Tumor-penetrating peptide for systemic targeting of Tenascin-C

Abstract

Extracellular matrix in solid tumors has emerged as a specific, stable, and abundant target for affinityguided delivery of anticancer drugs. Here we describe the homing peptide that interacts with the C-isoform of Tenascin-C (TNC-C) upregulated in malignant tissues. TNC-C binding PL3 peptide (amino acid sequence: AGRGRLVR) was identified by in vitro biopanning on recombinant tnc-c. Besides tnc-C, PL3 interacts via its C-end Rule (CendR) motif with cell-and tissue penetration receptor neuropilin-1 (NRP-1). Functionalization of iron oxide nanoworms (NWs) and metallic silver nanoparticles (AgNPs) with PL3 peptide increased tropism of systemic nanoparticles towards glioblastoma (GBM) and prostate carcinoma xenograft lesions in nude mice (eight and five-fold respectively). Treatment of gliomabearing mice with proapoptotic PL3-guided NWs improved the survival of the mice, whereas treatment with untargeted particles had no effect. PL3-coated nanoparticles were found to accumulate in TNC-C and NRP-1-positive areas in clinical tumor samples, suggesting a translational relevance. The systemic tumor-targeting properties and binding of PL3-NPs to the clinical tumor sections, suggest that the PL3 peptide may have applications as a targeting moiety for the selective delivery of imaging and therapeutic agents to solid tumors.

Expression Profiling of Extracellular Matrix Genes Reveals Global and Entity-Specific Characteristics in Adenoid Cystic, Mucoepidermoid and Salivary Duct Carcinomas

“…Several ECM components such as fibronectin ( FN1 ) [ 65 ], tenascin C ( TNC ) [ 66 ], thrombospondin 1 ( THBS1) [ 67 ] and osteopontin ( SPP1 ) [ 68 ], which were highly overexpressed in our dataset, are associated with an adverse prognosis and represent potential therapeutic targets [ 2 , 65 , 66 , 67 , 68 ]. Unfortunately, many ECM-related proteins are not exclusively expressed in cancer tissues, making direct targeting difficult.…”

“…In summary, we revealed an overexpression of ECM components, which are associated with enhanced migratory capacities of tumour cells ( TNC [ 76 , 77 ], FN1 [ 78 ]), resistance to chemotherapy ( COL11A1 [ 43 , 75 ], SPP1 [ 79 ]) and adverse outcome ( COL11A1 [ 42 ], TNC [ 80 ], FN1 [ 78 ]) in other primaries. The functional role of these molecules and their potential as therapeutic targets are currently under intense investigation [ 65 , 66 , 75 , 79 , 81 , 82 ]. Hence, as new therapeutic approaches for SGC are needed, our findings are of high translational relevance.…”

In vivo phage display: identification of organ-specific peptides using deep sequencing and differential profiling across tissues

“…iRGD peptide is clinically developed by CEND Therapeutics Inc. (La Jolla, CA, USA) in phase I clinical trial on pancreatic cancer patients as an add-on treatment in combination with Abraxane and gemcitabine (clinical trial identifier: NCT03517176). Other vascular-homing peptides cilengitide (sequence: RGDfV) ( 9 ), SFITGv6 (sequence: GRCTFRGDLMQLCYPD) ( 10 ), CNGRC (sequence: CNGRC) ( 11 ), tumor extracellular matrix (ECM) homing peptides DAG (sequence: CDAGRKQKC) ( 12 ), ZD2 (sequence: CTVRTSADC) ( 13 ), PL1 (sequence: PPRRGLIKLKTS) ( 14 ) and PL3 (sequence: AGRGRLVR) ( 15 ), IP3 (sequence: CKRDLSRRC) ( 16 ), CAR (sequence: CARSKNKDC) ( 17 ) and M2 tumor-associated macrophage targeting UNO peptide ( 18 ) have been selected for possible therapeutic use and reviewed recently ( 19 ). Moreover, healthy organs can be specifically targeted with homing peptides.…”

A distinct repertoire of cancer‐associated fibroblasts is enriched in cribriform prostate cancer

“…Endoglin (ENG) is another CAF marker associated with adverse outcomes, and it has been shown to promote castration-resistant prostate cancer [49][50][51]. Tenascin C (TNC), 5'-nucleotidase ecto (NT5E), and platelet-derived growth factor receptor beta (PDGFRβ) are other CAF markers that are currently candidate targets for imaging or therapeutics [52][53][54][55].…”

“…While the overall expression of NT5E, TNC, and PDGFRβ did not change in the tumor microenvironment, ASPN expression was altered in these cells. Studies are currently assessing NT5E, TNC, and PDGFRβ as candidates for therapeutic targeting [52][53][54][55]. To date, strategies targeting ASPN directly have not been reported, and therefore, therapies directed to these other markers may be an ideal way to target ASPN + fibroblasts.…”