https://cmapspublic3.ihmc.us/rid=1266358861321_2027852911_13457/Wound%20Healing%20Dressings%20and%20Drug%20Delivery%20Systems.pdf

Wound healing dressings and drug delivery systems: a review.

Enzymes inside lipid vesicles: preparation, reactivity and applications.

Chemical modifications of hyaluronic acid for the synthesis of derivatives for a broad range of biomedical applications

The paradigm of using nanoparticulate pharmaceutical carriers has been well established over the past decade, both in pharmaceutical research and in the clinical setting. Drug carriers are expected to stay in the blood for long time, accumulate in pathological sites with affected and leaky vasculature (tumors, inflammations, and infarcted areas) via the enhanced permeability and retention (EPR) effect, and facilitate targeted delivery of specific ligand-modified drugs and drug carriers into poorly accessible areas. Among various approaches to specifically target drug-loaded carrier systems to required pathological sites in the body, two seem to be most advanced – passive (EPR effect-mediated) targeting, based on the longevity of the pharmaceutical carrier in the blood and its accumulation in pathological sites with compromised vasculature, and active targeting, based on the attachment of specific ligands to the surface of pharmaceutical carriers to recognize and bind pathological cells. Here, we will consider and discuss these two targeting approaches using tumor targeting as an example.

Passive and active drug targeting: drug delivery to tumors as an example.

The complex system involved in the synthesis, degradation and binding of the high molecular weight glycosaminoglycan hyaluronic acid (hyaluronan or HA) provides a variety of structures that can be exploited for targeted cancer therapy. In many cancers of epithelial origin there is an upregulation of CD44, a receptor that binds HA. In other cancers, HA in the tumor matrix is overexpressed. Both CD44 on cancer cells and HA in the matrix have been targets for anticancer therapy. Even though CD44 is expressed in normal epithelial cells and HA is part of the matrix of normal tissues, selective targeting to cancer is possible. This is because macromolecular carriers predominantly extravasate into the tumor and not normal tissue; thus CD44-HA targeted carriers administered intravenously localize preferentially into tumors. Anti-CD44 antibodies have been used in patients to deliver radioisotopes or mertansine for treatment of CD44 expressing tumors. In early phase clinical trials, patients with breast or head and neck tumors treated with anti-CD44 conjugates experienced stabilized disease. A dose-limiting toxicity was associated with distribution of the antibody-drug conjugate to the skin, a site in the body with a high level of CD44. HA has been used as a drug carrier and a ligand on liposomes or nanoparticles to target drugs to CD44 overexpressing cells. Drugs can be attached to HA via the carboxylate on the glucuronic acid residue, the hydroxyl on the N-acetylglucosamine or the reducing end which are located on a repeating disaccharide. Drugs delivered in HA-modified liposomes exhibited excellent antitumor activity both in vitro and in murine tumor models. The HA matrix is also a potential target for anticancer therapies. By manipulating the interaction of HA with cell surface receptors, either by degrading it with hyaluronidase or by interfering with CD44-HA interactions using soluble CD44 proteins, tumor progression was blocked. Finally, cytotoxic drugs or prodrug converting enzymes can be attached to the HA matrix to generate a cytotoxic fence around the tumor. This review describes how the complex interplay among cancer biology, the CD44-HA interaction, drug carriers and drug targeting has been used to improve anticancer therapies. As these approaches evolve, they hold forth the prospect of significantly improved targeted anticancer treatments.

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Anticancer therapeutics: targeting macromolecules and nanocarriers to hyaluronan or CD44, a hyaluronan receptor.

Molecular and Cellular Studies of Hyaluronic Acid-Modified Liposomes as Bioadhesive Carriers for Topical Drug Delivery in Wound Healing

The mutagenicity of thiol (SH)-containing compounds was tested in Salmonella typhimurium TA102 in the liquid preincubation method. Cysteinyl-glycine (CG), cysteine ethyl ester (CEE), l - and d -penicillamine (PA), cysteine (Cys) and glutathione (GSH) were mutagenic to strain TA102 without metabolic activation. On a molar basis, CG was the most potent mutagen. The mutagenicity of the remaining compounds decreased in the order specified above. The mutagenic response of each thiol-containing compound was a function of the p K a of the thiol group and the pH of the preincubation mixture. This indicates that a thiolate anion, rather than a free thiol, is required for mutagenesis.

