Concentration-Induced J-Aggregate Formation Causes a Biphasic Change in the Release of trans-Combretastatin A4 Disodium Phosphate from Archaeosomes and the Subsequent Cytotoxicity on Mammary Cancer Cells.
Combretastatin A4 disodium phosphate (CA4P) is a fluorescent, water-soluble prodrug able to induce vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. As a continued effort to develop efficient liposomal CA4P to treat solid tumor, we herein investigate the physical and spectroscopic properties of CA4P in aqueous solution and the mechanism of CA4P release from archaeal tetraether liposomes (archaeosomes). We found that cis-CA4P can be photoisomerized to trans-CA4P. This photoisomerization results in an increase in fluorescence intensity. Both cis- and trans-CA4P undergo fluorescence intensity self-quenching after they reach a critical concentration Cq (∼0.15-0.25 mM). Moreover, both cis- and trans-CA4P in buffer exhibit a red shift in their excitation spectrum and an increase in excitation spectrum band sharpness with increasing concentration, which can be attributed to the formation of J-aggregates. The onset of the dramatic change in excitation maximum occurs at concentrations close to Cq, suggesting that the self-quenching arises from extensive J-aggregate formation and that, when CA4P concentration exceeds Cq, J-aggregate formation begins to increase sharply. Our data also suggest that the extent of J-aggregate formation plays a critical role in CA4P release from tetraether archaeosomes and in the subsequent cytotoxicity on cultured human breast cancer MCF-7 cells. The drug leakage and cytotoxicity rate constants vary with the initial CA4P concentration entrapped inside archaeosomes in a biphasic manner, reaching a local maximum at 0.25-0.50 mM. A mechanism based on the concept of J-aggregate formation has been proposed to explain the biphasic changes in drug release and cytotoxicity with increasing drug concentration. Tetraether archaeosomes are extraordinarily stable and relatively nontoxic to animals; thus, they are promising nano drug carriers. The results obtained from this study pave the way for future development of archaeosomal CA4P to treat solid tumors.
Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine , Philadelphia, Pennsylvania 19140, United States.
Varsha P
VP
Daswani
Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine , Philadelphia, Pennsylvania 19140, United States.
Umme
U
Ayesa
Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine , Philadelphia, Pennsylvania 19140, United States.
Berenice
B
Venegas
Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine , Philadelphia, Pennsylvania 19140, United States.
Parkson Lee-Gau
PL
Chong
D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000378:metabolism*; D061986:MCF-7 Cells / Q000187:drug effects* / Q000378:metabolism; D013267:Stilbenes / Q000493:pharmacokinetics* / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D005456:Fluorescent Dyes; D008081:Liposomes; D013267:Stilbenes; C058728:fosbretabulin
J-aggregates; archaeal tetraether liposomes; cis-to-trans isomerization; cytotoxicity; fluorescence; mechanism of drug release; self-quenching; vascular-disrupting agent