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.