Micelle/Monomer Control over the Membrane-Disrupting Properties of an Amphiphilic Antibiotic

Yamashita, Keiji; Janout, Václav; Bernard, Edward M.; Armstrong, Donald; Regen, Steven L.

doi:10.1021/ja00128a011

Cited by 48 publications

(61 citation statements)

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“…Therefore, molar absorptivity (e) of AmB at 412 nm compared to that of the peak at 350 nm has been suggested as a marker for self-aggregation status: the higher, the more prevalence of monomeric form. 17) Figure 4 shows the molar absorptivities of nanoparticular AmB micelles prepared with PBPA, AmB micelles without PBPA, and Fungizone ® at 412 nm, respectively. When AmB existed as nanoparticular AmB micelles prepared with PBPA, the molar absorptivity was significantly higher than those of both AmB micelles without PBPA and Fungizone ® .…”

Section: Fig 2 Transmission Electron Microscopic Photograph Of Nanomentioning

confidence: 99%

Reduced Renal Toxicity of Nanoparticular Amphotericin B Micelles Prepared with Partially Benzylated Poly-<small>L</small>-aspartic Acid

Yoo

Miah

Lee

et al. 2006

Biological & Pharmaceutical Bulletin

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Amphotericin B (AmB) has long been used as the drug of choice for the treatment of disseminated fungal diseases and other local infections such as meningitis, peritonitis, and bladder infections due to fungi. 1) Although AmB has been a gold standard for those infectious diseases, the use of conventional AmB deoxycholate is often limited by its various side effects. Nephrotoxicity has been the major factor discouraging clinicians from using the drug. Increased blood urea nitrogen and serum creatinine levels and decreased renal blood flow occur in most patients receiving conventional AmB deoxycholate. Furthermore, AmB can lead to serious renal tubular acidosis and acute tubular necrosis which may require hemodialysis. These adverse effects of AmB appear to be related to high cumulative doses of the drug, use of diuretics, abnormal serum creatinine level at the baseline, and the use of concomitant nephrotoxic drugs.The precise mechanism by which the kidneys are affected by AmB is uncertain. Nephrotoxicity associated with AmB appears to involve several mechanisms including a direct tubular damage through its vasoconstrictive effect on renal arterioles that reduces glomerular and renal tubular blood flow and a lytic action on cholesterol-rich lysosomal membranes of renal tubular cells.A number of studies have been performed to reduce renal toxicity of AmB during recent decades, leading to the development of three lipid formulations of the drug. AmB lipid complex, AmB colloidal dispersion, and liposomal AmB. 2-4)The main limitation of their use, however, is their high cost. The current recommendation is that these drugs be used for patients whose infections do not respond to conventional AmB formulation or those who become intolerant to the drug. 5)The present study was undertaken to investigate renal toxicity when AmB was administered as nanoparticular micelles prepared with partially benzylated poly-L-aspartic acid (PBPA). Polyaspartic acid has been studied both in vivo and in vitro to protect against aminoglycoside-induced nephrotoxicity by many researchers.6-8) However, polyaspartic acid has not been examined whether it has a similar effect on AmB-induced nephrotoxicity probably because polyaspartic acid is highly water-soluble and AmB is very water-insoluble unlike aminoglycoside antibiotics. In this study, we have introduced benzyl group to polyaspartic acid chain to provide appropriate hydrophobicity for the polymer to interact with AmB and investigated whether the PBPA affects self-aggregation behavior of AmB and exerts protective effect against nephrotoxicity of the drug. MATERIALS AND METHODSMaterials AmB, resin (N-Fmoc-4-t-butyl-L-aspartic acid SASRIN resin ester), N-Fmoc-L-aspartic acid-4-benzyl ester, piperidine, and 9-fluorenyl methyl chloroformate were purchased from Sigma and used as obtained. N-Fmoc-L-aspartic acid-4-t-butyl ester was purchased from Fluka. Fungizone ® (Squibb) was kindly donated by the Pharmacy Department of Yeungnam University Medical Center. Osmium tetroxide was obtained from Polysc...

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Section: Fig 2 Transmission Electron Microscopic Photograph Of Nanomentioning

confidence: 99%

Reduced Renal Toxicity of Nanoparticular Amphotericin B Micelles Prepared with Partially Benzylated Poly-<small>L</small>-aspartic Acid

Yoo

Miah

Lee

et al. 2006

Biological & Pharmaceutical Bulletin

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“…Dimers 2, 4, 5, and 6 were synthesized as described previously (23) by reaction of the same trisphosphate with p-nitrophenyl carbonate-activated poly(ethylene glycol) linkers followed by deprotection. Monomer 8 was synthesized in a similar way by the reaction of the trisphosphate with the p-nitrophenyl carbonate ester derived from monomethoxy-hexa(ethylene glycol) (24) followed by deprotection. D-2-O-(2-Aminoethyl)-myoinositol 1,4,5-trisphosphate (7) was synthesized by two-step deprotection of D-3,6- (23) employing hydrogenolysis over palladium on carbon followed by removal of the trifluoroacetyl protecting group with methanolic ammonia at 60°C.…”

Section: Inositol 145-trisphosphate (Ip 3 )mentioning

confidence: 99%

Interactions of Inositol 1,4,5-Trisphosphate (IP3) Receptors with Synthetic Poly(ethylene glycol)-linked Dimers of IP3 Suggest Close Spacing of the IP3-binding Sites

