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Cited by 300

The DOI matches its Crossref record; 20 of the 20 references it cites were found in a registry or an index.

Differential Interactions of Camptothecin Lactone and Carboxylate Forms with Human Blood Components

Mi, Zihou, Burke, Thomas G.·1994·Biochemistry
DOI 10.1021/bi00200a013
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Abstract

The intrinsic fluorescent emissions from the lactone and carboxylate forms of camptothecin have been exploited in order to elucidate their markedly different interactions with the various components of human blood. In phosphate-buffered saline (PBS) at pH 7.4, human serum albumin (HSA) preferentially binds the carboxylate form with a 150-fold higher affinity than the lactone form; these interactions result in camptothecin opening more rapidly and completely in the presence of HSA than in the protein's absence [Burke, T.G., & Mi, Z. (1993) Anal. Biochem. 212, 285-287]. In human plasma, at pH 7.4 and 37 degrees C, we have observed camptothecin lactone to open rapidly and fully to the carboxylate form (t1/2 = 11 min; % lactone at equilibrium, 0.2%). Substitution of a 10-hydroxy moiety into the camptothecin fluorophore makes the agent's emission spectrum highly sensitive to microenvironment polarity; we have observed pronounced blue shifting (from 530 to 430 nm) in the emission spectra of the hydroxy-substituted carboxylate both upon HSA association as well as upon drug dissolution in organic solvents of low dielectric strength. Hence, it appears that camptothecin carboxylate's fluorophore locates in a hydrophobic binding pocket in native HSA. Ionic interactions also appear to strongly affect binding between camptothecin carboxylate and the HSA binding pocket, since a 6-fold increase in solution salt concentration diminished camptothecin carboxylate binding by 10-fold. Our findings that HSA denaturation abolishes high-affinity binding indicate that interactions of the carboxylate drug form are specific for the native HSA conformation. Interestingly, high-affinity binding of the carboxylate appeared not to occur in the presence of other blood proteins, such as gamma-globulin, alpha 1-acid glycoprotein, fibrinogen, and the oxy and deoxy forms of hemoglobin. In whole blood versus plasma, camptothecin was found to display enhanced stability (t1/2 value of 22 min and a lactone concentration at equilibrium value of 5.3%). The enhanced stability of camptothecin in human blood was found to be due to drug associations with the lipid bilayers of red blood cells. Camptothecin lactone partitions into the lipid bilayers of erythrocytes, with the drug locating in a hydrophobic environment protected from hydrolysis.

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Metadata

Authors
Mi, Z., & Burke, T. G.
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
1994-08-30
Volume
33
Issue
34
Pages
10325-10336
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi00200a013
OpenAlex
W2072533818
Cited by
300
References
20
FWCI
2.94
Type
journal article
Language
en
Open access
closed

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