Besnard M, Chacun H, Lepêtre-Mouelhi S, Desmaële D, Rousseau B, Laugier C, Recherche Scientifique 8612, Institut Fédératif de Recherche 141, Université Paris XI, Châtenay-Malabry cedex, France

Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine; dFdC) is an anticancer nucleoside analog active against wide variety of solid tumors. However, this compound is rapidly inactivated by enzymatic deamination and can also induce drug resistance. To overcome the above drawbacks, we recently designed a new squalenoyl nanomedicine of dFdC [4-N-trisnorsqualenoyl-gemcitabine (SQdFdC)] by covalently coupling gemcitabine with the 1,1',2-trisnorsqualenic acid; the resultant nanomedicine displayed impressively greater anticancer activity compared with the parent drug in an experimental murine model. In the present study, we report that SQdFdC nanoassemblies triggered controlled and prolonged release of dFdC and displayed considerably greater t(1/2) (approximately 3-fold), mean residence time (approximately 7-fold) compared with the dFdC administered as a free drug in mice. It was also observed that the linkage of gemcitabine to the 1,1',2-trisnorsqualenic acid noticeably delayed the metabolism of dFdC into its inactive difluorodeoxyuridine (dFdU) metabolite, compared with dFdC. Additionally,  ordinary cleanser  of SQdFdC nanoassemblies was considerably lower compared with free dFdC, as indicated by lower radioactivity found in urine and kidneys, in accordance with the plasmatic concentrations of dFdU.

SQdFdC nanoassemblies also underwent considerably higher distribution to the organs of the reticuloendothelial system, such as spleen and liver (p < 05), both after single- or multiple-dose administration schedule. Herein, this paper brings comprehensive pharmacokinetic and biodistribution insights that may explain the previously observed greater efficacy of SQdFdC nanoassemblies Dynamic state of collagen: pathways of collagen degradation in vivo and their possible role in regulation of collagen mass.There is now evidence that collagen turnover in normal tissues can occur at rapid rates. In skin of adult rats, the mean rate lies between 3 and 5%/day, but rates of greater than 10%/day have been reported in some tissues, such as lung and periodontal ligament. The major sites of this degradation are still uncertain. Intracellular degradation, which occurs within minutes of synthesis, may be extensive, but its magnitude varies between tissues.  squalene  may have evolved to allow the adaptive advantages of rapid turnover without compromising the supportive role of fibrillar collagen.

There is now abundant evidence that changes in collagen degradation play an important role in the regulation of collagen mass. Increased breakdown of extracellular collagens may be required whether the mass is increased or decreased. However, preliminary evidence suggests that the degradation of newly synthesized collagen may be up- or down-regulated, depending on the direction of the change in content.The anomalous behavior of collagen peptides on sodium dodecyl sulfate-polyacrylamide gel electrophoresis is due to the low content of The anomalously low mobility of collagen peptides on SDS-gel electrophoresis was investigated, using tadpole skin collagen and bovine Type I, II, and III collagens. The free electrophoretic mobility of alpha 1 chains of collagen was found to be smaller than those of alpha 2 chain and common proteins of similar size, which migrate on SDS-gel according to their molecular weights. The retardation coefficient of collagen peptides was normal. Therefore, the overall SDS-collagen complex may be comparable in size with SDS complexes of common proteins with similar molecular weights.

One characteristic difference of collagen in comparison with common proteins is its low content of hydrophobic amino acid residues. This may account for the low free electrophoretic mobility in SDS of collagen alpha 1 chains, if the SDS-protein complex is of a necklace Inverse relationship between hyaluronan and collagens in development and The extracellular matrix plays a vital role in regulating normal tissue development and function--largely via the specific arrangement of macromolecules such as collagens, proteoglycans, glycosaminoglycans and glycoproteins. Previous reports have concentrated on associations between combinations of collagens/proteoglycans, collagens/glycoproteins and proteoglycans/glycosaminoglycans whilst little information is available on associations between collagens and free glycosaminoglycans. In this review, we discuss possible associations between collagens and the glycosaminoglycan hyaluronan; macromolecules which are known to exhibit changes in amount and composition during development and under pathological conditions. We demonstrate two types of collagen/hyaluronan association in vivo: the first, during the formation of extracellular matrix structures where neither collagens nor hyaluronan are degraded, resulting in the regulation of collagen fibrillogenesis, and the second, involving an inverse correlation between collagen synthesis and hyaluronan degradation and vice versa. We suggest that associations between collagens and hyaluronan play an important role in the initiation and maintenance of angiogenesis and put forward a model of cartilage vascularisation which relies on these associations.[Microscopic colitis and collagenous colitis.