Riley

Morris

Nerou

et al. 2002

Journal of Biological Chemistry

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The distances between the inositol 1,4,5-trisphosphate (IP 3 )-binding sites of tetrameric IP 3 receptors were probed using dimers of IP 3 linked by poly(ethylene glycol) (PEG) molecules of differing lengths (1-8 nm). Each of the dimers potently stimulated 45 Ca 2؉ release from permeabilized cells expressing predominantly type 1 (SH-SY5Y cells) or type 2 (hepatocytes) IP 3 receptors. The shortest dimers, with PEG linkers of an effective length of 1.5 nm or less, were the most potent, being 3-4-fold more potent than IP 3 . In radioligand binding experiments using cerebellar membranes, the shortest dimers bound with highest affinity, although the longest dimer (8 nm) also bound with almost 4-fold greater affinity than IP 3 . The affinity of monomeric IP 3 with only the PEG attached was 2-fold weaker than IP 3 , confirming that the increased affinity of the dimers requires the presence of both IP 3 motifs. The increased affinity of the long dimer probably results from the linked IP 3 molecules binding to sites on different receptors, because the dimer bound with greater affinity than IP 3 to cerebellar membranes, where receptors are densely packed, but with the same affinity as IP 3 to purified receptors. IP 3 and the IP 3 dimers, irrespective of their length, bound with similar affinity to a monomeric IP 3 -binding domain of the type 1 IP 3 receptor expressed in bacteria. Short dimers therefore bind with increased affinity only when the receptor is tetrameric. We conclude that the four IP 3 -binding sites of an IP 3 receptor may be separated by as little as 1.5 nm and are therefore likely to be placed centrally in this large (25 ؋ 25 nm) structure, consistent with previous work indicating a close association between the central pore and the IP 3 -binding sites of the IP 3 receptor.Inositol 1,4,5-trisphosphate (IP 3 ) 1 receptors are intracellular Ca 2ϩ channels that are expressed in many cells and that mediate the release of Ca 2ϩ from intracellular stores evoked by receptors that stimulate IP 3 formation. The three subtypes of mammalian IP 3 receptor are closely related to each other and to the receptors expressed in birds, Xenopus, crayfish, Drosophila and Caenorhabditis elegans (2). For each of these receptors, the functional IP 3 -gated Ca 2ϩ channel is thought to be a tetramer, which may either be homomeric or, in those species that express more than one receptor subtype, heteromeric (3). Although the different subtypes of mammalian IP 3 receptor differ in their distribution (2), differ modestly in their affinity for IP 3 and their ability to recognize different inositol phosphates (4), and may be differentially modulated (5), the physiological significance of this diversity is unclear. More striking than the differences between IP 3 receptor subtypes are the similarities: the primary sequences of the subunits are closely related, each assembles to form a tetrameric IP 3 -gated Ca 2ϩ channel, they recognize similar ligands with broadly similar affinities, and most are biphasically regulated by cytosolic Ca 2...

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“…[28][29][30][31] Namely, hyAbstract: Hydrophilic anchoring is introduced as a promising strategy to constructively control the various interactions of synthetic pore sensors with the surrounding biphasic environment. Artificial rigid-rod b barrels are selected as classical synthetic multifunctional pores and random-coil tetralysines are attached as hydrophilic anchors.…”

Section: Introductionmentioning

confidence: 99%

“…Exploited to perfection in biology, these various benefits from hydrophilic anchoring are rarely considered in synthetic functional systems. [28][29][30][31] Herein, we report hydrophilic anchoring of rigid-rod b-barrel pores, such as 1, as a promising approach toward multicomponent sensors that can operate at low concentrations with high selectivity (Figure 1). …”

Section: Introductionmentioning

confidence: 99%

Interface Engineering of Synthetic Pores: Towards Hypersensitive Biosensors

Mora

Tran

Oudry

et al. 2008

Chemistry A European J

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Hydrophilic anchoring is introduced as a promising strategy to constructively control the various interactions of synthetic pore sensors with the surrounding biphasic environment. Artificial rigid-rod beta barrels are selected as classical synthetic multifunctional pores and random-coil tetralysines are attached as hydrophilic anchors. The synthesis of this advanced pore is accomplished in 32 steps from commercially available starting materials. With regard to pore activity as such, the key impact of hydrophilic anchoring is a change from a Hill coefficient n<1 to n=4. This change confirms successful suppression of the competing self-assembly with precipitation from the aqueous phase as the origin of the accomplished increase in pore activity. The hydrophilic anchors do not interfere with the blockage of the synthetic pore sensors by anionic analytes. In the case of stoichiometric binding of blockers (K(D)=EC(50) of the pore; EC(50)=concentration needed to observe 50 % pore activity), however, the increase in pore activity achieved by hydrophilic anchoring results in improved pore blockage under high dilution conditions. Controls confirm that this increase does not occur with analytes that do not exhibit stoichiometric binding (K(D)>EC(50)). These results not only reveal stoichiometric binding as the expected origin of the sensitivity limit of synthetic pore sensors, they also provide promising solutions for this problem. The combination of hydrophilic anchoring with targeted pore formation emerges as a particularly promising strategy to further reduce effective pore concentrations. The scope and limitations of this approach are exemplified with pertinent analyte pairs that are essential for the sensing of sucrose, lactose, acetate, and glutamate with synthetic pores in samples from the supermarket.

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Micelle/Monomer Control over the Membrane-Disrupting Properties of an Amphiphilic Antibiotic

Cited by 48 publications

References 0 publications

Reduced Renal Toxicity of Nanoparticular Amphotericin B Micelles Prepared with Partially Benzylated Poly-<small>L</small>-aspartic Acid

Reduced Renal Toxicity of Nanoparticular Amphotericin B Micelles Prepared with Partially Benzylated Poly-<small>L</small>-aspartic Acid

Interactions of Inositol 1,4,5-Trisphosphate (IP3) Receptors with Synthetic Poly(ethylene glycol)-linked Dimers of IP3 Suggest Close Spacing of the IP3-binding Sites

Interface Engineering of Synthetic Pores: Towards Hypersensitive Biosensors

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