title: An in vitro assessment of liposomal topotecan simulating metronomic chemotherapy in combination with radiation in tumor-endothelial spheroids.
abstract: Low dose metronomic chemotherapy (LDMC) refers to prolonged administration of low dose chemotherapy designed to minimize toxicity and target the tumor endothelium, causing tumor growth inhibition. Topotecan (TPT) when administered at its maximum tolerated dose (MTD) is often associated with systemic hematological toxicities. Liposomal encapsulation of TPT enhances efficacy by shielding it from systemic clearance, allowing greater uptake and extended tissue exposure in tumors. Extended release of TPT from liposomal formulations also has the potential to mimic metronomic therapies with fewer treatments. Here we investigate potential toxicities of equivalent doses of free and actively loaded liposomal TPT (LTPT) and compare them to a fractionated low dose regimen of free TPT in tumor-endothelial spheroids (TES) with/without radiation exposure for a prolonged period of 10 days. Using confocal microscopy, TPT fluorescence was monitored to determine the accumulation of drug within TES. These studies showed TES, being more reflective of the in vivo tumor microenvironment, were more sensitive to LTPT in comparison to free TPT with radiation. More importantly, the response of TES to low-dose metronomic TPT with radiation was comparable to similar treatment with LTPT. This TES study suggests nanoparticle formulations designed for extended release of drug can simulate LDMC in vivo.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors.forename: Amar
authors.initials: A
authors.lastname: Jyoti
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Fugit
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Sethi
authors.affiliation: Department of Radiation Medicine, University of Kentucky Chandler Hospital, Lexington, KY.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: McGarry
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Upreti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005720:Gamma Rays; D007150:Immunohistochemistry; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D019772:Topotecan / Q000737:chemistry* / Q000633:toxicity
chemical_list: D008081:Liposomes; D019772:Topotecan; D020928:Mitogen-Activated Protein Kinases