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.
Highlights
Using a spectroscopic method developed in previous work to monitor the release kinetics of LTPT in aqueous buffer and biological fluids[24], TPT release was monitored in cell culture medium to determine if LTPT formulations provided sustained release in Tumor-endothelial cell spheroids (TES) media
The typical treatment options available for triple negative breast cancer (TNBC) are a combination of therapies such as surgery, chemotherapy and radiation[44]
Chemotherapy followed by radiotherapy has been shown to significantly increase the survival outcomes in TNBC women after mastectomy[45]
Summary
The 3D system of tumor and endothelial cells co-cultured in ‘hanging drops’ recreates aspects of the tumor microenvironment, offering a simple yet potentially powerful in vitro tumor model to study therapeutic response. These avascular multicellular TES recreate the gradient of hypoxia, pH and interstitial pressure that results in the inner necrotic and the outer proliferating layer of cells similar to solid tumors in vivo[19,20]. A TES model of triple negative breast cancer (TNBC) was used to investigate whether the extended release and drug penetration from liposomal TPT provided similar cytotoxicity as metronomic dosing. This study investigates the combined effect of a clinically relevant dose of radiation (3 Gy) in conjunction with free or liposomal on avascular tumor-endothelial spheroids over an extended period of 10 days
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