We report application of affinity-targeted silver nanoparticles (AgNPs) for selective delivery and potentiation of the activity of cytotoxic compound, monomethyl auristatin E (MMAE), in malignant cells. AgNPs were loaded with MMAE via a lysosomal protease cathepsin B sensitive linker and functionalized with a prototypic CendR peptide (RPARPAR) that targets neuropilin-1 (NRP-1) to give the AgNPs a dual tumor specificity as both cathepsin B and NRP-1 are overexpressed in many types of solid tumors. Cellular imaging, flow cytometry, viability assays and high performance liquid chromatography-mass spectrometry (HPLC-MS) analysis showed that the RPARPAR-MMAE-AgNPs are internalized and induce apoptotic cell death in NRP-1-positive PPC-1 prostate cancer cells while sparing NRP-1-negative M21 melanoma cells. The anticancer activity of precision target therapeutic AgNPs will be next studied in series of in vivo models, to determine the effect of nanoformulation and affinity targeting on the therapeutic index of MMAE.
This study, published in Advanced Therapeutics, is a sequel to a series of our studies on precision AgNPs. In addition to the contribution of the members of the Cancer Biology team ( PhD cand. Allan Tobi, Dr. Anne-Mari A. Willmore, PhD cand. Valeria Sidorenko and Prof. Tambet Teesalu) the study included contributions of our collaborators in the US (Prof. Erkki Ruoslahti and Ass. Prof. Kazuki N. Sugahara), Canada (Dr. Gary B Braun), and University of Tartu (Prof. Ursel Soomets and Dr. Kalle Kilk).
Journal Title - Advanced Therapeutics Article Title - Silver Nanocarriers Targeted with a CendR Peptide Potentiate the Cytotoxic Activity of an Anticancer Drug Manuscript ID - adtp.202000097 https://onlinelibrary.wiley.com/doi/10.1002/adtp.202000097
Uptake of nanoparticles functionalized with prototypic C-end Rule peptide RPARPAR-OH in cultured PPC-1 prostate carcinoma cells (movie: Tambet Teesalu)