Hydrophobic doxorubicin

In this situation, cell lines are shown to be resistant to colchicine, doxorubicin, vinblastine, and actinomycin D. This syndrome is accompanied by an increase in measurable membrane glycoprotein (the P-170 or permeability glycoprotein). It is believed that this protein transports hydrophobic chemicals out of cells and thereby prevents drug action. Current efforts to inhibit this efferent transport protein are currently underway but, sadly, have to date been largely unsuccessful (i5). 

In addition to the hydrophobic interaction mentioned above to encapsulate guest molecules, other types of nonspecific interactions have also been explored to enhance binding. For example, block copolymer micelles based on PEO as hydrophilic segments and poly(/3-benzyl L-aspartate) as hydrophobic blocks have used to encapsulate doxombicin. The encapsulation efficiency of doxombicin, an aromatic anticancer drug molecule, has been found to be significantly higher. This observation has been attributed to the tt-tt interaction between the anthracycUne moiety of doxorubicin and the benzyl group of poly(/3-benzyl L-aspartate) (Cammas-Marion et al. 1999). 

Non-covalent bonding includes hydrogen bonding, ionic bonds, or hydrophobic bonds. These types of bonding are involved in binding of chemicals to plasma proteins. They could also underlie the interaction between a chemical and a receptor or enzyme. Thus, the interaction between TCDD and the Ah receptor (AhR) and the intercalation of doxorubicin in DNA involve non-covalent bonds. 

The B block may consist of a water-soluble polymer, for example, poly(aspartic acid) P(Asp), that is rendered hydrophobic by the chemical conjugation of a hydrophobic drug (Yokoyama et al., 1992, 1993, 1996 Nakanishi et al., 2001), or is formed through the association of two oppositely changed polyions (polyion complex micelles) (Hatada etal., 1995,1998 Kataoka etal., 1996). Drugs used to couple the B block include cyclophosphamide, doxorubicin, cisplatin, pyrene, and iodine derivative of benzoic acid (Kwon and Kataoka, 1995 Trubetskoy et al., 1997 Yu etal., 1998). 

Micellar systems based on amphipathic block-copolymers have gained most attention as intravenously administered drug carrier systems over the years. These block-copolymers are composed of a hydrophilic PEG block and a hydrophobic block based on doxorubicin conjugated poly(aspartic acid) or poly(/i-bcnzyl L-aspartate). 

These block-copolymers form micelles in aqueous solution with spherical core/shell structures and diameters around 20-40 nm (Figure 5.9). The hydrophobic core of these micelles can be loaded with a hydrophobic drug such as doxorubicin. After intravenous administration the micelles tend to accumulate at tumor sites and release the entrapped drug there. Some of the characteristics of these micellar systems are listed in Table 5.5. 

The hydrophilic delivery system described in this review can be extended to drugs with a low water-solubility (e.g., doxorubicin). Such compounds may be incorporated in CT/TPP nanoparticles by means of dextran sulfate complex prior to entrapment [54] or by dissolving them in a polar solvent (acetone, ethanol or acetonitrile) as demonstrated for the relatively hydrophobic peptide cyclosporin A [26,81]. It is quite possible that this approach would work in a multicomponent polymer system as well. 

Preparations of liposomes via SCF processing are designated as critical fluid liposomes (CFLs). CFLs have successfully encapsulated hydrophobic drugs such as taxoids, camptothecins, doxorubicin, vincristine, and cisplatin. In addition, stable paclitaxel liposomes with a size of 150-250 nm were obtained. Aphios Co. s patent (US Patent 5,776,486) on Super-Fluids CFL describes a method that is useful for the nanoencapsulation of paclitaxel and campothecin in aqueous liposomal formulations called Taxosomes and Camposomes , respectively. 

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