Antitumor Activity of Auger Electron Emitter 111In Delivered by Modular Nanotransporter for Treatment of Bladder Cancer With EGFR Overexpression

Abstract

Gamma-ray emitting 111In, which is extensively used for imaging, is also a source of short-range Auger electrons (AE). While exhibiting negligible effect outside cells, these AE become highly toxic near DNA within the cell nucleus. Therefore, these radionuclides can be used as a therapeutic anticancer agent if delivered precisely into the nuclei of tumor target cells. Modular nanotransporters (MNTs) designed to provide receptor-targeted delivery of short-range therapeutic cargoes into the nuclei of target cells are perspective candidates for specific intracellular delivery of AE emitters. The objective of this study was to evaluate the in vitro and in vivo efficacy of 111In attached MNTs to kill human bladder cancer cells overexpressing epidermal growth factor receptor (EGFR). The cytotoxicity of 111In delivered by the EGFR-targeted MNT (111In-MNT) was greatly enhanced on EJ-, HT-1376-, and 5637-expressing EGFR bladder cancer cell lines compared with 111In non-targeted control. In vivo microSPECT/CT imaging and antitumor efficacy studies revealed prolonged intratumoral retention of 111In-MNT with t½ = 4.1 ± 0.5 days as well as significant dose-dependent tumor growth delay (up to 90% growth inhibition) after local infusion of 111In-MNT in EJ xenograft-bearing mice.

Targeted Delivery of 111In Into the Nuclei of EGFR Overexpressing Cells via Modular Nanotransporters With Anti-EGFR Affibody

“…When 111 In was delivered into the nuclei of target cancer cells via MNT, its cytotoxicity was markedly greater than that of the free 111 In used as a control. These data correspond to those previously reported (Slastnikova et al, 2017b;Rosenkranz et al, 2018). However, 111 In-NOTA-MNT N-affibody and 111 In-NOTA-MNT C-EGF demonstrates higher cytotoxicity than 111 In-NOTA-MNT N-EGF ( Figure 8).…”

“…We investigated the effects of MNT on cell proliferation on the non-atypical cell model MCF-7, for which activation of EGFR leads to mitogenic effect. We used A431 cell line for the other experiments, since the results for the previously described MNT C-EGF were obtained on this cell line (Gilyazova et al, 2006;Rosenkranz et al, 2008;Slastnikova et al, 2012a;Koumarianou et al, 2014;Slastnikova et al, 2017b;Rosenkranz et al, 2018), however for A431 activation of EGFR leads to inhibition of the tumor cell proliferation (Kawamoto et al, 1983;Bromberg et al, 1998). We showed that MNT N-affibody did not affect cell growth ( Figure 10), that was consistent with the properties of this affibody (Friedman et al, 2008;Beuttler et al, 2009;Ekerljung et al, 2012).…”

“…However, since the part of the EGF transported to the nucleus is extremely small (about 7-8%) compared to the cell-bound EGF within 4 h after adding (Reilly et al, 2000), another method should be developed to increase the efficiency of delivery of the cytotoxic agent to the cell nuclei. One of these developments is the modular nanotransporters (MNT) designed in our laboratory (Gilyazova et al, 2006;Rosenkranz et al, 2018). MNT were designed to deliver locally acting drugs such as photosensitizers and radionuclide-emitting short-range particles to the nuclei of the target cells (Sobolev, 2008;Sobolev et al, 2016;Sobolev, 2018).…”

“…The experiments with this MNT were carried out on several cell lines in particular on human A431 epidermoid carcinoma cells. It was shown that MNT C-EGF efficiently delivered drugs to the cell nucleus of the target cells and enhanced their cytotoxic efficacy in vitro (Gilyazova et al, 2006;Rosenkranz et al, 2008;Slastnikova et al, 2012a;Koumarianou et al, 2014;Slastnikova et al, 2017b;Rosenkranz et al, 2018) and in vivo (Slastnikova et al, 2012a;Slastnikova et al, 2012b;Slastnikova et al, 2017b;Rosenkranz et al, 2018). Thus, in in vitro experiments it was shown that the concentration of the drug agent (Auger electron emitters 111 In, 67 Ga, 125 I, or alpha-particle emitter 211 At or photosensitizers bacteriochlorin p or chlorin e 6 ) corresponding to 50% survival of cancer cells was up to 3000 times higher for free chlorin e 6 or corresponding to 37% survival up to 4000 times for 125 I compared to MNT-agent conjugates (Gilyazova et al, 2006;Rosenkranz et al, 2008;Slastnikova et al, 2012a;Koumarianou et al, 2014;Slastnikova et al, 2017b).…”

Membrane Trafficking and Subcellular Drug Targeting Pathways

“…Another aspect of membrane trafficking constitutes the design of targeting strategies such that some very specific molecules viz. folate receptors (Slastnikova et al, 2017), epidermal growth factor receptros (Rosenkranz et al, 2018), melanocortin receptor-1 (Durymanov et al, 2012), and a-melanocyte stimulating hormone (Rosenkranz et al, 2003), overexpressed on the diseased (e.g. cancerous) cells, act as the target and receptor-specific ligand bearing transportation carriers that are designed for the delivery of therapeutic payloads.…”