6-Aminocaproic acid as a linker to improve near-infrared fluorescence imaging and photothermal cancer therapy of PEGylated indocyanine green

• 6-Aminocaproic acid was designed as a linker to construct mPEG-ACA-ICG nanomicelles. • mPEG-ACA-ICG nanomicelle reduced the risk of fluorescence attenuation of ICG. • Real-time determination ability for fluorescence image-guided surgery of mPEG-ACA-ICG was confirmed. • mPEG-ACA-ICG displayed higher light-to-heat conversion efficiency than free ICG and mPEG-ICG. • mPEG-ACA-ICG achieved superior in vivo tumor photothermal therapy activity. Clinical extensive application of indocyanine green (ICG) is limited by several drawbacks such as poor bioenvironmental stability, aggregate propensity, and rapid elimination from the body, etc. In this study, we construct a novel amphiphilic mPEG-ACA-ICG conjugate by modifying synthetic heptamethine cyanine derivative ICG-COOH with a hydrophobic linker 6-aminocaproic acid (ACA) and amino-terminal poly(ethylene glycol) (mPEG-NH 2 ). The as-prepared mPEG-ACA-ICG conjugate has the ability to self-assemble into micellar aggregates in an aqueous solution with a lower CMC value than mPEG-ICG conjugate without ACA linker. More importantly, compared with free ICG and mPEG-ICG conjugate, mPEG-ACA-ICG nanomicelles exhibited better stability and higher photothermal conversion efficiency upon near-infrared light irradiation due to the intramolecular introduction of a hydrophobic ACA segment. In our in vivo experiment, mPEG-ACA-ICG nanomicelles ensured the formidable effect on tumor photothermal therapy (PTT) and the maximum tumor inhibition rate reached 72.6 %. In addition, real-time determination ability for fluorescence image-guided surgery (FIGS) of mPEG-ACA-ICG nanomicelles was also confirmed on tumor xenograft mice model. Taken together, mPEG-ACA-ICG conjugate may hold great promise for non-invasive cancer theranostics.