Flexible-Structured Cyanine–Cyanine Conjugate Affords Highly Efficient Photothermal Therapy via Enhanced Tumor Accumulation and Heating Performance

Simultaneous optimization of tumor accumulation and photothermal
conversion efficiency (PCE) remains a major challenge in photothermal
agent (PTA) development. Here, benzene-thiol/-dithio/-trithiol was
introduced at the meso-position of heptamethine cyanine (Cy7) via
sulfhydryl substitution. The obtained derivatives, denoted as M-Cy7,
D-Cy7, and T-Cy7, conferred enhanced molecular flexibility, promoting
self-assembly and passive tumor accumulation. Although increasing
the number of Cy7 units reduced molecular flexibility in the D- and
T-derivatives, the central phenyl linker enabled covalent coupling
of intramolecular Cy7 moieties, resulting in a “covalent aggregation”
effect and boosting PCE to 77%nearly seven times higher than
that of the prototypic Cy7. Among them, D-Cy7 demonstrated the most
favorable balance of tumor accumulation and photothermal efficiency,
achieving optimal in vivo PTT efficacy. This novel molecular design
strategy successfully integrated high PCE and tumor-targeting capability
into a single PTA, offering new insights for advancing photothermal
therapy.