Tumor sentinel lymph node (SLN) metastasis plays a vital role in tumor staging and therapeutic decision-making process. However, precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imaging resolution and poor photostability of fluorescent probes. Herein, we report three novel IR820-fatty acid (FA) conjugates (IR-OA, IR-LA, and IR-PA) for precise lymphatic metastasis illumination and primary tumor diagnosis. The IR-FA conjugates are able to non-covalently bound to albumin in vivo, and the fluorescence quantum yield is significantly enhanced after incubation with bovine serum albumin (BSA) in vitro. Moreover, the BSA-IR-FA conjugates display large Stokes shift (> 120 nm), dramatically improving in vivo imaging resolution. Among them, IR-PA demonstrates distinct advantage over IR-OA, IR-LA, and IR-maleimide (MAL) (fluorescent probe previously reported by our group) in terms of fluorescence quantum yield, photostability, and imaging resolution. As a result, IR-PA exhibits satisfactory imaging results with high fluorescence intensity and imaging resolution in sentinel lymph node metastasis illumination and primary tumor location. Our findings provide a self-adaptive albumin-binding near-infrared probe conjugate for accurate diagnosis of primary tumors and lymphatic metastases.

Self-engineered small-molecule prodrug-nanoassemblies have emerged as promising nanomedicines for cancer treatment. Modular design of prodrug molecules is crucial to guarantee the favorable assembly stability, tumor-specific prodrug activation, and satisfactory antitumor effect. However, too much attention has been paid to the pharmacophores and chemical linkages in prodrug molecules while neglects the vital roles of nonpharmacological moieties. Herein, we found that iso-carbon fatty acids with different number, position, and cis-trans configuration of double bonds dramatically affect the nanoassembly feature and drug delivery fates of thioether-linked paclitaxel prodrug-nanoassemblies. Particularly, the number and cis-trans configuration of double bonds in fatty acid moieties not only dominate the self-assembly ability and colloidal stability of prodrugs, but also exert significant influences on the pharmacokinetics, prodrug activation, and antitumor activity of prodrug-nanoassemblies. Finally, oleic acid with one cis double bond stands out as the optimal nonpharmacological moiety for thioether-linked paclitaxel prodrug-nanoassemblies. This study elucidates the crucial roles of nonpharmacological moieties in prodrugs, and provides new insights into the modular design of prodrug-based nanomedicines for cancer therapy.