Dynamic contrast enhanced MRI detects changes in vascular transport rate constants following treatment with thermally-sensitive liposomal doxorubicin

Abstract

Temperature-sensitive liposomal formulations of chemotherapeutics, such as doxorubicin, can achieve locally high drug concentrations within a tumor and tumor vasculature while maintaining low systemic toxicity. Further, doxorubicin delivery by temperature-sensitive liposomes can reliably cure local cancer in mouse models. Histological sections of treated tumors have detected red blood cell extravasation within tumors treated with temperature-sensitive doxorubicin and ultrasound hyperthermia. We hypothesize that the local release of drug into the tumor vasculature and resulting high drug concentration can alter vascular transport rate constants along with having direct tumoricidal effects. Dynamic contrast enhanced MRI (DCE-MRI) coupled with a pharmacokinetic model can detect and quantify changes in such vascular transport rate constants. Here, we set out to determine whether changes in rate constants resulting from intravascular drug release were detectable by MRI. We found that the accumulation of gadoteridol was enhanced in tumors treated with temperature-sensitive liposomal doxorubicin and ultrasound hyperthermia. While the initial uptake rate of the small molecule tracer was slower in treated compared to untreated tumors (k1 = 0.0478 ± 0.011 s-1 versus 0.116 ± 0.047 s-1), the tracer was retained after treatment due to a larger reduction in the rate of clearance (k2 = 0.291 ± 0.030 s-1 versus 0.747 ± 0.24 s-1). While DCE-MRI assesses a combination of blood flow and permeability, ultrasound imaging of microvascular flow rate is sensitive only to changes in vascular flow rate; based on this technique, blood flow was not significantly altered 30 minutes after treatment. In summary, DCE-MRI provides a means to detect changes that are associated with treatment by thermally-activated particles and such changes can be exploited to enhance local delivery.

Vascular and extracellular matrix remodeling by physical approaches to improve drug delivery at the tumor site

“…However, and as underlined here-above, moderate increase of blood flow in tumours was observed, as described more than 20 years ago by Baronzio et al [82], and recently confirmed by Dynamic Contrast Enhanced MRI characterising the delivery of doxorubicin from thermosensitive liposomes to mammary carcinoma. No increase of blood flow rate was observed even though an increased drug delivery could be seen [83]. Recent investigations highlighted that longer exposure to temperature above 42.5 °C could result in impairment of blood flow since fragile and chaotic neoangiogenic tumour microcirculation is severely damaged [76,84].…”

“…Upon increasing temperature over 44 °C, various studies repetitively described predictable deformation of the vessels, stiffening of red and white blood cells, leading to their sticking to the wall, coagulation [85] and haemorrhage [83,86,87].…”

“…Increased delivery/cell uptake of doxorubicin loaded in thermosensitive liposomes [83], elastin-like peptides [89], iron oxide nanocubes [90], nanospheres [101], DOX-loaded in thermoresponsive PNIPAM liposomes [96] or mertansine-lipoproteins [104] (in vivo), iron oxide nanoparticles [97] (in vitro)…”

The effects of doxorubicin‑loaded liposomes on viability, stem cell surface marker expression and secretion of vascular endothelial growth factor of three‑dimensional stem cell spheroids

“…To solve this problem, doxorubicin-loaded nanoparticles including liposomes were developed and they could result in improved tumor-growth inhibition with less general toxicity compared to the free drug molecules ( 3 ). Liposomal formulations of doxorubicin, can achieve locally high drug concentrations within a tumor and tumor vasculature while maintaining low systemic toxicity ( 4 ). In previous reports, various liposomes showed sustained release of doxorubicin and produced a reliable cure of local cancer in mouse models ( 4 ).…”

“…Liposomal formulations of doxorubicin, can achieve locally high drug concentrations within a tumor and tumor vasculature while maintaining low systemic toxicity ( 4 ). In previous reports, various liposomes showed sustained release of doxorubicin and produced a reliable cure of local cancer in mouse models ( 4 ).…”