Development of phage display-derived targeted cancer therapy and net-work scaffold for 3D cancer cell culture

Abstract

Precision medicine emphasizes the patient-specific formulation for treating diseases, especially cancer. For targeted cancer treatment, however, since the expression level of tumor receptors on each patient varies even for the same type of cancer, the ligand-receptor mediated approach does not seem promising for precision medicine. In this study, we first identified a tubulin-interactive peptide (TIP) from Tau protein that is a well-known microtubule binding protein. The TIP was attached on an up-converting nano-particle (UCNP) core with other functional peptides, including the SKBR-3 cell-targeting peptide that was selected via in vitro biopanning by our lab and cell penetrating peptide R8, to synthesize multi-functional nanoparticle complex CTP/TIP-UCNPs. We have demonstrated CTP/TIP-UCNPs for a potential tubulin interfering anti-cancer reagent, which could be specifically delivered to the breast cancer cells, interrupt the cellular microtubule function and finally killed the cells. To better apply the precision medicine on anti-breast cancer therapy, through in vivo biopanning, we first selected an MCF-7 breast tumor-targeting peptide, then tested the effectiveness of the as-selected peptide in tumor homing, and finally conjugated the peptide to a model photothermal drug, the gold nanorods, to achieve enhanced cancer killing efficacy. The peptides identified by phage display technique can guide the drug to tumors without the need of first knowing the exact receptors on the tumor, which will take significantly less effort to explore the patient-specific targeting molecules for precision medicine. However, we also developed the substitute of tumor-bearing model with low cost for tumor-targeting reagents discovery, the 3D cultured breast cancer cell spheroids, which can mimic the in vivo tumor microenvironment and have similar drug resistance to real tumor tissues rather than two dimensionally cultured cancer cells.