Many cancers at advanced stages require a combination of chemotherapy and radiotherapy. A big challenge with this approach is accumulated toxicity because both of these treatment modalities are non-selective and inevitably damage non-target tissues. Nanoparticles such as liposomes provide the ability to differentiate between healthy and cancerous tissues and thus offer efficient delivery of chemotherapy to cancerous tissues. Recently, we developed a matrix metalloproteinase (MMP)-sensitive liposomal platform to carry anticancer agents to the tumor. High local expression of MMPs within the tumor microenvironment ensures bioavailability of the carried agent by converting a polyethylene glycol (PEG)ylated anionic liposome into a dePEGylated cationic liposome that is readily internalized by cells. Using oxaliplatin-loaded MMP-sensitive liposomes, we previously demonstrated great in-vivo efficacy in mice bearing CT26 tumors.
In the present study, we assessed the combinatorial effect of MMP-sensitive liposomes and radiotherapy in head and neck squamous cell carcinoma models. Using a clonogenic cell survival assay, we evaluated MMP-sensitive liposomes combined with radiotherapy. A slightly sensitizing effect was produced by oxaliplatin-loaded MMP-sensitive liposomes while free oxaliplatin produced an additive effect. Similarly, levels of platinum intercalated into DNA were three times higher in cells treated with oxaliplatin-loaded MMP-sensitive liposomes than in those treated with free oxaliplatin. The in-vivo efficacy of oxaliplatin-loaded MMP-sensitive liposomes combined with radiotherapy was studied in the same tumor models, FaDu and HN5, where zymogram gels confirmed an MMP-positive tumor microenvironment. MMP-sensitive liposomes and radiation had a much greater anti-tumor effect than any of the monotherapies or free oxaliplatin combined with radiation. In FaDu, the mean tumor size between liposomes + radiation and liposomes only were significantly different (p<0.05). Thus, our preliminary results suggest that MMP-sensitive liposomes in combination with radiation hold a great potential for clinical translation. The MMP-sensitive liposome offers a valuable tool to deliver the payload in a controlled fashion into the tumor microenvironment, where radiation can potentially amplify the therapeutic index.
Note: This abstract was not presented at the meeting.
Citation Format: Rikke Y. Brogaard, Allison Khoo, Rasmus Eliasen, Fredrik Melander, Awalpreet Chadha, Kathryn Aziz, Sunil Krishnan, Thomas L. Andresen. MMP sensitive liposomes followed by radiotherapy improves tumor control in head and neck cancer mice models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1065. doi:10.1158/1538-7445.AM2017-1065