Hepatocellular Carcinoma: Intra-arterial Delivery of Doxorubicin-loaded Hollow Gold Nanospheres for Photothermal Ablation—Chemoembolization Therapy in Rats

Abstract

Purpose To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with Lipiodol (Dox@PEG-HAuNS/Lipiodol) for improved photothermal ablation (PTA)-chemoembolization therapy (CET; PTA-CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods All animal experiments were approved by the Institutional Animal Care and Use Committee, and were performed in 45 Sprague-Dawley rats (male, 12 weeks old) from Feb. 2014 to April 2015. Eight days after inoculation of N1S1 HCC cells in the liver of rats. Animals were randomly divided into 2 groups of 10 rats each. Rats in group 1 received intrahepatic arterial (IA) injection of PEG-HAuNS/Lipiodol alone, and rats in group 2 received IA injection of CA4P followed by PEG-HAuNS/Lipiodol 5 min later. Each group was subdivided, and the Au content of tumors and tissues excised at 1 h or at 24 h was quantified using neutron activation analysis (NAA, n=5/time point). Five rats received CA4P plus PEG-[64Cu]-HAuNS/Lipiodol and underwent μPET/CT. In a separate study, therapeutic effects were compared among 3 groups of 6 rats each that received IA injection of saline (control group), CA4P plus Dox@PEG-HAuNS/Lipiodol (CET group), or CA4P plus Dox@PEG-HAuNS/Lipiodol plus near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified with postmortem histopathology and/or autoradiography. Wilcoxon rank-sum test was used to test the difference between groups, Pearson correlation analyses were performed to evaluate correlations. Results PEG-HAuNS uptake in CA4P-pretreated tumors was significantly higher than that in non–CA4P-pretreated tumors at both 1 h (P<0.03) and 24 h (P<0.01). The tumor-to-liver PEG-HAuNS uptake ratios at 1 h and 24 h were 5.63±3.09 and 1.68±0.77, respectively, in the CA4P-treated group and 1.29±2.40 and 0.14±0.11, respectively, in the non–CA4P-treated group. μPET/CT clearly delineated the tumors, enabling quantitative imaging analysis. Laser irradiation increases temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Tumor volumes 10 d after therapy were 1.68±1.01, 3.96±1.75, and 6.13±2.27 cm3 in the PTA-CET, CET, and control groups, respectively, with significant differences between the PTA-CET group and other groups (P<0.05). Conclusion CA4P pretreatment causes a higher concentration of Dox@PEG-HAuNS to be trapped inside the tumor, thereby enhancing the anti-HCC efficacy of PTA-CET in rats.

Effects of VEGF‐ANG‐1‐PLA nano‐sustained release microspheres on proliferation and differentiation of ADSCs

“…Nevertheless, there was a lack of feedback to allow precise delivery of these therapeutic agents to the target site. In the past years, emerging evidence has showed that several nano/micrometer‐sized materials served as drug‐delivery agents and had less potential damage to surrounding tissues (Li et al, ; Wen et al, ).…”

Photoactivation Strategies for Therapeutic Release in Nanodelivery Systems

“…Photothermal nanomaterials refer to those that are able to produce a localized heat through plasmonic activation. [16,29,30,[69][70][71] These comprise of nanogold (Au) and nanosilver (Ag) that exist in various shapes such as spherical gold NP (AuNP), [68,70,72,73] gold nanorod (AuNR), [70] hollow gold nanosphere (HAuNS), [41,[74][75][76][77] and porous gold nanocage (AuNC). [69,78,79] Their photothermal activation occurs by irradiation at a visible (vis) and near infrared (NIR) region (500-800 nm).…”

“…The produced heat rapidly dissipates, causing a localized hyperthermia which is potent enough to kill cells in a close proximity. [80,81] Besides these functional properties, certain types of nanogold such as HAuNS [41,74,75,77] and AuNC [78,79,82] offer unique structural benefits for drug delivery based on tunable cavities for drug loading and large surface areas available for ligand conjugation. This is illustrated with tumor targeted applications using HAuNS conjugated with folic acid, [83,84] RGD peptide, [41] tumor-specific aptamer, [76] or anti-EGFR antibody, [74] and AuNC conjugated with anti-HER2 antibody.…”

<p>Transcatheter Intra-Arterial Infusion Combined with Interventional Photothermal Therapy for the Treatment of Hepatocellular Carcinoma</p>

“…30,31 However, PTT is restricted by several limitations, including a limited light penetration depth for deeply buried tumors, the possibility of damaging normal tissues, compromised therapeutic effects by threshold laser power for skin tolerance, 32 and low concentrations of nanomaterials in tumors by intravenous administration. 33 Given these issues, the transcatheter intra-arterial infusion has been applied in previous studies, [34][35][36] but studies have seldom evaluated the efficacy of transcatheter intra-arterial infusion combined with IPTT compared with other therapy modalities for hepatic carcinoma. Herein, to improve the therapeutic effect of HCC, we developed a new therapeutic method of transcatheter intra-arterial infusion of Bi-based nanoparticles (Bi-Ln NPs) combined with IPTT.…”