Transcatheter intra-arterial infusion of doxorubicin loaded porous magnetic nano-clusters with iodinated oil for the treatment of liver cancer

Abstract

A promising strategy for liver cancer treatment is to deliver chemotherapeutic agents with multifunctional carriers into the tumor tissue via intra-arterial (IA) transcatheter infusion. These carriers should release drugs within the target tissue for prolonged periods and permit intra-procedural multi-modal imaging of selective tumor delivery. This targeted transcatheter delivery approach is enabled via the arterial blood supply to liver tumors and utilized in current clinical practice which is called chemoembolization or radioembolization. During our study, we developed Doxorubicin (Dox) loaded porous magnetic nano-clusters (Dox-pMNCs). The porous structure and carboxylic groups on the MNCs achieved high-drug loading efficiency and sustained drug release, along with magnetic properties resulting in high MRI T2-weighted image contrast. Dox-pMNC within iodinated oil, Dox-pMNCs, and Dox within iodinated oil were infused via hepatic arteries to target liver tumors in a rabbit model. MRI and histological evaluations revealed that the long-term drug release and retention of Dox-pMNCs within iodinated oil induced significantly enhanced liver cancer cell death.

Keywords: Cancer treatment; Drug delivery; Interventional radiology; Liver cancer; Nano medicine.

Fig. 1

(a, b) TEM images of porous magnetic nanoclusters, (c) TG-DSC curves of porous magnetic nanoclusters showing surface adsorbed water and decomposition of carboxyl groups of PAA in the pMNCs, (d) BET nitrogen adsorption-desorption and (inset) pore size distribution of the pMNCs, (e) zeta potential changes of pMNCs in aqueous solution by increasing doxorubicin (Dox) loading amounts, and (f) T2-weighted MRI images (3T, spin-echo sequence) of various concentrations of pMNCs and ferucarbotran in agarose gel and T2 relaxation rates (1/T2, s⁻¹) as a function of iron concentration (mM) of pMNCs and ferucarbotran in agarose gel (3T, 25 °C).

Fig. 2

(a) Schematic illustration of Dox-loaded pMNCs for IA drug delivery, (b) digital image of sample solutions (Dox-pMNCs, Dox-pMNCs with Lipiodol and Dox with Lipiodol) and (b) Release profiles of Dox from the samples (Dox-pMNCs, Dox-pMNCs with Lipiodol and Dox with Lipiodol). The profiles of Dox-pMNCs and Dox-pMNCs with Lipiodol showed relatively slow and sustained drug release over 100 hours (at 37 ^cC).

Fig. 3

(a) MRI T2-weightd image of VX2 liver tumor in rabbit model before intra-arterial (IA) infusion procedure, (b) Digital subtraction angiography (DSA) during IA infusion of samples. A micro-catheter was advanced via the right ear artery, the descending thoracic aorta, and the celiac trunk, and the catheter tip was positioned at a feeder of the left hepatic artery (arrowhead). DSA during the IA infusion showed contrast agent opacification of the tumor tissues and feeding vessels (arrows indicate region of hypervascular tumor periphery). (c) MRI T2-weighted image of VX2 rabbit liver tumor after intra-arterial (IA) delivery of Dox-pMNCs with Lipiodol.

Fig. 4

MRI T2* weighted images and CT images from (a) Group A rabbit (Dox-pMNCs with Lipiodol administered via IA infusion) and (b) Group B rabbit (Dox- pMNCs administered via IA infusion). In MR images before IA infusion, the tumor in the left hepatic lobe demonstrates high signal intensity (tumor position denoted with dashed-line ROI) in T2*-weighted images. At both days 7 and 14 after IA infusion, the tumor shows marked signal reduction in both Group A and B rabbits, due to deposition of the Dox-pMNCs in the tumor. CT images in Group A also showed dense Lipiodol deposits in the tumor at days 7 and 14 after the delivery. (c) Tumor-to-back muscle signal intensity ratios for the T2*-weighted images of Group A and B collected at 0, 7 and 14 days post-infusion. (d) Microscopic analysis (25×) of HCC tumor tissues harvested at 14 days and stained with Prussian blue. The iron in the deposits of the Dox-pMNCs was visible as a blue spots located at the inner edges of vascular structures.

Fig. 5

(a) Histological sections of VX2 liver tumors 14 days after treatment were TUNEL stained. The representative images from Group A and B rabbits are shown. Scattered positive cells were found study groups but a significant increase was observed for Group A (Dox-pMNCs within Lipiodol), and (b) quantitative analysis of TUNEL positive cells for Groups A, B and control. Data (means ± SD) represent the means of independent experiments (each n=5 in Group A and B, control). *p<0.05. (Group A and B). Increased TUNEL positive cells were observed in Group A vs. Group B and Group A vs. Control.