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J Control Release. 2014 Dec 10;195:37-48. doi: 10.1016/j.jconrel.2014.07.058. Epub 2014 Aug 29.

Targeted and heat-triggered doxorubicin delivery to tumors by dual targeted cationic thermosensitive liposomes.

Author information

1
Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
2
Unit Hyperthermia, Department Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
3
Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Institut Gustave Roussy, Villejuif, France.
4
Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. Electronic address: g.koning@erasmusmc.nl.

Abstract

Liposomal nanoparticles can circumvent toxicity of encapsulated chemotherapeutic drugs, but fall short in tumor-specific and efficient intracellular drug delivery. To overcome these shortcomings, we designed a multifunctional dual targeted, heat-responsive nanocarrier encapsulating doxorubicin (Dox) as a chemotherapeutic content. Dox-loaded cationic thermosensitive liposomes (Dox-CTSL) carry targeting functions addressing tumor cells and tumor vasculature and have a heat-responsive lipid bilayer. Targeted Dox-CTSL demonstrated superior uptake by and toxicity to different tumor cell lines and endothelial cells compared to non-targeted TSL. Heat triggered intracellular Dox release in acidic cell compartments was visualized as fluorescent Dox nanobursts by live cell confocal microscopy. In vivo, using high resolution intravital microscopy, we demonstrated that Dox-CTSL upon an external heat-trigger delivered 3-fold higher Dox quantity to tumors than TSL. Dox-CTSL bound specifically to tumor vasculature, which in combination with the heat-triggered drug release caused significant tumor vessel damage, which was not observed when non-targeted TSL were administered. Therefore, Dox-CTSL have strong potency to increase drug efficacy due to targeted delivery and heat-triggered drug release in tumors.

KEYWORDS:

Cancer chemotherapy; Cationic thermosensitive liposomes; Cytotoxicity; Hyperthermia; Triggered drug release

PMID:
25176578
DOI:
10.1016/j.jconrel.2014.07.058
[Indexed for MEDLINE]

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