Modifications in high-density lipoprotein lipid composition and structure alter the plasma distribution of free and liposomal annamycin.
Recent studies have shown that changes in lipoprotein cholesterol and triglyceride concentration alters the plasma distribution of free (Ann.) and liposomal annamycin (LAnn) and that the majority of Ann. is associated with high-density lipoproteins (HDL) following the incubation in plasma of LAnn. To demonstrate that alterations in HDL lipid composition and HDL structure may influence the plasma distribution of Ann. and LAnn, Ann. and LAnn (20 micrograms/mL) were incubated in plasma pretreated with dithionitrobenzoate (DTNB, a compound which inhibits the conversion of free cholesterol to esterified cholesterol) 18 h prior to the experiment or in untreated plasma for 60 min at 37 degrees C. In addition, Ann. and LAnn were co-incubated with DTNB in plasma for 60 min at 37 degrees C. Following incubation the plasma was separated into its HDL, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and lipoprotein-deficient plasma (LPDP) fractions by ultracentrifugation and assayed for Ann. by fluorimetry. The HDL plasma cholesterol:triglyceride concentration ratio was significantly decreased following 18 h of DTNB pretreatment compared to untreated plasma controls. No significant differences in LDL/VLDL plasma cholesterol:triglyceride concentration ratio following 18 h of DTNB pretreatment was observed. An increased number of discoidal HDL particles were observed following 18 h of DTNB pretreatment. When Ann. was incubated in plasma pretreated with DTNB for 18 h the percentage of Ann. recovered in the HDL, LDL, and VLDL fractions significantly increased. However, the percentage of Ann. recovered within the LPDP fraction was significantly decreased. When LAnn was incubated in plasma pretreated with DTNB for 18 h the percentage of Ann. recovered in the HDL fraction significantly decreased. The percentage of Ann. recovered in the LPDP fraction significantly increased when LAnn was incubated in plasma pretreated with DTNB for 18 h. No significant differences in Ann. lipoprotein distribution were observed when Ann. and LAnn were co-incubated with DTNB in plasma for 1 h. These findings suggest that the cholesterol:triglyceride concentration ratio and physical structure of HDL maybe important in defining the capacity of HDL to sequester Ann.
Wasan
K M
KM
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
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Cassidy
S M
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D000903:Antibiotics, Antineoplastic / Q000097:blood* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D004337:Drug Carriers; D006801:Humans; D008081:Liposomes; D014280:Triglycerides / Q000097:blood
D000903:Antibiotics, Antineoplastic; D008076:Cholesterol, HDL; D004337:Drug Carriers; D008081:Liposomes; D014280:Triglycerides; D004317:Doxorubicin; D004228:Dithionitrobenzoic Acid; C080315:annamycin