Cytotoxicities of Tumor‐Seeking Dyes: Impact on Future Clinical Trials

Abstract Heptamethine (Cy7) dyes with meso ‐Cl substituents injected intravenously ( iv ) into mice accumulate in tumors and persist there over several days. We believe this occurs via meso ‐Cl displacement by the only free cysteine residues of albumin; therefore, conjugating tumor‐seeking dyes with fragments can increase selective therapeutic delivery to tumors and drug residence. This strategy has elevated significance recently because the first tumor‐seeking dye‐drug conjugate has moved into clinical trials. Options for further clinical research include modifying the dye, and use of preformed albumin adducts instead of dyes alone. Herein we show correlations of cytotoxicities, lipophilicities, organelle localization, apoptosis, cell‐cycle arrest, wound healing/migration assays, and reactivities/affinities with human serum albumin are difficult to observe. However, our studies arrived at an important conclusion: preformed dye‐drug‐HSA adducts are less cytotoxic, and therefore preferable for subsequent clinical work, relative to direct injection of meso ‐Cl‐containing forms.