of drugs to localized regions of tissue within the body is a complex problem, representing one path through which the efficacy of many pharmaceutical compounds can be enhanced. Many pharmaceutical compounds show excellent activity in vitro, but their uses are severely limited in vivo. Unstable active conformations, limited membrane diffusion, rapid metabolism and/or clearance, decreased solubility, and dose-limiting systemic toxicity are just a few areas in which potential problems exist, halting drug development. Compounds exist possessing ideal pharmacologic activity for treating specific disease states, but they are simply unable to be delivered in adequate quantities or in the proper active conformation to the target site in the body. The following dissertation details the synthesis, characterization, and performance of a series of polyurethane drug delivery systems based on amino acids and the simple carbohydrates. The materials were synthesized from lysine diisocyanate (LDI) and glycerol with the aid of various tertiary amine and organometallic urethane catalysts. Candidate drugs were incorporated into the materials by way of labile urethane and urea linkages; subsequent drug release relied on the passive hydrolysis of the tethering bonds. Drug release from the materials correlated to material morphology, urethane catalyst, and chemical functionality of the incorporated drug. A single-phase polyurethane material was designed, synthesized, and shown capable of simultaneously releasing multiple pharmacologic agents at different rates. Finally, naturally occurring ionic ligands were incorporated into the LDI-glycerol polyurethanes to alter their swelling characteristics and release kinetics. This endeavor has resulted in the formulation of a series of polyurethane materials, capable of long-term controlled release of pharmacologic agents within the body. The structure-function relationships elucidated provide key design criteria, which can ultimately be used to develop such advanced degradable polyurethane materials

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

International audienceNaphthalene 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

Incorporation of ionic ligands accelerates drug release from LDI–glycerol polyurethanes

International audienceThis study seeks to determine the effect of ionic ligands on the drug delivery characteristics of biodegradable polyurethane materials synthesized from lysine diisocyanate (LDI) and glycerol. Two naturally occurring, structurally related ionic species, choline chloride (CC) and isethionic acid (ISE), along with 3,3-dimethyl-butanol (DMB), their neutral carbon analog, were covalently incorporated into LDI-glycerol polyurethane materials. Selected organometallic and tertiary amine catalysts were used to fashion films and foams, respectively. The potent anticancer compound DB-67, a fluorescent camptothecin derivative, was also covalently linked to the polyurethane constructs. It was first determined that the sulfonate functional group on ISE does not react to a significant degree with isocyanate. The morphological characteristics of the polyurethane films and foams were assessed via scanning electron microscopy, showing significant differences related to the ionic ligands. The ionic materials displayed increased swelling in aqueous media over the neutral control materials. Differences in the distribution of DB-67 throughout the films and foams were then detected by fluorescence microscopy. The drug delivery characteristics of the materials were then evaluated in vitro, revealing accelerated release from ionic materials. The results of this study demonstrate the unique effects that incorporation of ionic ligands into LDI-glycerol polyurethanes have on the morphology and drug distribution of the materials. These differences have a significant impact on the drug delivery characteristics of the materials, and this information should prove useful in the design and synthesis of biodegradable controlled release systems

Catalyst-dependent drug loading of LDI–glycerol polyurethane foams leads to differing controlled release profiles

International audienceThe purpose of the present study was to develop biodegradable and biocompatible polyurethane foams based on lysine diisocyanate (LDI) and glycerol to be used as drug-delivery systems for the controlled release of 7-tert-butyldimethylsilyl-10-hydroxy-camptothecin (DB-67). The impact of urethane catalysts on cellular proliferation was assessed in an attempt to enhance the biocompatibility of our polyurethane materials. DB-67, a potent camptothecin analog, was then incorporated into LDI-glycerol polyurethane foams with two different amine urethane catalysts: 1,4-diazobicyclo[2.2.2]-octane (DABCO) and 4,4'-(oxydi-2,1-ethane-diyl)bismorpholine (DMDEE). The material morphologies of the polyurethane foams were analyzed via scanning electron microscopy, and DB-67 distribution was assessed by way of fluorescence microscopy. Both foam morphology and drug distribution were found to correlate to the amine catalyst used. Hydrolytic release rates of DB-67 from the polyurethane foams were catalyst dependent and also demonstrated greater drug loads being released at higher temperatures. The foams were capable of delivering therapeutic concentrations of DB-67 in vitro over an 11week test period. Cellular proliferation assays demonstrate that empty LDI-glycerol foams did not significantly alter the growth of malignant human glioma cell lines (P<0.05). DB-67 loaded LDI-glycerol polyurethane foams were found to inhibit cellular proliferation by at least 75% in all the malignant glioma cell lines tested (P<1.0x10(-8)). These results clearly demonstrate the long-term, catalyst-dependent release of DB-67 from LDI-glycerol polyurethane foams, indicating their potential for use in implantable drug-delivery devices

LDI–glycerol polyurethane implants exhibit controlled release of DB-67 and anti-tumor activity in vitro against malignant gliomas

International audienceThe purpose of the present study was to develop a biodegradable and biocompatible polyurethane drug delivery system based on lysine diisocyanate (LDI) and glycerol for the controlled release of 7-tert-butyldimethylsilyl-10-hydroxy-camptothecin (DB-67). DB-67 has yet to be implemented in any clinical therapies due to the inability to delivered it in sufficient quantities to impact tumor growth and disease progression. To remedy this, DB-67 was covalently incorporated into our delivery system by way of an organometallic urethane catalyst and was found to be dispersed evenly throughout the LDI-glycerol polyurethane discs. Scanning electron micrographs indicate that the LDI-glycerol discs are uniform and possess a pore distribution typical of the non-solvent casting technique used to prepare them. The release rates of DB-67 from the LDI-glycerol discs were found to vary with both time and temperature and were shown capable of delivering therapeutic concentrations of DB-67 in vitro. Cellular proliferation assays demonstrate that empty LDI-glycerol discs alone do not significantly alter the growth of malignant human glioma cell lines (U87, T98G, LN229 and SG388). DB-67-loaded LDI-glycerol polyurethane discs were found to inhibit cellular proliferation by 50% on average in all the malignant glioma cell lines tested. These results clearly demonstrate the long-term, slow release of DB-67 from LDI-glycerol polyurethane discs and their potential for postoperative intracranial chemotherapy of cancers

Pediatric Upper Extremity Replantation: Courage in the Face of a Life-altering Injury

Background:. Pediatric plastic surgeons perform reconstructive surgeries for various congenital, oncologic, and traumatic injuries. Methods:. Our Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC) Plastic Surgery team was tasked to care for a young man who suffered a proximal humeral amputation of his dominant upper extremity. Results:. A multidisciplinary team collaborated throughout his entire acute care and postoperative course, guiding treatment and care in effort to maximize function of his replanted extremity. Conclusions:. This case report details the patient’s unique journey and highlights his determination and courage to return back to a normal life

Delivery of adipose-derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration

INTRODUCTION Peripheral nerve damage is associated with high long-term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose-derived stem cells (ASC) represents a promising therapeutic modality. METHODS Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical-sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. RESULTS On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. DISCUSSION Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58: 251-260, 2018