Thermosensitive and biodegradable polymeric micelles with transient stability.
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Biocompatible Materials↗
Biomedical subjects
C F van Nostrum
Publications and source records attributed to C F van Nostrum.
Biodegradable dextran hydrogels crosslinked by stereocomplex formation for the controlled release of pharmaceutical proteins.
Hydrogels are based on hydrophilic polymers, which are crosslinked to prevent dissolution in water. Because hydrogels can contain large amounts of water, they are interesting devices for the delivery of proteins. In this contribution a biodegradable dextran hydrogel is described which is based on physical interactions and is particularly suitable for the controlled delivery of pharmaceutically active proteins. The unique feature of our system is that the preparation of the hydrogels takes place in an all-aqueous solution, by which the use of organic solvents is avoided. Furthermore, chemical crosslinking agents are not needed to create the hydrogels, since crosslinking is established physically by stereocomplex formation between enantiomeric oligomeric lactic acid chains. The hydrogel is simply obtained after mixing aqueous solutions of dextran(l)-lactate and dextran(d)-lactate. In this contribution, the formation of the hydrogels as well as their protein release properties and degradation behavior are discussed.
Biocompatible Materials↗
Water-soluble biodegradable cationic polyphosphazenes for gene delivery.
Polyphosphazenes bearing cationic moieties were synthesized from poly(dichloro)phosphazene, which in turn was obtained by thermal polymerization of hexachlorocyclotriphosphazene in 1,2,4-trichlorobenzene. Next, either 2-dimethylaminoethanol (DMAE) or 2-dimethylaminoethylamine (DMAEA) side groups were introduced by a substitution reaction. The polymers were purified by dialysis against water and tetrahydrofuran, lyophilized and evaluated as polymeric transfectants. The polyphosphazenes were able to bind plasmid DNA yielding positively charged particles (polyplexes) with a size around 80 nm at a polymer/DNA ratio of 3:1 (w/w). The polyphosphazene-based polyplexes were able to transfect COS-7 cells in vitro with an efficiency comparable to a well-known polymeric transfectant [poly(2-dimethylaminoethyl methacrylate), pDMAEMA]. The toxicity of both polyphosphazenes was lower than pDMAEMA. The transfection efficiency for the poly(DMAE)phosphazene-based polyplexes was about threefold higher in the absence of serum than in the presence of 5.0% fetal bovine serum. This is probably caused by unfavorable interactions of the polyplexes with serum proteins. In contrast, the poly(DMAEA)phosphazene-based polyplexes showed a threefold lower transfection activity in the absence of serum. For this system, serum proteins likely masked the toxicity of the polyplexes, as shown by the XTT cell viability assay and confocal laser scanning microscopy studies. Preliminary degradation studies indicate that the polymers were indeed degradable. The half-life at pH 7.5 and 37 degrees C was around 7 days for poly(DMAE)phosphazenes and 24 days for poly(DMAEA)phosphazenes. This study shows that polyphosphazenes are a suitable and promising new class of biodegradable polymeric carriers for gene delivery.
Animals↗
Novel crosslinking methods to design hydrogels.
Hydrogels are presently under investigation as matrices for the controlled release of bioactive molecules, in particular pharmaceutical proteins, and for the encapsulation of living cells. For these applications, it is often required that the gels degrade under physiological conditions. This means that the originally three-dimensional structure has to disintegrate preferably in harmless products to ensure a good biocompatibility of the hydrogel. In this overview, different chemical and physical crosslinking methods used for the design of biodegradable hydrogels are summarized and discussed. Chemical crosslinking is a highly versatile method to create hydrogels with good mechanical stability. However, the crosslinking agents used are often toxic compounds, which have been extracted from the gels before they can be applied. Moreover, crosslinking agents can give unwanted reactions with the bioactive substances present in the hydrogel matrix. Such adverse effects are avoided with the use of physically crosslinked gels.
Biocompatible Materials↗
Biodegradable hydrogels based on stereocomplex formation between lactic acid oligomers grafted to dextran.
A novel hydrogel system in which crosslinking is established by stereocomplex formation between lactic acid oligomers of opposite chirality is proposed. To investigate the feasibility of this novel system, we first investigate whether there is an operation window where lactic acid oligomers in either the D- or L-form do not give a crystalline phase, whereas in a blend of the D- and L-form stereocomplex formation occurs. Therefore, D- and L-lactic acid oligomers with different degrees of polymerization (DP) were prepared and analyzed using DSC. It was shown that crystallinity was present in D- or L-oligomers with DP > or = 11. On the other hand, in blends of D- and L-oligomers of lactic acid crystallinity (stereocomplexation) was already observed at a DP > or = 7. In the next step, L- and D-lactic acid oligomers were coupled via their terminal hydroxyl group to dextran, yielding dex-(L)lactate and dex-(D)lactate, respectively. Upon dissolving each product in water separately and mixing the solutions, a hydrogel is formed at room temperature as demonstrated by rheological measurements. The storage modulus of the obtained hydrogel strongly decreased upon heating to 80 degrees C, while it was restored upon cooling to 20 degrees C demonstrating the thermo-reversibility and the physical nature of the cross-links. The storage modulus of the gels depends on the degree of polymerization of the lactate acid grafts and their degree of substitution on dextran. Interestingly, gel formation was favored when one lactic oligomer was coupled via its hydroxyl group whereas the oligomer of opposite chirality was coupled via its carboxylic acid group. This is ascribed to the parallel packing of the oligomers in stereocomplexes.
Calorimetry, Differential Scanning↗
Physically crosslinked dextran hydrogels by stereocomplex formation of lactic acid oligomers: degradation and protein release behavior.
Hydrogels, physically crosslinked through stereocomplex formation, were obtained by mixing aqueous solutions of dextran with L-lactic acid grafts and dextran with D-lactic acid grafts. Protein-loaded hydrogels were simply prepared by dissolving the protein in these dextran solutions prior to mixing. It was shown that under physiological conditions the gels are fully degradable. When the gels were exposed to an aqueous buffer solution, they first showed a swelling phase in which their weight increased 2-3 times due to absorption of water, followed by a dissolution phase. The degradation time depended on the composition of the hydrogel, i.e., the number of lactate grafts, the length and polydispersity of the grafts and the initial water content, and varied from 1 to 7 days. Most likely, the degradation of the stereocomplex hydrogel started with hydrolysis of the carbonate ester, which links the lactate graft to dextran. The gels showed a release of the entrapped model proteins (IgG and lysozyme) over 6 days and the kinetics depended on the gel characteristics, such as the polydispersity of the lactate grafts and the initial water content. Lysozyme was mainly released by Fickian diffusion, indicating that its hydrodynamic diameter is smaller than the hydrogel mesh size. On the other hand the release of IgG was governed by diffusion as well as swelling/degradation of the hydrogel. Importantly, the proteins were quantitatively released from the gels and with full preservation of the enzymatic activity of lysozyme, emphasizing the protein-friendly preparation method of the protein-loaded stereocomplex hydrogel.
Algorithms↗