<p>Modulated electro-hyperthermia-enhanced liposomal drug uptake by cancer cells</p>

Abstract

Purpose Modulated electro-hyperthermia (mEHT) stands to be a significant technological advancement in the hyperthermia field, utilizing autofocusing electromagnetic power on the cell membrane to create massive apoptosis. Since mEHT possesses the unique ability to excite cell membranes, we hypothesized that mEHT could enhance the uptake of liposomal drugs by enhancing phagocytic activity. Materials and methods Water bath control and mEHT were used to compare the enhancement of liposome-encapsulated doxorubicin (Lipodox ® ) uptake by cancer cells. Cancer cells were made visible by doxorubicin fluorescence to investigate drug uptake. Viable cell yield was determined via the Trypan Blue exclusion method. Various substrates were used to investigate the mechanism of drug-uptake enhancement. The murine colon carcinoma model, CT26, was used to confirm the tissue infiltration of Lipodox ® and its therapeutic effect. Results mEHT treatment showed a significant enhancement of Lipodox ® uptake of doxorubicin fluorescence compared with 37°C or 42°C water bath treatment. Tumor tissue sections also confirmed that mEHT treatment achieved the highest doxorubicin concentration in vivo (1.44±0.32 µg/g in mEHT group and 0.79±0.32 µg/g in 42°C water bath). Wortmannin was used to inhibit the macropinocytosis effect and 70 kDa dextran-FITC served as uptake substance. The uptake of dextran-FITC by cancer cells significantly increased after mEHT treatment whereas such enhancement was significantly inhibited by wortmannin. Conclusion The result showed mEHT-induced particle-uptake through macropinocytosis. mEHT-enhanced uptake of Lipodox ® may amplify the therapeutic effect of liposomal drugs. This novel finding warrants further clinical investigation.

Exhaustion of Protective Heat Shock Response Induces Significant Tumor Damage by Apoptosis after Modulated Electro-Hyperthermia Treatment of Triple Negative Breast Cancer Isografts in Mice

“…The tumor-cell-killing effect of mEHT and the consequent reduction in viable tumor cell count has been already demonstrated in several in vitro experiments using other cell lines [ 10 , 12 , 25 , 42 , 44 ], such as U87-MG and A172 human glioma cells [ 10 ], OVCAR-3, SK-OV-3, HeLa, and SNU-17 human ovarian and cervical cancer cells [ 25 ], CT26 colorectal carcinoma cells [ 42 ] and B16F10 mouse melanoma cells [ 12 ]. However, the acute viability-reducing ability of mEHT treatment has not yet been confirmed with imaging techniques, in vivo.…”

Review of the Clinical Evidences of Modulated Electro-Hyperthermia (mEHT) Method: An Update for the Practicing Oncologist

“…Given the ability of mEHT to heat tumors to within the moderate hyperthermia heating range [as demonstrated in a porcine model (58), other animal models (59–61). and human (44) studies], the improved perfusion, and ability to increase drug absorption, mEHT is a safe, and effective heating technology which can be easily applied to treat tumors which have demonstrated benefits with the addition of hyperthermia.…”

Modulated Electro-Hyperthermia-Induced Tumor Damage Mechanisms Revealed in Cancer Models

“…Tumor chemotherapy can also be improved in combination with mEHT, as has been confirmed by series of preclinical studies. While doxorubicin (Dox) treatment of C26 (also called CT26) CRC cell culture primarily led to tumor cell necrosis, mEHT monotherapy resulted in a massive apoptosis with significantly higher γ H2ax levels, indicating DNA DSBs, compared with after Dox [ 40 ]. Both treatments reduced long-term tumor colony formation after 10 days, indicating that they are also targeting the tumor progenitor/stem cell populations [ 91 ].…”

“…Liposomal doxorubicin (lipodox) treatment resulted in the most efficient in vitro killing of human hepatocellular (HepG2) and lung (A549) adenocarcinomas and U87-MG glioblastoma, as well as of mouse CT26 CRC, when combined with mEHT compared to WB heating either at 37 °C or at 42 °C [ 40 ]. Lipodox uptake measured by its fluorescence was facilitated by mEHT in vitro in the HerG2 > A549 > U87-MG > CT26 cell line order.…”