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Open Access Green as soon as Postprint is submitted to ZB.
Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy.
J. Control. Release 168, 142-150 (2013)
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 (similar to 80 nm) 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 degrees C) and HT (42 degrees 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 degrees C, while released over 95% Dox within 1 min in 90% serum at 42 degrees 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 plusmild 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 plusmild HT was 22%. This combination of Dox-TSL and local mild HT offers promising clinical opportunities to improve liposomal Dox delivery to solid tumors.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Thermosensitive Liposomes ; Hyperthermia ; Doxorubicin ; Triggered Drug Release ; Intravital Microscopy ; Tumor Growth Control; Temperature-sensitive Liposomes ; Intensity Focused Ultrasound ; Metastatic Breast-cancer ; Soft-tissue Sarcoma ; In-vitro ; Radiofrequency Ablation ; Local Hyperthermia ; Liver-cancer ; Cells ; Trial
ISSN (print) / ISBN
0168-3659
e-ISSN
1873-4995
Journal
Journal of Controlled Release
Quellenangaben
Volume: 168,
Issue: 2,
Pages: 142-150
Publisher
Elsevier
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
CCG Tumor Therapy with Hyperthermia (IMI-KTH)