Cima "Biocompatibility and biofouling of MEMS drug delivery devices

Abstract The biocompatibility and biofouling of the microfabrication materials for a MEMS drug delivery device have been evaluated. The in vivo inflammatory and wound healing response of MEMS drug delivery component materials, metallic gold, silicon nitride, silicon dioxide, silicon, and SU-8 TM photoresist, were evaluated using the cage implant system. Materials, placed into stainless-steel cages, were implanted subcutaneously in a rodent model. Exudates within the cage were sampled at 4, 7, 14, and 21 days, representative of the stages of the inflammatory response, and leukocyte concentrations (leukocytes/ml) were measured. Overall, the inflammatory responses elicited by these materials were not significantly different than those for the empty cage controls over the duration of the study. The material surface cell density (macrophages or foreign body giant cells, FBGCs), an indicator of in vivo biofouling, was determined by scanning electron microscopy of materials explanted at 4, 7, 14, and 21 days. The adherent cellular density of gold, silicon nitride, silicon dioxide, and SU-8 TM were comparable and statistically less (po0:05) than silicon. These analyses identified the MEMS component materials, gold, silicon nitride, silicon dioxide, SU-8 TM , and silicon as biocompatible, with gold, silicon nitride, silicon dioxide, and SU-8 TM showing reduced biofouling

In vivo release from a drug delivery MEMS device

A drug delivery microelectromechanical systems (MEMS) device was designed to release complex profiles of multiple substances in order to maximize the effectiveness of drug therapies. The device is based on micro-reservoirs etched into a silicon substrate that contain individual doses of drug. Each dose is released by the electrochemical dissolution of the gold membrane that covers the reservoir. The first in vivo operation of this device was reported in this study. Subcutaneous release was demonstrated in rats using two tracer molecules, fluorescein dye and radiolabeled mannitol, and one radiolabeled chemotherapeutic agent, carmustine (BCNU). BCNU was chosen because of the need to improve the direct delivery of chemotherapy to malignant tumors. The spatial profile of fluorescein dye release from the drug delivery device was evaluated by fluorimetry, the temporal profile of C labeled mannitol release was evaluated by liquid scintillation counting, and the temporal profile of C labeled BCNU release was evaluated by accelerator mass spectrometry (AMS). Release profiles obtained from injected controls were compared with those from activated devices. The in vivo dye release results showed high concentration of fluorescein in the flank tissue surrounding the devices 1 h after activation. The C labeled mannitol released from the drug delivery devices was rapidly cleared (1 day) from the rat urine. In vivo release of activated devices showed slightly slower kinetics than the injected and in vitro controls, and the time to reach the steady-state C concentration was on the order of 1 h. All these results demonstrated the capability of this drug delivery device to achieve localized delivery of various compounds with well-defined temporal profiles

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates

Lomibuvir (<b>1</b>) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound <b>2</b>, a molecule with comparable potency and an improved physicochemical profile relative to <b>1</b>. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by <b>12f</b>, provided 3–5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure–activity relationships, <i>in vitro</i> ADME characterization, and <i>in vivo</i> evaluation of this novel series are discussed

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (<b>1</b>) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound <b>23</b>, a compound with comparable potency and improved physicochemical properties

Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (<b>1</b>) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound <b>23</b>, a compound with comparable potency and improved physicochemical properties