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Marina Simón,1,* Jesper Tranekjær Jørgensen,1,* Kamilla Norregaard,1 Jonas Rosager Henriksen,2 Gael Clergeaud,2 Thomas L Andresen,2 Anders Elias Hansen,2 Andreas Kjaer1 1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Department of Health Technology, Section for Biotherapeutic Engineering and Drug Targeting, Technical University of Denmark, Kongens Lyngby, Denmark*These authors contributed equally to this workCorrespondence: Andreas Kjaer, Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark, Email akjaer@sund.ku.dkIntroduction: Traditional cancer treatments, such as chemotherapy, are often incapable of achieving complete responses as standalone therapies. Hence, current treatment strategies typically rely on a combination of several approaches. Nanoparticle-based photothermal therapy (PTT) is a technique used to kill cancer cells through localized, severe hyperthermia that has shown promise as an add-on treatment to multiple cancer therapies. Here, we evaluated whether the combination of gold nanoshell (NS)-based PTT and liposomal doxorubicin could improve outcome in a mouse model of colorectal cancer.Methods: First, NS-based PTT was performed on tumor-bearing mice. Radiolabeled liposomes were then injected at different timepoints to follow their accumulation in the tumor and determine the ideal injection time after PTT. In addition, fluorescent liposomes were used to observe the liposomal distribution in the tumor after PTT. Finally, we combined PTT and doxorubicin-loaded liposomes and studied the effect of the treatment strategy on the mice by following tumor growth and survival.Results: PTT significantly improved liposomal accumulation in the tumor, but only when the liposomes were injected immediately after the therapy. The liposomes accumulated mostly in regions adjacent to the ablated areas. When PTT was combined with liposomal doxorubicin, the mice experienced a slowdown in tumor growth and an improvement in survival.Conclusion: According to our preclinical study, NS-based PTT seems promising as an add-on treatment for liposomal chemotherapy and potentially other systemic therapies, and could be relevant for future application in a clinical setting.Graphical Abstract: Keywords: liposomes, PET imaging, chemotherapy, hyperthermia, gold nanoparticles