Effective Anticancer Therapy by Combination of Nanoparticles Encapsulating Chemotherapeutic Agents and Weak Electric Current

• Published in: Biological & pharmaceutical bulletin 2022/02/01, Vol.45(2), pp.194-199
• Main Authors: Khatun, Anowara, Hasan, Mahadi, El-Emam, Mahran Mohamed Abd, Fukuta, Tatsuya, Mimura, Miyuki, Tashima, Riho, Yoneda, Shintaro, Yoshimi, Shintaro, Kogure, Kentaro
• Format: Article
• Language: English
• Subjects: Animals; anticancer therapy; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Cancer; Cancer therapies; Cell signaling; Chemotherapy; Connexin 43; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - therapeutic use; Drug delivery; Drug Delivery Systems - methods; Electric currents; Electrochemical Techniques; enhanced permeability and retention effect; Gap junctions; Growth inhibition; Intravenous administration; Male; Melanoma; Melanoma - drug therapy; Mice; Mice, Inbred C57BL; nanoparticle; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Neoplasms, Experimental; Permeability; Phosphorylation; Polyethylene glycol; Skin; Tumors; weak electric current; Xenograft Model Antitumor Assays
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b21-00714

Delivery of medicines using nanoparticles via the enhanced permeability and retention (EPR) effect is a common strategy for anticancer chemotherapy. However, the extensive heterogeneity of tumors affects the applicability of the EPR effect, which needs to overcome for effective anticancer therapy. Previously, we succeeded in the noninvasive transdermal delivery of nanoparticles by weak electric current (WEC) and confirmed that WEC regulates the intercellular junctions in the skin by activating cell signaling pathways (J. Biol. Chem., 289, 2014, Hama et al.). In this study, we applied WEC to tumors and investigated the EPR effect with polyethylene glycol (PEG)-modified doxorubicin (DOX) encapsulated nanoparticles (DOX-NP) administered via intravenous injection into melanoma-bearing mice. The application of WEC resulted in a 2.3-fold higher intratumor accumulation of nanoparticles. WEC decreased the amount of connexin 43 in tumors while increasing its phosphorylation; therefore, the enhancing of intratumor delivery of DOX-NP is likely due to the opening of gap junctions. Furthermore, WEC combined with DOX-NP induced a significant suppression of tumor growth, which was stronger than with DOX-NP alone. In addition, WEC alone showed tumor growth inhibition, although it was not significant compared with non-treated group. These results are the first to demonstrate that effective anticancer therapy by combination of nanoparticles encapsulating chemotherapeutic agents and WEC.