Enhanced Specificity and Drug Delivery in Tumors by cRGD - Anchoring Thermosensitive Liposomes

Dicheva, B. M. and Ten Hagen, T. L. M. and Seynhaeve, A. L. B. and Amin, M. and Eggermont, A. M. M. and Koning, G. A. (2015) Enhanced Specificity and Drug Delivery in Tumors by cRGD - Anchoring Thermosensitive Liposomes. Pharmaceutical Research, 32 (12). pp. 3862-3876.

[img] Text

Download (10MB)


Purpose: To develop RGD-targeted thermosensitive liposomes with increased tumor retention, improving drug release efficiency upon mild hyperthermia (HT) in both tumor and angiogenic endothelial cells. Methods: Standard termosensitive liposomes (TSL) and TSL containing a cyclic Arg-Gly-Asp (cRGD) pentapeptide with the sequence Arg-Cys-D-Phe-Asp-Gly (RGDfN-MetC) were synthetized, loaded with Dox and characterized. Temperature- and time-dependent drug release profiles were assessed by fluorometry. Intracellular Dox delivery was studied by flow cytometry and confocal microscopy. Cytotoxic effect of TSL and RGD-TSL was studied on B16Bl6 melanoma, B16F10 melanoma and HUVEC. Intravital microscopy was performed on B16Bl6 tumors implanted in dorsal-skin fold window-bearing mice. Pharmacokinetic and biodistribution of Dox-TSL and Dox-RGD-TSL were followed in B16Bl6 tumor bearing mice upon normothermia or initial hyperthermia conditions. Results: DLS and cryo-TEM revealed particle homogeneity and size of around 85 nm. Doxorubicin loading efficiency was >95%as assessed by spectrofluorometry. Flow cytometry and confocal microscopy showed a specific uptake of RGD-TSL by melanoma and endothelial cells when compared to TSL and an increased doxorubicin delivery. High resolution intravital microscopy demonstrated specific accumulation of RGD-TSL to the tumor vasculature. Moreover, application of hyperthermia resulted in massive drug release from RGD-TSL. Biodistribution studies showed that initial hyperthermia increases Dox uptake in tumors from TSL and RGD-TSL. Conclusion: RGD-TSL have potency to increase drug efficacy due to higher uptake by tumor and angiogenic endothelial cells in combination with heat-triggered drug release. © 2015 The Author(s).

Item Type: Article
Additional Information: Cited By :30 Export Date: 16 February 2020 CODEN: PHREE Correspondence Address: Dicheva, B.M.; Laboratory Experimental Surgical Oncology, Section Surgical Oncology Department of Surgery, Erasmus MC Cancer CenterNetherlands; email: b.dicheva@erasmusmc.nl
Uncontrolled Keywords: Doxorubicin drug delivery hyperthermia RGD - thermosensitive liposomes arginylglycylaspartic acid liposome pentapeptide antineoplastic antibiotic cyclic arginine-glycine-aspartic acid peptide cyclopeptide delayed release formulation animal cell animal experiment animal model Article body temperature confocal microscopy controlled study cytotoxicity drug delivery system drug distribution drug release endothelium cell flow cytometry fluorometry melanoma microscopy mouse neoplasm nonhuman priority journal temperature tumor vascularization animal C57BL mouse chemistry human pathology tissue distribution tumor cell line umbilical vein endothelial cell Animals Antibiotics, Antineoplastic Cell Line, Tumor Delayed-Action Preparations Human Umbilical Vein Endothelial Cells Humans Liposomes Mice Mice, Inbred C57BL Peptides, Cyclic
Subjects: QV pharmacology
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib5 lib5
Date Deposited: 05 May 2020 06:40
Last Modified: 05 May 2020 06:40
URI: http://eprints.mums.ac.ir/id/eprint/18818

Actions (login required)

View Item View Item