TY - JOUR
T1 - Targeted and heat-triggered doxorubicin delivery to tumors by dual targeted cationic thermosensitive liposomes
AU - Dicheva, Bilyana M.
AU - Ten Hagen, Timo L.M.
AU - Schipper, Debby
AU - Seynhaeve, Ann L.B.
AU - Van Rhoon, Gerard C.
AU - Eggermont, Alexander M.M.
AU - Koning, Gerben A.
N1 - Publisher Copyright:
© 2014 Elsevier B.V. All rights reserved.
PY - 2014/12/10
Y1 - 2014/12/10
N2 - 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.
AB - 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.
KW - Cancer chemotherapy
KW - Cationic thermosensitive liposomes
KW - Cytotoxicity
KW - Hyperthermia
KW - Triggered drug release
UR - http://www.scopus.com/inward/record.url?scp=84908592600&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2014.07.058
DO - 10.1016/j.jconrel.2014.07.058
M3 - Article
C2 - 25176578
AN - SCOPUS:84908592600
SN - 0168-3659
VL - 195
SP - 37
EP - 48
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -