The first examples of highly water soluble taxol derivatives (0.1 mmol/mL) were prepared by the attachment of polyethylene glycol (molecular weight 2-5 kD) at the 7-position of taxol via a urethane or carbonate linkage. When lower molecular weight polyethylene glycols (350 and 750) were used, the solubilities were considerably lower (1.87 x mmob"L) but still substantially greater than taxol itself. Additional 7-substituted taxol derivatives were also prepared by utilizing small molecules consisting of sugars and ionic and multifunctional compounds. However, most of these derivatives had solubilities, calculated from HPLC retention times, that did not differ significantly from taxol itself. The use of methoxyacetate as a protecting group during these syntheses is discussed.Early difficulties in obtaining sufficient quantities of taxol for clinical studies to assess antitumor activity in ovarian, breast, and lung cancer have been overcome, but the associated problem of poor aqueous solubility still remains. Modification of both the 3' and 10 position has been achieved by French researchers1 to yield a 10deacetyl tert-butyl carbamate derivative (Taxotere) which produced a slightly more water soluble taxol analogue. Taxotere has also been reported to possess antitumor activity comparable to or greater than that of taxol itself.Considering the scope of interest manifested in taxol, few modifications of the 7 position and subsequent oncolytic activities have been reported. Most accounts to date have been concerned with esterifications of the hindered secondary alcohol moiety at the 7 position which could improve solubility while maintaining cytotoxic Polyethyleneglycol (PEG) is known to enhance water solubilitys8 and reduce immunogenicity of high molecular weight protein a d d u~t s~~-~ and therefore seemed like a n activity.2-43-10 @ Abstract published in Advance ACS Abstracts, January 1, 1995.(1) Commercon, A.; Bizard, D.; Bernard, F; Baurzat, J. D. Tetrahedron Lett. 1992, 33, 5785-5788 and references cited.
We have developed a combinatorial method for screening cell-biomaterial interactions in a 3D format. Previous highthroughput approaches for screening cell-material interactions have focused on planar 2D surfaces or films. However, biomaterials are commonly used in a 3D scaffold format and cells behave more physiologically when cultured in 3D. Hence, combinatorial scaffold libraries were fabricated in 96-well plates in which polymeric, salt-leached scaffolds of varied composition and properties were present in each well. Libraries were fabricated from two biodegradable tyrosinederived polycarbonates: poly(desaminotyrosyl-tyrosine ethyl ester carbonate) (pDTEc) and poly(desaminotyrosyl-tyrosine octyl ester carbonate) (pDTOc). During culture, osteoblast adhesion and proliferation into scaffolds were enhanced as the pDTEc content of the scaffolds increased. To our knowledge, this is the first demonstration of a method for fabricating combinatorial arrays of large-pore scaffolds (diameter (d) > 0.1 mm) for screening cell-material interactions in a 3D format.Despite significant investments, few profitable tissueengineering products have come to market.[1] As a result, combinatorial methods, which have accelerated pharmaceutical research, [2,3] are beginning to impact biomaterials research. [4][5][6][7][8][9][10][11] However, methods for screening cell-biomaterial interactions are mostly limited to 2D films or surfaces, [4][5][6][7][8][9][10][11][12][13][14] despite the facts that biomaterials are frequently used to fabricate 3D scaffolds, [15] cells exist in vivo in a 3D environment, and cells cultured in vitro in a 3D environment typically behave more physiologically than those cultured on a 2D surface. [16][17][18][19][20] Films and surfaces typically display a ''nanoscale'' roughness, [11,21] while processing of biomaterials into 3D scaffolds yields structures with a topographical roughness at multiple size scales. Cells are very sensitive to material topography and the large difference in structure between 2D films and 3D scaffolds should be considered when screening materials. For these reasons, a combinatorial approach in which cell-biomaterial interactions are screened using a 3D polymer-scaffold configuration will provide more relevant information regarding cell responses to test biomaterials. We have developed a method for fabricating combinatorial libraries of polymer scaffolds where the materials are presented to cells as 3D, porous, salt-leached polymer scaffolds and many scaffold compositions can be tested in a single experiment. The libraries are designed for screening cell response so that scaffold formulations that promote or suppress cellular activity can rapidly be identified. In the current study, we have used the combinatorial approach to fabricate scaffold libraries of varying composition of two amorphous, biodegradable, biocompatible, tyrosine-derived polycarbonates: pDTEc [poly(desaminotyrosyl-tyrosine ethyl ester carbonate)] and pDTOc [poly(desaminotyrosyl-tyrosine octyl ester carbonate)]. [22] ...
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