Degradation product cytotoxicity

The data produced to date suggests that if the poly(organo) phosphazene side groups are carefully selected, the degradation products are nontoxic [25, 48, 69]. That the backbone degradation products consist of a benign mixture of phosphates and ammonia is well proven [46]. Phosphates have a well-known metabolic 

Treiser, S. Abramson, R. Langer and J. Kohn in Biomaterials Science, 3 Edition, Eds., B.D. Ratner, 

Biodegradable Polymers in Clinical Use and Clinical Development, Eds., N.K. Abraham J. Domb and A. Ezra, John Wiley Sons, Inc, Hoboken, NJ, USA, 2011. 

Enislidis, S. Pichorner, F. Kainberger and R. Ewers, Journal of Cranio-Maxillofacial Surgery, 1997,25, 6, 316. 

Robello, T.D. Eldridge and M.T. Swanson, Journal of Polymer Science, Part A Polymer Chemistry Edition, 1999, 37, 24, 4570. 

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An example is poly(bis(p-carboxyphenoxy)propane) (PCPP) which has been prepared as a copolymer with various levels of sebacic anhydride (SA). Injection molded samples of poly (anhydride) / dmg mixtures display 2ero-order kinetics in both polymer erosion and dmg release. Degradation of these polymers simply releases the dicarboxyhc acid monomers (54). Preliminary toxicological evaluations showed that the polymers and degradation products had acceptable biocompatibiUty and did not exhibit cytotoxicity or mutagenicity (55). 

Urethane hydrolyzes into an amine, an alcohol, and carbon dioxide. So the possible degradation products of a poly(phosphoester-urethane) are diamines, diols, phosphates, carbon dioxide, and even ureas. Urea is possible because the isocyanate is extremely sensitive to moisture, which would convert the isocyanate to an amino group. One is therefore bound to have traces of diamine in the polymerization that leads to a urea bond in the backbone. We think the cytotoxicity seen in the macrophage functional assay comes from the TDI structure. 

Pro-Oxidant and Cytotoxic Properties of the Degradation Products of Carotenoids.329... 

Pro-Oxidant and Cytotoxic Effects of Carotenoids and Their Degradation Products... 

PRO-OXIDANT AND CYTOTOXIC PROPERTIES OF THE DEGRADATION PRODUCTS OF CAROTENOIDS... 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

PRO-OXIDANT AND CYTOTOXIC EFFECTS OF CAROTENOIDS AND THEIR DEGRADATION PRODUCTS IN CULTURED RPE CELLS... 

It may be speculated that in the previously mentioned study on ARPE-19 cells exposed to lutein of low purity (Kanofsky and Sima, 2006), the apparent cytotoxic effects observed in dark that are exacerbated upon irradiation of lutein-laden cells with blue or green light may have been caused by (some) degradation products of lutein. 

Certainly, the identification of the degradation products responsible for the cytotoxic effects and their metabolic pathways require a thorough elucidation, and a cultured RPE offers a good model for these investigations. 

In recent years it has become apparent that the reaction of NO with superoxide radical is possibly the most likely reaction to occur in vivo. Peroxynitrite is a strong oxidant and the cytotoxicity previously ascribed to NO or superoxide alone may actually be due to their reaction and degradation products. The reactions are shown below. 

Bisphenol A is used as a raw material to make polycarbonate and epoxy adhesives and can coatings. It is also used in flame-retardants, in unsaturated polyesters and in polyacrylate resins. Many foodstuff containers are made of these resins, including containers for oven and microwave cooking. Recent studies have shown that bisphenol type compounds have both mutagenic and cytotoxic properties [84]. Nerin et al. developed a fast screening method based on SPME and HPLC with fluorescence detection suitable for the analysis of several bisphenol derivatives and their degradation products in aqueous canned foods such as tuna, olives and corn [85]. The best results were obtained with carbowax and PDMS/DVB fibers. The detection limits were between 0.7 and 2.4ngmL while RSDs were between 14 and 32%. After the extraction parameters were optimized, the method was applied to... 

Initial biocompatibility studies were conducted on polyanhydrides. As evaluated by mutation assays (29), the degradation products of the polymer were non-mutagenic and non-cytotoxic. Teratogenicity tests were also negative. Growth of mammalian cells in tissue culture was also not affected by these polymers (29). 

Alisamycin (48) is a potent antibiotic isolated from Streptomyces actuosus and it also shows weak antifungal and cytotoxic activity [100]. Its structure was established by Chatterjee etal. [101] using spectroscopic methods and the absolute configuration (4R,5S,6R) was determined using the exciton chirality method and CD studies of degradation products [102]. This is the only member of the family which has been synthesized in racemic form [103]. 

A similar strategy has been followed for the preparation of the naphthoquinone nucleus (118) [202], a precursor of awamycin (119), another ansamycin antibiotic isolated from several Streptomyces species and active against Gram-positive bacteria, protozoa and marine tumors in vivo. The compound is also cytotoxic to Hela cells in vitro [203]. The structure of awamycin (119) has been determined by X-ray analysis [204] and it is structurally similar to damavaricin D (120), a degradation product and biosynthetic precursor of streptovaricin D (108). 

SLN — especially when they are composed of optimized matrix lipid and surfac-tant/stabilizer — are in general well-tolerated carrier systems. In particular, compared with many polymeric particles, they possess a lower cytotoxicity and then-degradation products are of a physiological nature (fatty acids). Based on these facts, exploitation of SLN in delivery systems for various routes and entry of products for the patients is feasible. 

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