Poly(N5-hydroxyalkylglutamines). IV. Enzymatic degradation of n5-(2-hydroxyethyl)-L-glutamine homopolymers and copolymers

Pytela, Jindřich; Saudek, Vladimı́r; Drobník, J.; Rypáček, František

doi:10.1016/0168-3659(89)90014-x

Cited by 45 publications

(36 citation statements)

References 13 publications

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“…The results are presented in Figure 2. During the first 10 h of incubation a strong increase in free amine concentration was observed for PHEGDODASuc and pGlu, demonstrating that both relatively low molecular weight polymers are degraded by papain, as previously reported for their high molecular weight counterparts (14)(15)(16)(17)(18)(19)(20)(21)32). Figure 2 also shows that a plateau value in amine concentration was obtained after 48-72 h. As mentioned, papain was still active after 72 h indicating that the degradation process did not stop due to inactivity of the enzyme.…”

Section: Resultssupporting

confidence: 80%

Enzymatic Degradation of Liposome-Grafted Poly(hydroxyethyl l-glutamine)

et al. 2005

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Liposomes coated with poly(hydroxyethyl L-glutamine) (PHEG) show prolonged circulation times and biodistribution patterns comparable to PEG-coated liposomes. While PEG is a nondegradable polymer, PHEG is expected to be hydrolyzed by proteases. In this study the enzymatic degradability of PHEG both in its free form and grafted onto liposomes was investigated, using the proteases papain, pronase E, and cathepsin B. Enzymatic action was monitored with a ninhydrin assay, which quantifies amine groups formed due to hydrolysis of amide bonds, and the degradation products were characterized by MALDI-ToF mass spectrometry. PHEG, both in its free form and when grafted onto liposomes, showed degradation into low molecular weight peptides by the enzymes. Thus, we present a polymer-coated long-circulating liposome with an enzymatically degradable coating polymer, avoiding the risk of cellular accumulation.

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Section: Resultssupporting

confidence: 80%

Enzymatic Degradation of Liposome-Grafted Poly(hydroxyethyl l-glutamine)

et al. 2005

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“…48 Degradation of poly(HEGln) by papain was investigated before this study. 37,[49][50][51] Dickinson and coworkers reported that the degradation of poly(HEGln) by papain generated products ranging from tetrapeptides to nonapeptides. 37,51 Yaacobi et al proposed that the degradation followed a modified MichaelisMenten model and suggested that the reaction stopped when the degradation fragments were tetrapeptides.…”

Section: Discussionmentioning

confidence: 98%

“…Poly(HEGln) is resistant to cleavage by chymotrypsin as reported in the literature. 49 The degradation of poly(HEGln, Phe) and poly(HEGln, Leu) by chymotrypsin generates mainly dipeptides, tripeptides, and tetrapeptides. The difference between the degradation of these two substrates is probably due to the different sequential distribution of comonomer residues along the polymer chain.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal degradability of poly(?-amino acids)

Chiu

Kopečková

Deshmane

et al. 1997

J. Biomed. Mater. Res.

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The lysosomal degradability of poly(alpha-amino acids) based on poly(L-glutamic acid) and its derivatives/copolymers was evaluated to gain insight into the subcellular fate of the macromolecules as water soluble polymeric drug carriers. The results indicate that both the incorporation of hydrophobic comonomers and modification of the carboxylic groups of glutamic acid side chains with hydroxyalkylamine increase the lysosomal degradability of the copolymers. Decreased lysosomal degradability of L-glutamic acid copolymers containing tripeptides terminated in p-nitroanilide (drug model) in the side chains confirmed that drug conjugation alters the degradation pattern of the polymeric carriers. The percentages of the enzymatic release of p-nitroaniline from its polymeric complex with time is relatively independent of the contents of the tripeptidyl p-nitroanilides attached to the polymeric conjugates. Determination of the degradation products by electrospray mass spectroscopy showed that no fragments less than 10(3) D were generated by lysosomal enzymes, whereas the main degradation products by papain and chymotrypsin were tripeptides and tetrapeptides. The conclusions derived from these data strongly suggest that these macromolecules, if used as lysosomotropic drug carriers, may accumulate in the lysosomes and limit their usefulness in some applications.

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“…Dabei wurde gezeigt, dass die Poly(aminosäuren) sowohl in Oligomere mit vier bis neun Wiederholungseinheiten als auch in ihre Monomere zerlegt werden. [96,114] . [96,[115][116][117] Allerdings zeigten PHEG und PHEA erhöhte SC5b-9-Werte (SC5b-9 = Komplementfaktor, der bei der Hydrolyse von C3 auftritt) in ELISA-Assays, was auf eine Aktivierung des Komplementsystems schließen lässt.…”

Section: Potenzielle Alternativen Für Pegunclassified

Anwendung von Poly(ethylenglycol) beim Wirkstoff‐Transport: Vorteile, Nachteile und Alternativen

et al. 2010

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Im stetig wachsenden Feld der Polymer‐basierten Wirkstoff‐Transport‐Systeme gilt Poly(ethylenglycol) (PEG) als der Goldstandard für Stealth‐Polymere. Welche Eigenschaften PEG aufweist, die diese herausragende Stellung rechtfertigen, soll in diesem Aufsatz diskutiert werden. Die ersten PEGylierten Produkte erschienen bereits vor 20 Jahren auf dem Markt. Seither konnten viele Erkenntnisse in klinischen Untersuchungen gewonnen werden, allerdings wurden dabei nicht nur Vorteile festgestellt, sondern auch mögliche Nebenwirkungen und Komplikationen bei der Anwendung aufgedeckt. Diese möglichen Nachteile, die eine tiefergehende Untersuchung erfordern, können in folgende Kategorien unterteilt werden: Hypersensitivität, Veränderungen der Pharmakokinetik, toxische Nebenprodukte sowie ein Abbauparadoxon, das aus der Etherstruktur resultiert: Einerseits kann das Polymer relativ einfach unter mechanischer Belastung abgebaut werden, andererseits wird jedoch ein biologischer Abbau verhindert, was bei In‐vivo‐Anwendungen zur Anreicherung im Körper führen kann. Der Aufsatz diskutiert diese möglichen Nachteile und stellt alternative Polymere vor.

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Poly(N5-hydroxyalkylglutamines). IV. Enzymatic degradation of n5-(2-hydroxyethyl)-L-glutamine homopolymers and copolymers

Cited by 45 publications

References 13 publications

Enzymatic Degradation of Liposome-Grafted Poly(hydroxyethyl l-glutamine)

Enzymatic Degradation of Liposome-Grafted Poly(hydroxyethyl l-glutamine)

Lysosomal degradability of poly(?-amino acids)

Anwendung von Poly(ethylenglycol) beim Wirkstoff‐Transport: Vorteile, Nachteile und Alternativen

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