Abstract
High sensitivity differential scanning calorimetry was employed to study the thermotropic behavior of multilamellar vesicles of neutral and acidic phospholipids and binary mixtures thereof in the presence of anthracycline antibiotics. Adriamycin and its lipophilic analogue, N-trifluoroacetyladriamycin-14-valerate (AD32) were investigated and compared to chlorpromazine and quinidine with respect to their ability to affect the pretransition and the main transition of the phospholipids suspended in physiological buffer. With liposomes of neutral dipalmitoylphosphatidylcholine the observed effects paralleled to some extent the corresponding octanol/buffer partition coefficients, with adriamycin being the least effective. Calorimetric measurements on liposomes prepared from pure dipalmitoylphosphatidylglycerol or from binary mixtures of dipalmitoylphosphatidylglycerol and dipalmitoylphosphatidylcholine showed that modulation of bilayer properties by adriamycin was greatly enhanced in the presence of negatively charged lipid headgroups presumably as a result of electrostatic interactions. AD32 interacted differently from adriamycin with the acidic bilayers at low drug concentrations, in a manner similar to that of its interaction with neutral bilayers. At high drug concentrations both adriamycin and AD32 produced transitions with multiple peaks not exhibited by chlorpromazine and quinidine which may be the result of a specific association of the anthracyclines with dipalmitoylphosphatidylglycerol. All four drugs produced only minor changes in the enthalpy of the main transition of the investigated lipids. The present findings are discussed in terms of their possible physiological relevance.
Highlights
AD32 produced transitions with multiple peaks not to show that drugs, like local anaesthetics [12,13,14], antiarexhibited by chlorpromazine and quinidinwe hich may rhythmics [13],tranquillizers [15,16,17], and antibiotics[18]are be the result of a specific association of the anthracy- capable of affecting the thermotropic phase transition of clines with dipalmitoylphosphatidylglycerol
In contrast to what we have observed, Goldman et al [6] found that adriamycin decreased the t, of the main transition of DPPC and reduced considerably the enthalpy. These authors employed a calorimeter of low sensitivity and used high scan rates, so that comparisons with our results obtained with a highly sensitive calorimeter and at a very low scan rate aredifficult
The four drugs studied in the present investigation, adriamycin, AD32, chlorpromazine, and quinidine, produced only minor changes inthe enthalpy of the main transition of DPPC
Summary
Effects of Anthracyclines on Neutral Bilayers-Typical DSC transitions became broader andwere shifted tolower temperthermograms of multilamellar vesicles formed from DPPC atures particularlyat low drug concentrations, with theeffect containing AD32 at increasing drug:lipid molar ratios inPBS on the pretransition beinlgarger. are shownin Fig. 1. These effects were reproducible and as t , of DPPC consistently showed nonreversibility. This behave-xpected, adriamycin alone in PBS at a concentration of 2.4 ior is seen only at high concentrations of AD32, and may be x IOA4M showed no transition in the temperature range of InteracAtinotnhsracycline-Liposome c I
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