Handling and performance characteristics of a new small caliber radiopaque embolic microsphere

Abstract

The in vitro and in vivo handling and performance characteristics of a small caliber radiopaque embolic microsphere, 40-90 μm DC Bead LUMI™ (LUMI40-90), were studied. Microsphere drug loading and elution and effects on size, suspension, and microcatheter delivery were evaluated using established in vitro methodologies. In vivo evaluations of vascular penetration (rabbit renal artery embolization), long-term biocompatibility and X-ray imaging properties, pharmacokinetics and local tissue effects of both doxorubicin (Dox) and irinotecan (Iri) loaded microspheres (swine hepatic artery embolization) were conducted. Compared to 70-150 μm DC Bead LUMI (LUMI70-150), LUMI40-90 averaged 70 μm versus 100 μm, which was unchanged upon drug loading. Handling, suspension, and microsphere delivery studies were successfully performed. Dox loading was faster (20 min) and Iri equivalent (<10 min) while drug elution rates were similar. Contrast suspension times were longer with no delivery complications. Vascular penetration was statistically greater (rabbit) with no unexpected adverse safety findings (swine). Microspheres ± drug were visible under X-ray imaging (CT) at 90 days. Peak plasma drug levels and area under the curve were greater for LUMI40-90 compared to LUMI70-150 but comparable to 70-150 μm DC BeadM1™ (DC70-150). Local tissue effects showed extensive hepatic necrosis for Dox, whereas Iri displayed lower toxicity with more pronounced lobar fibrosis. LUMI40-90 remains suspended for longer and have greater vessel penetration compared to the other DC Bead LUMI sizes and are similarly highly biocompatible with long-term visibility under X-ray imaging. Drug loading is equivalent or faster with pharmacokinetics similar to DC70-150 for both Dox and Iri.

Keywords: DC Bead LUMI; X-ray imageability; biocompatibility; drug loading and elution; microsphere penetration; pharmacokinetics; suspension and delivery.

FIGURE 1

Comparison of LUMI40‐90 and LUMI75‐150: (a) Microsphere size distributions (inset, optical micrographs of each product, scale bar = 500 μm); (b) Effect of Dox (37.5 mg/mL) and Iri (50 mg/mL) loading on average microsphere size and range; (c) Dox (37.5 mg/mL) (d) and Iri (50 mg/mL) loading rates; (e) Dox and (f) Iri elution rates using “jar” and open‐loop methods

FIGURE 2

(a) Effect of microsphere size and suspension composition on force to deliver through a microcatheter; (b) Effect of contrast agent fraction in the suspension medium on viscosity; (c) Visual comparison of microsphere size suspensions and dilution on the mixture exiting the hub into the microcatheter lumen

FIGURE 3

Comparative distributions by microsphere type in the renal model zones 1–5 (a) by microsphere size (b) by percentage of volume injected

FIGURE 4

Multi Detector Computed Tomography (MDCT) (top) and maximum intensity projection (MIP) (bottom) imaging findings for LUMI40‐90 (a) pre‐embolization non‐contrast CT images showing no abnormal observations in the liver. (b) Non‐contrast CT images immediately post‐embolization showing presence of LUMI40‐90 in the main arteries of liver left lobe. (c) Non‐contrast and (d) IV contrast‐enhanced CT imaging 90 days post‐embolization with LUMI40‐90 still clearly visible, even in smaller more distal arteries. (e, f) typical histological sections containing LUMI40‐90 microspheres (stained purple) embedded within tissue within the remodeled artery with the occasional instance of inflammatory cells contacting the microsphere surface

FIGURE 5

Pharmacokinetic (PK) profiles for DC70‐150, LUMI70‐150, and LUMI40‐90 loaded with (a) Dox and (b) Iri

FIGURE 6

Non‐contrast CT at (a) 1 hr post‐embolization and (b) 14 days post‐embolization with LUMI40‐90 loaded with Dox (37.5 mg/mL). (c) 1 hr post‐embolization and (d) 14 days post‐embolization with LUMI40‐90 loaded with Iri (50 mg/mL). (e) Histological section of a portion of the liver treated with LUMI40‐90 + Dox showing widespread hepatic necrosis, bile duct hyperplasia, and interlobular fibrosis. (f) Histological section of a portion of the liver treated with LUMI40‐90 + Iri showing comparatively less local tissue damage compared to Dox but with some interlobular fibrosis and bile duct hyperplasia

FIGURE 7

(a) Parabolic flow profile of laminar flow within a microcatheter showing velocity profiles across the cross section; (b) diagram illustrating the effect of steady versus pulsed injection relative speed of microsphere travel along the catheter; (c) relative confinement ratio of LUMI40‐90 and LUMI70‐150 as a function of a 2.4 Fr microcatheter internal lumen demonstrating ability of significantly smaller microspheres to avoid transient microcatheter occlusions compared to LUMI100‐300