Overcoming hypoxia-induced chemoresistance to cisplatin through tumor oxygenation monitored by optical imaging

Abstract

Perfluorocarbon nanoparticles have been reported to deliver oxygen to tumors and reduce hypoxia-induced radioresistance, however few studies have been carried out to study its role in reducing hypoxia-induced chemoresistance. The oxygenation effect also varies dramatically between different perfluorocarbon formulations and protocols, and there have been no efficient tools to monitor dynamic changes of tumor oxygenation non-invasively. Our goal was to promote tumor oxygenation using perfluorooctyl bromide (PFOB) nanoemulsion and to assess its role in sensitizing tumors to cisplatin treatment. A novel optical imaging protocol was also created to monitor the dynamic changes of tumor oxygenation in real-time. Methods: PFOB nanoemulsion with high oxygen-carrying capacity was prepared and administered to tumor-bearing mice intravenously. Tumor oxygenation was monitored using optical imaging with a hypoxia probe injected intratumorally, thus the oxygenation dynamics and best oxygenation protocol were determined. Various treatment groups were studied, and the tumor growth was monitored to evaluate the role of oxygenation in sensitizing tumors to cisplatin treatment. Results: PFOB nanoemulsion with and without pre-oxygenation along with carbogen breathing resulted in much better tumor oxygenation compared to carbogen breathing alone, while PFOB with air breathing did not show significant increase in tumor oxygenation. Pre-oxygenated PFOB with carbogen breathing produced the most effective oxygenation as early as 5 min post administration. In vitro and in vivo data showed preoxygenated PFOB nanoemulsion with carbogen breathing could increase cisplatin-mediated apoptosis of cancer cells and inhibited tumor growth at a low dose of cisplatin (1 mg/kg) treatment. Furthermore, the treatment did not induce nephrotoxicity. Conclusions: Preoxygenated PFOB nanoemulsion with carbogen breathing can effectively increase tumor oxygenation, which has a great potential to prevent/overcome hypoxia-induced chemotherapy resistance. In addition, optical imaging with intratumoral injection of the hypoxia probe was an efficient tool to monitor tumor oxygenation dynamics during PFOB administration, providing better understanding on oxygenation effects under different protocols.

Escape From Cisplatin-Induced Senescence of Hypoxic Lung Cancer Cells Can Be Overcome by Hydroxychloroquine

“…However, p53 knockdown did not modulate resistance to cisplatin (66). A preoxygenated perfluorooctyl bromide (PFOB) nanoemulsion with carbogen breathing effectively increased tumor oxygenation in mouse model, which associated with an increase in cisplatin-mediated apoptosis of cancer cells and inhibition of tumor growth with low doses of cisplatin treatment (67).…”

Immunotherapy Using Oxygenated Water and Tumor‐Derived Exosomes Potentiates Antitumor Immune Response and Attenuates Malignancy Tendency in Mice Model of Breast Cancer

“…The initial idea of oxygen therapy for cancer treatment using ozone or hydrogen peroxide, decomposing into oxygen, dates back decades ago [30][31][32][33][34][35][36][37]. Later studies have also shown beneficial effects of oxygen therapy in some cancers [9,[38][39][40][41]. For example, it has been shown that the effect of chemotherapy is significantly increased immediately after hyperbaric oxygen therapy [42].…”

Oxygen-Based Nanocarriers to Modulate Tumor Hypoxia for Ameliorated Anti-Tumor Therapy: Fabrications, Properties, and Future Directions

“…Hence, the oxygen-absorbed PFTBA@HSA NPs possess two-stage oxygen delivery, that is, oxygen evaporation from PFTBA as the first stage and elevated RBC infiltration as the second stage, which was demonstrated to be effective in reliving the hypoxic level ( Zhou et al, 2018a ; Zhou et al, 2018b ). In addition to the PFTBA, some other PFC derivatives such as Perfluoropentane (PFP) ( Chen S. et al, 2018 ) and Perfluorooctylbromide (PFOB) ( Song et al, 2019 ), are also good oxygen carriers, which have been studied to relieve tumor hypoxia ( Table 4 ).…”

“…Results from their study revealed that hypoxia could be alleviated at a moderate rate and the intracellular EP level was significantly elevated, thus effectively decreasing the hypoxia-induced CMT resistance. Similarly, PFOB nanoemulsion has proven to have great potential to overcome hypoxia-induced cisplatin resistance ( Song et al, 2019 ). PFTBA-based HSA NP capable of enhancing oxygen carrier RBC distribution in tumor site was originally engineered by Zhou et al (2018b) , which significantly amplified CMT efficacy with in vivo TGI of more than 80% by improving tumor oxygen concentration.…”