SW43‐DOX ± loading onto drug‐eluting bead, a potential new targeted drug delivery platform for systemic and locoregional cancer treatment – An in vitro evaluation

Abstract

Treatment of unresectable primary cancer and their distant metastases, with the liver representing one of the most frequent location, is still plagued by insufficient treatment success and poor survival rates. The Sigma-2 receptor is preferentially expressed on many tumor cells making it an appealing target for therapy. Thus, we developed a potential targeted drug conjugate consisting of the Sigma-2 receptor ligand SW43 and Doxorubicin (SW43-DOX) for systemic cancer therapy and for locoregional treatment of primary and secondary liver malignancies when loaded onto drug-eluting bead (DEB) which was compared in vitro to the treatment with Doxorubicin alone. SW43-DOX binds specifically to the Sigma-2 receptor expressed on hepatocellular (Hep G2, Hep 3B), pancreatic (Panc-1) and colorectal (HT-29) carcinoma cell lines with high affinity and subsequent early specific internalization. Free SW43-DOX showed superior concentration and time depended cancer toxicity than treatment with Doxorubicin alone. Action mechanisms analysis revealed an apoptotic cell death with increased caspase 3/7 activation and reactive oxygen species (ROS) production. Only ROS scavenging with α-Tocopherol, but not the caspase inhibition (Z-VAD-FMK), partly reverted the effect. SW43-DOX could successfully be loaded onto DEB and showed prolonged eluting kinetics compared to Doxorubicin. SW43-DOX loaded DEB vs. Doxorubicin loaded DEB showed a significantly greater time dependent toxicity in all cell lines. In conclusion, the novel conjugate SW43-DOX ± loading onto DEB is a promising drug delivery platform for targeted systemic and locoregional cancer therapy.

Targeted Yttrium 89-Doxorubicin Drug-Eluting Bead—A Safety and Feasibility Pilot Study in a Rabbit Liver Cancer Model

“…On a molecular basis, the SW43 moiety targets the sigma-2 receptor expressing tumor cells with subsequent specific internalization and acts synergistically with the attached doxorubicin. 14 Although not tested with an radioactive isotope in this study, the chelator L-NETA of this compound bears the potential to additionally deliver radiation (e.g., 90 yttrium or 177 lutetium) for treatment and imaging purposes. 14 As for every newly developed drug, evaluation of treatment safety and determination of tolerated treatment dose is of utmost importance prior to efficacy evaluation.…”

“…SW43-DOX-L-NETA synthesis and loading procedure onto drug-eluting beads is outlined in Figure 2 and has been described in detail previously. 14 Briefly, the sigma-2 agonist SW43 (1R,3R,5S)-9-(10-aminodecyl)-9-azabicyclo[3.3.1]nonan-3-yl (2-methoxy-5-methylphenyl)-carbamate was synthesized and modified with a linker bearing azide and amino group followed by the coupling of an oxyamine group in order to attach doxorubicin. The synthesized BFC L-NETA (2,2’-((6-amino-1-(4,7-bis-(carboxymethyl)-1,4,7-triazonan-1-yl)hexan-2-yl)azanediyl)-diacetic acid) was conjugated with SW43-DOX via copper free click chemistry, and the resulting SW43-DOX-L-NETA was chelated with 89 Y 3+ : SW43-DOX-L-NETA and YCl 3 were mixed in DI water at molar ratio of 1:1, and the resulting mixture was incubated at 40 °C for 30 min.…”

“…12–15 Sigma-2 receptor agonists, such as SW43, have been described to induce a potent antiproliferative and proapoptotic effect in cancer cells with only very limited to no harm to nontumorous tissue. 14,16,17 Additionally, SW43 acts synergistically with antineoplastic drugs, such as doxorubicin and, when attached to SW43, internalizes specifically and quickly into the tumor cells with increased intracellular accumulation and treatment efficacy making it an ideal molecule for developing a cancer targeting drug compound. 14,17–19…”

Future Interventional Oncology Catheter-Based Therapies

“…In addition, this molecule has both intrinsic anticancer properties and can be chemically linked to conventional chemotherapeutic agents for improved tumorkilling efficacy. 19 Although it has not yet been studied in humans, results in animal models have been promising.…”

“…1). 19 This was done to combat the numerous off-target side effects known to occur with systemic doxorubicin. In vitro, pancreatic cancer (Panc-1), HCC (Hep G2 and Hep 3B), and colorectal cancer (HT-29) cell lines were found to have specific binding for SW43-DOX via the sigma-2 receptor.…”