Effect of pH on mutagenesis by thiols in Salmonella typhimurium TA102

Lipsome-formulated enzymes for organophosphate scavenging: Butyrylcholinesterase and Demeton-S

Exogenous cholinesterases have the potential to take part in defence against organophosphate toxins, by acting as scavenger systems. Postulating that formulation in liposomes could enhance the toxin-scavenging potential of these enzymes, we have initiated studies of such formulations and are reporting here our first steps, exploring butyrylcholinesterase (BChE) in multilamellar liposomes composed of phosphatidylcholine. We started by developing an essential research tool: a multisample, sensitive and rapid enzyme-activity assay, based on the Ellman reaction, that could be performed directly on liposome-containing samples. Using an ELISA reader equipped to follow time-dependant absorbency changes, 10 min sufficed to assay 96 samples simultaneously. Next, several key properties of liposome-formulated BChE were explored and the major findings were: (i) the encapsulated enzyme was found to retain its activity. (ii) Enzyme activity was found to increase (at constant enzyme concentration) in the presence of the lipid, in a lipid-concentration-dependant manner. Through data analysis it was possible to attribute this effect to changes in k(cat). (iii) Good, reproducible, encapsulation efficiencies (for macromolecules) in the range of 30% were obtained at liposome concentrations of 100 mM lipid. (iv) Free BChE was completely susceptible to proteolysis under conditions mimicking enzymically-hostile biological environments, whereas > or = 60% of the liposome-formulated BChE was protected, found to be inaccessible to the proteolytic enzymes. (v) Short-term exposures of free and liposome-encapsulated BChE to the inhibitor paraoxon, generated significant losses in enzyme activity. Residual activities of both BChE formulations dropped considerably over the paraoxon concentration range of 0.02-0.11 microM, down to 3 and 11% for free and liposome-encapsulated enzyme respectively. These data are a clear indication that the encapsulated BChE was accessible to the inhibitor, indicating that such liposomal formulations have the potential to perform as the desired scavenger systems.

Butyrylcholinesterase formulated in liposomes.

This is the first study to describe a series of 13 patients with medullary tegmental cap dysplasia. The cap has different shapes: distinct in Joubert-Boltshauser syndrome and fibrodysplasia ossificans progressive. BACKGROUND AND PURPOSE: Medullary tegmental cap dysplasia is a rare brainstem malformation, first described and defined by James Barkovich in his book Pediatric Neuroimaging from 2005 as an anomalous mass protruding from the posterior medullary surface. We describe the neuroimaging, clinical, postmortem, and genetic findings defining this unique malformation. MATERIALS AND METHODS: This is a multicenter, international, retrospective study. We assessed the patients’ medical records, prenatal ultrasounds, MR images, genetic findings, and postmortem results. We reviewed the medical literature for all studies depicting medullary malformations and evaluated cases in which a dorsal medullary protuberance was described. RESULTS: We collected 13 patients: 3 fetuses and 10 children. The medullary caps had multiple characteristics. Associated brain findings were a rotated position of the medulla, a small and flat pons, cerebellar anomalies, a molar tooth sign, and agenesis of the corpus callosum. Systemic findings included the following: polydactyly, hallux valgus, large ears, and coarse facies. Postmortem analysis in 3 patients revealed that the cap contained either neurons or white matter tracts. We found 8 publications describing a dorsal medullary protuberance in 27 patients. The syndromic diagnosis was Joubert-Boltshauser syndrome in 11 and fibrodysplasia ossificans progressiva in 14 patients. CONCLUSIONS: This is the first study to describe a series of 13 patients with medullary tegmental cap dysplasia. The cap has different shapes: distinct in Joubert-Boltshauser syndrome and fibrodysplasia ossificans progressive. Due to the variations in the clinical, imaging, and postmortem findings, we conclude that there are multiple etiologies and pathophysiology. We suggest that in some patients, the pathophysiology might be abnormal axonal guidance.

Aya Arad

Papers

Molecular and Cellular Studies of Hyaluronic Acid-Modified Liposomes as Bioadhesive Carriers for Topical Drug Delivery in Wound Healing

Effect of pH on mutagenesis by thiols in Salmonella typhimurium TA102

Lipsome-formulated enzymes for organophosphate scavenging: Butyrylcholinesterase and Demeton-S

Butyrylcholinesterase formulated in liposomes.

Medullary Tegmental Cap Dysplasia: Fetal and Postnatal Presentations of a Unique Brainstem Malformation