Biodegradable ion-exchange microspheres based on modified polylysines

H.F.M. Cremers, J.P. Lens, L. Seymour, J. Feijen

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Abstract

Poly-L-lysine was synthesized via a triethylamine initiated ring-opening polymerization of Z-L-lysine-N'~-carboxyanhydride, followed by deprotection of the E-amino group. Subsequently the polylysine was sulfamated using a pyridinium-sulfate complex to obtain polymers with varying degrees of sulfamation ranging from 0 to 100%. Cytotoxicity of these materials was tested using tetrazolium metabolism (MTI') assays with B16F10 and P388 cell lines. Cytotoxicity of sulfamated polylysines with a degree of sulfamation of 80% and higher was significantly reduced as compared with the native polylysines. In both cell lines, LDso of the sulfamated materials was higher than 5 mg/ml, which was the highest dose tested. LDso of the native polylysines was lower than 0.1 mg/ml in the case of B16F10 and lower than 0.01 mg/ml in the case of P388 cells. Sulfamated polylysines with a degree of sulfamation of 80% were used to prepare microspheres (SPLMS). The microspheres were stabilized using glutaraldehyde or oxidized dextran as a crosslinking agent. The swelling ratio (defined as V~wollen/Vdr~ed) of the SPLMS in aqueous media decreased with increasing ionic strength and crosslink density. The pH (ranging from 3 to 11) had no influence on the swelling ratio of SPLMS. The maximal swelling ratio was approximately 35 (SPLMS crosslinked with 0.5% glutaraldehyde in distilled water). SPLMS could be loaded with adriamycin up to a payload of 60%, which was not influenced by the crosslinking method. The adriamycin release was controlled by the ionic strength of the release medium: no drug was released in non-ionic medium such as distilled water, while 80% of the drug was released in phosphate buffered saline. This effect of the change in ionic strength could be applied to prepare a microsphere suspension in non-ionic medium such as 5% glucose solution, which does not contain free adriamycin. The drug would only be release after intra-arterial administration of this suspension, due to the presence of the blood.
Original languageEnglish
Pages (from-to)167-179
JournalJournal of controlled release
Volume36
Issue number1-2
DOIs
Publication statusPublished - 1995
Event3rd European Symposium on Controlled Drug Delivery, ESCDD 1994 - Noordwijk aan Zee, Netherlands
Duration: 6 Apr 19948 Apr 1994
Conference number: 3

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