Functional imaging and targeted drug delivery in mice and patient tumors with a cell nucleolus-localizing and tumor-targeting peptide

Tumor-targeting peptides have profound clinical implications in early detection and delineation of microscopic lesions for surgical resection, and also delivery of therapeutics with reduced systemic toxicity. Here, we demonstrate that a peptide (RS), selected from a rationally-designed variant library of a reported hepatocellular carcinoma (HCC)-targeting peptide P47, enables discrimination of HCC from noncancerous tissues in orthotopic HCC mice and patient biopsies, and delineation of micrometastases in lung, with up to 21-fold contrast between tumor and surrounding liver, significantly higher than P47. Importantly, RS targets non-small cell lung (NSCLC) and colon cancers in mice and patient biopsies, with higher selectivity for highly proliferative tumor nodules. Moreover, RS localizes to cell nucleoli of HCC, NSCLC, breast, colon and cervical cancer cells and induces cell nucleolar stress when conjugated with chemotherapeutic Oxaliplatin (OXA) (RS-OXA), demonstrating both cellular and subcellular targeting. RS-delivered OXA elicits significant tumor retardation in orthotopic HCC mice with markedly reduced systemic toxicity compared to OXA alone. Injection of fluorescence-labeled RS enables dynamic visualization of tumor growth in RS-OXA-treated subcutaneous HCC mice. Our study demonstrates that RS targets a spectrum of tumors and localizes to cell nucleolus, and enables functional imaging and targeted delivery of OXA in HCC mice, and thus provides a versatile tool for tumor imaging and targeted therapeutics.