Macromolecular dextrans

Probably the most promising polymeric drug carrier system involves polysaccharide molecules. These are natural polymers and are often biodegradable to products that are useful to the host or easily eliminated by the host. Dextrans have been the most extensively used polysaccharide for macromolecular prodrug preparations (79). These materials are biocompatible and the in vivo fate is directly related to their molecular weight. Moreover these macromolecules can be easily targetted to the hepatocytes with D-mannose or L-fucose (20). 

F Harboe, C Larsen, MJ Johansen, HP Olesen. Macromolecular prodrugs. XV. Colon-targeted delivery—Bioavailability of naproxen from orally administered dextran-naproxen ester prodrugs varying in molecular size in the pig. Pharm Res 6(11) 919—923, 1989. 

Dextrans are also attractive as macromolecular carriers of paramagnetic chelates because of their hydrophilicity, the different available molecular weights with narrow polydispersity, and the versatility of activation methods applicable. Several DTPA- or DOTA-loaded carboxymethyl dextran (CMD) derivatives have been prepared and tested in blood pool MRI.136-139 The relaxivities reported for these compounds are, however, relatively moderate. 

Table I lists physical data for a number of the carbamate and ester derivatives of cellulose, chitin, amylose, amylopectin, and dextran synthesized as described in the Experimental Section. The solubility of the polysaccharide starting materials as well as that of the produced derivatives allows for macromolecular characterization through techniques including UV, NMR, IR, high pressure liquid chromatography, etc.

DESIGN OF MACROMOLECULAR PRODRUG OF CISPLATIN ATTACHED TO DEXTRAN THROUGH COORDINATE BOND... 

Design of Macromolecular Prodrug of Cisplatin Attached to Dextran through Coordinate Bond... 

Molteni, L. 1982. Effects of the polysaccharidic carrier on the kineticfate of drugs linked to dextran and inulin in macromolecular compounds. Optimization of Drug Delivery, edited by H. Bundgaard.A. B. Hansen, and H. Kofod, 285-300. Copenhagen Munksgaard. 

Meyer, F.A., Koblentz, M. and Silberberg, A. (1977) Structural investigation of loose connective tissue by using a series of dextran fractions as non-interacting macromolecular probes. Biochem. J., 161, 285-291. 

The most important effect of concentration polarization is to reduce the membrane flux, but it also affects the retention of macromolecules. Retention data obtained with dextran polysaccharides at various pressures are shown in Figure 6.12 [17]. Because these are stirred batch cell data, the effect of increased concentration polarization with increased applied pressure is particularly marked. A similar drop of retention with pressure is observed with flow-through cells, but the effect is less because concentration polarization is better controlled in such cells. With macromolecular solutions, the concentration of retained macromolecules at the membrane surface increases with increased pressure, so permeation of the macromolecules also increases, lowering rejection. The effect is particularly noticeable at low pressures, under which conditions increasing the applied pressure produces the largest increase in flux, and hence concentration polarization, at the membrane surface. At high pressure, the change in flux with... 

C. Larsen, E. Harboe, M. Johansen, and H. P. Olesen, Macromolecular prodrugs Naproxen-dextran esters, Pharm. Res. 6 919-923, 995-999 (1989). 

These degradation studies of dextran derivatives, mutually differing in the nature and the degree of modification, clearly demonstrate that the biodegradability of dextran is significantly reduced upon chemical modification of the polymer backbone. This phenomenon should be beared in mind when using dextran as a carrier molecule for the preparation of macromolecular drug derivatives. 

In this chapter, we provide protocols to determine the ability of a peptide to mediate DNA internalization in cultured human tumor cells. Fluorescence-assisted cell sorting (FACS) analysis is used to obtain quantitative data on the time and temperature dependence of macromolecular delivery. Confocal microscopy is used to study the subcellular localization in both fixed and live cells. Fluorescently labeled transferrin and dextran are used to label the clathrin-dependent (15) and the non-clathrin, non-caveolar (16) endocytic compartments, respectively. Expression of a caveolin-l-YFP fusion protein is used to label cell surface caveolae and intracellular caveosomes (17). Finally a protocol, for the overexpression of dominant-negative dynamin [GTPase deficient dynamin-2 containing the amino acid substitution K44A (18)] is provided to evaluate the dynamin dependence of the uptake mechanism. 

Dolk M, Pla F, Yan JF, McCarthy JL (1986) Lignin 22 Macromolecular characteristics of alkali lignin from western hemlock wood Macromolecules 19 1464-1470 Flodin P (1962) Dextran gels and their applications m gel filtration Thesis, University of Uppsala, Uppsala, Sweden... 

In the case of glucoamylase, we have also seen a marked effect of dextran attachment on the ability of the enzyme to interact with starch, although not with maltose. In the case of this enzyme, however, we have gone one stage further and intentionally tried to eliminate all activity towards the macromolecular substrate by suitable choice of the coupling conditions. The results of this work are described in more detail below. 

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