Preparation, cytotoxicity, and in vivo antitumor efficacy of ¹¹¹In-labeled modular nanotransporters

Development and evaluation of a new modular nanotransporter for drug delivery into nuclei of pathological cells expressing folate receptors

“…For the in vivo proof of principle, we chose the locoregional administration route for our initial experiments to get rid of numerous factors influencing the drug on its way to the target in the blood circulation. The retention of 111 In-MNT-PEG-FA within the tumor is similar to our previously published data obtained for another type of MNT targeted at MC1R 21. Compared to intratumorally injected 188 Re-labeled anti-HER2 antibody Herceptin (~150 kDa), 38 111 In-labeled MNTs possess significantly prolonged tumor retention.…”

“…To accomplish this, we have developed a concept of MNTs providing specific transport of the attached therapeutic agent from the surface to the target pathological cell nucleus. This concept realized previously in melanocortin receptors-1 (MC1R) and EGFR-targeted MNTs proved its feasibility and high potency in vitro15–17,19,20 and in vivo,17,21 with each module retaining functionality and asserting the necessity of its inclusion within the MNT 15,16. The goal of this study was to develop a new targeted system combining FR-targeting strategy with the MNT approach that provides specific transport of the attached therapeutic agent from the surface to the target pathological cell nucleus, where the delivered agent is the most potent.…”

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

“…EGFRs are highly convenient for the targeted delivery of various drugs into cancer cells. A number of drug delivery vehicles were produced for this purpose and evaluated in vitro and in vivo [ (Chen et al, 2002;Lu et al, 2005;Liu et al, 2010;Song et al, 2016;Slastnikova et al, 2017b;Zahaf et al, 2017;Rosenkranz et al, 2018), etc.]. The main areas of EGFR-targeted drug therapy include: (1) development of drugs based on anti-EGFR antibodies binding to the extracellular EGFR domain, preventing ligand binding, and interrupting signal cascades (Herbst, 2004;Friedman and Stahl, 2009;Scott et al, 2012); (2) tyrosine kinase inhibitors binding to the intracellular EGFR domain and inhibiting the downstream effects of EGFR ligand binding (Herbst, 2004;Dassonville et al, 2007;Gazdar, 2009); and (3) delivery of drugs to cancer cells by fusion constructs containing EGF (Scott et al, 2012).…”

“…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).…”

“…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). In vivo experiments on tumor-bearing mice proved that locoregional injection of MNT C-EGF conjugated with 111 In resulted in significant tumor growth inhibition compared to tumorbearing animals receiving a corresponding dose of non-labeled MNT or free 111 In .…”