title: Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy.
abstract: Liposome mediated anticancer drug delivery has the advantage of reducing cytotoxicity in healthy tissues. However, undesired slow drug release impedes the therapeutic efficacy of clinically applied PEG-liposomal doxorubicin (Dox). The aim of this study is to combine stealth thermosensitive liposomes (TSL) and local mild hyperthermia (HT) to increase bioavailable Dox levels in tumors. Dox was encapsulated in stealth TSL (~80nm) with optimized PEG concentration in the membrane, and compared with lysolipid-based Dox-LTSL for in vitro stability, release kinetics, and in vivo tumor growth control. In vitro cytotoxicity of Dox-TSL against murine BFS-1 sarcoma and, human BLM melanoma cell lines and Human Umbilical Vein Endothelial Cells (HUVEC) under normothermia (37°C) and HT (42°C) was compared with non-encapsulated Dox. In vitro Dox uptake in nuclei was imaged in BLM and HUVEC. In vivo intravascular Dox release from TSL in BFS-1 tumors under local mild HT in dorsal skin flap window chamber models was captured by intravital confocal microscopy. Intravascular Dox-TSL release kinetics, penetration depth and interstitial Dox density were subjected to quantitative image analysis. Systemic Dox-TSL administration in combination with local mild HT on subcutaneous tumor growth control was compared to Dox-LTSL plus local mild HT. Dox-TSL was stable at 37°C, while released over 95% Dox within 1min in 90% serum at 42°C. Dox-TSL demonstrated efficient in vivo intratumoral Dox release under local mild HT, followed by significant Dox uptake by tumor and tumor vascular endothelial cells. Dox-TSL plus mild HT showed improved tumor growth control over Dox-LTSL plus mild HT. Survival after a single treatment of Dox-TSL plus mild HT was 67%, while survival after Dox-LTSL plus mild HT was 22%. This combination of Dox-TSL and local mild HT offers promising clinical opportunities to improve liposomal Dox delivery to solid tumors.
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
authors.forename: Martin
authors.initials: M
authors.lastname: Hossann
authors.forename: Regine
authors.initials: R
authors.lastname: Süss
authors.forename: Gerard C
authors.initials: GC
authors.lastname: van Rhoon
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Dieter
authors.initials: D
authors.lastname: Haemmerich
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced; D008081:Liposomes; D008545:Melanoma / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin