Radiation-Guided Drug Delivery to Mouse Models of Lung Cancer

Abstract

Purpose: The purpose of this study was to achieve improved cancer-specific delivery and bioavailability of radiation-sensitizing chemotherapy using radiation-guided drug delivery.Experimental Design: Phage display technology was used to isolate a recombinant peptide (HVGGSSV) that binds to a radiation-inducible receptor in irradiated tumors. This peptide was used to target nabpaclitaxel to irradiated tumors, achieving tumor-specificity and enhanced bioavailability of paclitaxel.Results: Optical imaging studies showed that HVGGSSV-guided nab-paclitaxel selectively targeted irradiated tumors and showed 1.48 ± 1.66 photons/s/cm 2 /sr greater radiance compared with SGVSGHV-nab-paclitaxel, and 1.49 ± 1.36 photons/s/cm 2 /sr greater than nab-paclitaxel alone (P < 0.05). Biodistribution studies showed >5-fold increase in paclitaxel levels within irradiated tumors in HVGGSSV-nab-paclitaxel-treated groups as compared with either nab-paclitaxel or SGVSGHVnab-paclitaxel at 72 hours. Both Lewis lung carcinoma and H460 lung carcinoma murine models showed significant tumor growth delay for HVGGSSV-nab-paclitaxel as compared with nab-paclitaxel, SGVSGHV-nab-paclitaxel,and saline controls. HVGGSSV-nab-paclitaxel treatment induced a significantly greater loss in vasculature in irradiated tumors compared with unirradiated tumors, nab-paclitaxel, SGVSGHV-nab-paclitaxel, and untreated controls.Conclusions: HVGGSSV-nab-paclitaxel was found to bind specifically to the tax-interacting protein-1 (TIP-1) receptor expressed in irradiated tumors, enhance bioavailability of paclitaxel, and significantly increase tumor growth delay as compared with controls in mouse models of lung cancer. Here we show that targeting nab-paclitaxel to radiation-inducible TIP-1 results in increased tumor-specific drug delivery and enhanced biological efficacy in the treatment of cancer. Clin Cancer Res; 16(20); 4968-77. ©2010 AACR.

Anti-tax interacting protein-1 (TIP-1) monoclonal antibody targets human cancers

“…Previously we have demonstrated improved radiation therapy with a peptide that specifically bound to TIP-1 (HVGGSSV) conjugated with nano-albumin-paclitaxel. HVGGSSV-nab-paclitaxel showed tumor-specific binding and enhanced bioavailability of the drug [11]. …”

“…Recently TIP-1 was shown to activate Rho GTPases and facilitate cell migration in glioblastoma [10]. Mouse models of lung cancer were specifically targeted by TIP-1 specific peptide HVGGSSV [11, 12]. Overall, TIP-1′s involvement in many different cancer pathways demonstrates its potential to be explored as a molecular target for cancer therapy.…”

Combinatorial Peptide Libraries: Mining for Cell-Binding Peptides

“…These include nanoworms, 103,276 particles created from a phage coat protein, 156 nab-paclitaxel, 265,274,275,301 microbubbles, 300 and polyester-based particles. 320 In particular, nab-paclitaxel, a nanoparticle formed by albumin-coated paclitaxel, has been conjugated to several peptides for tumor inhibition in rodents.…”

Neoantigen activation, Protein Translocation and Targeted Drug Delivery in Combination With Radiotherapy

“…Administration of HVGGSSV-nab-paclitaxel NPs 4 h after x-ray irradiation resulted in significantly greater tumor accumulation and growth delay by 10 d in murine lung cancer and 15 d in human lung cancer models in mice compared with a delay of 2 d in murine lung cancer and 6 d in human lung cancer models with nab paclitaxel or radiation alone. This approach also resulted in higher levels of targeted nab paclitaxel in irradiated tumors future science group Review Sethuraman & Ranjan than in heart, lungs, brain, liver, kidneys and nonirradiated tumors [28]. Lowery et al used fractionated x-ray treatment at 3 Gy for 5 d to induce TIP-mediated translocation in lung cancer endothelial cells [29].…”