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ABSTRACT: Boron phenylalanine is one of the lead drug candidates in the field of Boron Neutron Capture Therapy. Its inherent low toxicity allows large doses to be administered, but this makes it important to identify, rationalise and quantify impurities. Here we report a chromatographic assay method, the conditions under which the parent compound is unstable, and the suggested degradation mechanisms.
Journal of pharmaceutical and biomedical analysis 11/2011; 56(3):633-6. · 2.45 Impact Factor
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ABSTRACT: This paper investigates the physicochemical properties of possible pharmaceutical alternatives to L-p-boronphenylalanine (BPA)-fructose intravenous formulation currently employed in boron neutron capture therapy. The physicochemical properties of BPA in the absence and presence of fructose, mannitol, trehalose and hydroxypropyl-β-cyclodextrin (HPCD) was investigated by determination of pKa values, solubility, precipitation and dissolution using a Sirius T3 instrument. Complex formation was also assessed using (10) B-Nuclear magnetic resonance (NMR). The results indicate that fructose and mannitol form a complex with BPA through a reversible interaction with the boronic acid group, determined by changes in the pKa of the boronic acid group, the ultraviolet and NMR spectra, and increase in kinetic solubility. Trehalose and HPCD did not undergo this reaction and, consequently, did not affect boronphenylalanaine physicochemical properties. Although mannitol is complexed with BPA in an identical manner to fructose, it is superior because it provides increased kinetic solubility. Replacement of fructose by mannitol in the current clinical BPA formulation is, therefore, feasible with advantages of increased dosing and removal of issues related to fructose intolerance and calorific load. Results also indicated that important pharmaceutical parameters are the complex's solubility and dissociation behaviours rather than, as originally assumed, the complex formation reaction.
Journal of Pharmaceutical Sciences 09/2011; 101(1):223-32. · 3.06 Impact Factor
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ABSTRACT: Chronic Myeloid Leukemia (CML) stem/progenitor cells, which over-express Bcr-Abl, respond to imatinib by a reversible block in proliferation without significant apoptosis. As a result, patients are unlikely to be cured owing to the persistence of leukemic quiescent stem cells (QSC) capable of initiating relapse. Previously, we have reported that intracellular levels of imatinib in primary primitive CML cells (CD34+38(lo/⁻)), are significantly lower than in CML progenitor cells (total CD34+) and leukemic cell lines. The aim of this study was to determine if potentially sub-therapeutic intracellular drug concentrations in persistent leukemic QSC may be overcome by targeted drug delivery using synthetic Low Density Lipoprotein (sLDL) particles. As a first step towards this goal, however, the extent of uptake of sLDL by leukemic cell lines and CML patient stem/progenitor cells was investigated. Results with non-drug loaded particles have shown an increased and preferential uptake of sLDL by Bcr-Abl positive cell lines in comparison to Bcr-Abl negative. Furthermore, CML CD34+ and primitive CD34+38(lo/⁻) cells accumulated significantly higher levels of sLDL when compared with non-CML CD34+ cells. Thus, drug-loading the sLDL nanoparticles could potentially enhance intracellular drug concentrations in primitive CML cells and thus aid their eradication.
Journal of Controlled Release 12/2010; 148(3):380-7. · 5.73 Impact Factor
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ABSTRACT: Low density lipoprotein (LDL) is a normal plasma component, which is of interest in a number of research areas such as hypercholesterolaemia, drug targeting in cancer chemotherapy and as a lipid supplement in tissue culture systems. Currently, however, it can only be obtained by extraction from fresh plasma samples, which yields only small quantities. Synthetic LDL (sLDL) has been prepared using readily available lipid components coupled with a synthetic amphiphatic peptide molecule containing the apoprotein B receptor sequence. sLDL was capable of supporting the growth of Chinese Hamster Ovary (CHO) and fibroblast cells in serum-free culture media in a cholesterol-dependent manner that was related to the presence of the receptor peptide molecule. sLDL could be fluorescently labelled with 3,3'-dioctadecyloxalocarbocyanine perchlorate (DiO), and once labelled was assimilated by CHO and fibroblast cells in a time- and temperature-dependent manner that was dependent upon the presence of the receptor peptide. In addition, assimilation was reduced by an excess of unlabelled native LDL. The results indicated that the interaction of sLDL with CHO and fibroblast cells occurred via a receptor dependent system, most likely the LDL cellular receptor. sLDL is therefore a useful, easily obtained substitute for native LDL with potential applications in the areas of drug targeting to cells and serum-free tissue culture systems.
Journal of Pharmacy and Pharmacology 11/2006; 58(10):1337-42. · 2.17 Impact Factor
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ABSTRACT: Lipid supplementation in serum-free tissue culture employs solubilization techniques to permit the addition of lipids, but these systems are potentially cytotoxic and do not present lipid in a natural form. In this research a simplified preparation method for synthetic low-density lipoprotein (sLDL) has been developed that involves microfluidization of a solvent lipid solution in a simple aqueous solution. This produces material with size and zeta potential characteristics similar to those of native LDL. sLDL supplementation in tissue culture media provides cholesterol concentrations higher than those achieved by 10% serum supplementation and existing chemically defined lipid supplements. sLDL stimulates NS0 and U937 cellular proliferation in completely serum-free media, the former in a lipid concentration dependent manner that is also related to both the receptor peptide structure employed and its concentration on the particle. The greatest NS0 cellular proliferation was obtained at the highest cholesterol concentration tested (0.5 mg/mL), which was 10 times higher than the cholesterol concentration achieved by standard 10% serum supplementation. U937 cellular proliferation was influenced by variation of sLDL's fatty acid constituents with a natural mixture producing maximal effect. Cell uptake studies in NS0 with fluorescently labeled sLDL indicated that assimilation is reduced by competition from native LDL. The planktonic nature of NS0 cell growth meant that cell binding and uptake experiments were difficult to conduct because of cellular aggregation. However, sLDL-induced U937 proliferation is ablated by the presence of an anti-LDL receptor antibody. The results indicate that sLDL uptake is via the LDL receptor and that sLDL can function as a lipid supplement for serum-free media capable of supplementation to cholesterol concentrations up to 0.5 mg/mL. Cellular uptake studies also suggest that sLDL will be useful for the targeting and delivery of materials to cells. sLDL therefore represents a new and promising synthetic biomimetic alternative to native LDL with multiple applications.
Biotechnology Progress 21(4):1262-8. · 2.34 Impact Factor
