Triggered radiosensitizer delivery using thermosensitive liposomes and hyperthermia improves efficacy of radiotherapy: An in vitro proof of concept study

Abstract

IntroductionTo increase the efficacy of chemoradiation and decrease its toxicity in normal tissue, a new concept is proposed, local radiosensitizer delivery, which combines triggered release of a radiosensitizer from thermosensitive liposomes with local hyperthermia and radiotherapy. Here, key aspects of this concept were investigated in vitro I) the effect of hyperthermia on the enhancement of radiotherapy by ThermoDox (thermosensitive liposome containing doxorubicin), II) the concentration dependence of the radiosensitizing effect of doxorubicin and III) the sequence of doxorubicin, hyperthermia and radiotherapy maximizing the radiosensitizing effect.MethodsSurvival of HT1080 (human fibrosarcoma) cells was measured after exposure to ThermoDox or doxorubicin for 60 minutes, at 37 or 43°C, with or without irradiation. Furthermore, cell survival was measured for cells exposed to different doxorubicin concentrations and radiation doses. Finally, cell survival was measured after applying doxorubicin and/or hyperthermia before or after irradiation. Cell survival was measured by clonogenic assay. In addition, DNA damage was assessed by γH2AX staining.ResultsExposure of cells to doxorubicin at 37°C resulted in cell death, but exposure to ThermoDox at 37°C did not. In contrast, ThermoDox and doxorubicin at 43°C resulted in similar cytotoxicity, and in combination with irradiation caused a similar enhancement of cell kill due to radiation. Doxorubicin enhanced the radiation effect in a small, but significant, concentration-dependent manner. Hyperthermia showed the strongest enhancement of radiation effect when applied after irradiation. In contrast, doxorubicin enhanced radiation effect only when applied before irradiation. Concurrent doxorubicin and hyperthermia immediately before or after irradiation showed equal enhancement of radiation effect.ConclusionIn vitro, ThermoDox resulted in cytotoxicity and enhancement of irradiation effect only in combination with hyperthermia. Therefore hyperthermia-triggered radiosensitizer release from thermosensitive liposomes may ultimately serve to limit toxicities due to the radiosensitizer in unheated normal tissue and result in enhanced efficacy in the heated tumor.

Release of doxorubicin from its liposomal coating via high intensity ultrasound

“…These particles have been better tolerated compared to conventional liquid chemotherapy (30,31). Drug release can increase with time and be enhanced by ultrasound, hyperthermia or other methods, as previously described (32,33). Since the interaction of complex particles with peritoneal tissue has not yet been fully investigated, further studies are required to analyze benefits and disadvantages of LD application with HIUS.…”

The Impact of Nanomedicine on Soft Tissue Sarcoma Treated by Radiotherapy and/or Hyperthermia: A Review

“…A 2018 study proposed an innovative approach for enhancing radiation therapy’s (RT) effectiveness while minimizing side effects by combining it with thermo-sensitive chemotherapeutic agents [ 51 ]. RT often faces limitations due to the risk of radiation-induced toxicity in healthy surrounding tissue, despite its potential for effective tumor control.…”

Combination Therapy of Radiation and Hyperthermia, Focusing on the Synergistic Anti-Cancer Effects and Research Trends

“…HT acts as a radiosensitizer and makes tumor cells more susceptible to irradiation [ 15 ]. When combined with RT, HT can lead to increased cell death in cancer cells, help to shrink the tumor, and improve survival rates [ 16 ].…”