Evaluation of pharmacokinetics of galactose analog, hyaluronic acid, gold nanoparticle and micelle in various animal disease models via radiotracer technology

• Main Authors: Hao-Wen Kao, 高顥文
• Other Authors: Hsin-Ell Wang
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/55655296877345148240

博士 === 國立陽明大學 === 生物醫學影像暨放射科學系 === 101 === Radiotracer techniques are commonly employed in the R&;D of new drugs. In the various stages of drug discovery and development, either identification of lead compounds or development of various formulations, molecular imaging provides a unique bridge from the bench to the bedside, facilitates drug development process and improves the cost-effectiveness. Thereby, it can also help terminate the development of unfavorable drugs at early stage to reduce unnecessary costs. This study established an integrated platform for the investigation of the pharmacokinetics of kinds of biomaterials, such as galactose analog, hyaluronic acid, gold nanoparticle and micelle in various animal models. Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. This study developed a new 18F-labeled monovalent galactose derivative, 4-18F-fluoro-N-(6-((3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide (18F-FBHGal), by conjugation with N-succinimidyl-4-18F-fluorobenzoate. After intraperitoneal administration (3 doses per week for 4 weeks) of dimethylnitrosamine (DMN), a hepatic fibrosis mouse model with lower ASGPR expression was established. The microPET imaging, biodistribution study and pharmacokinetic study of 18F-FBHGal in both normal mice and hepatic fibrosis mice were demonstrated. The finding in biological characterization suggested that 18F-FBHGal, as an ASGPR-specific PET probe, is a feasible agent for PET imaging of hepatic fibrosis in mice and may provide new insights into ASGPR-related liver dysfunction. Viscosupplementation treatment has become a universally accepted therapeutic approach of osteoarthritis (OA). Intra-articular injection of hyaluronic acid (HA) provides pain relief by lessening the frictional resistance of the cartilage and improving joint function. Hyaluronic acid with different molecular weights (HA 22, 0.22×106 dalton; HA142, 1.42×106 dalton) were conjugated with tyramine and labeled with I-131 to afford 131I-Tyr-HAs. Osteoarthritis is developed in the left knee of New Zealand white rabbits at six weeks post unilateral anterior and posterior cruciate ligaments transection surgery. After intra-articular injection of 131I-Tyr-HAs and 131I-tyramine into the OA and the normal knee joints, longitudinal monitoring with planar gamma imaging was performed. The pharmacokinetics parameters derived from scintigraphic images showed that the higher molecular weight HA (131I-Tyr-HA142) retained longer than the lower molecular weight (131I-Tyr-HA22) in both normal and OA knees. Gold nanoparticle (AuNP) was biocompatible and could be modified with target-specific ligands via gold-thiolate bonding. Epidermal growth factor receptor (EGFR) is highly expressed in a significant number of human malignancies. Activation of the EGFR signaling pathways in cancer cells has been linked with increased cell proliferation, angiogenesis, and metastasis, and decreased apoptosis. Cetuximab (Erbitux®, C225), a recombinant human/mouse chimeric immunoglobulin G1 monoclonal antibody, binds specifically to the extracellular domain of the human EGFR. In this study, gold nanoparticles was conjugated with cetuximab and labeled with theranostic radionuclides such as In-111 and I-131 to afford active targeting radio-immuno gold nanoparticles (111In/131I-C225-AuNPs). Specific uptake and cytotoxicity of 111In/131I-C225-AuNPs in high EGFR-expressed A549 human lung cancer cell line was investigated. A549 cells displayed significantly higher uptake (14.9-fold) of immuno gold nanoparticles 111In-C225-AuNPs compared to that of 111In-AuNPs, while those labeled with therapeutic radionuclide (131I-C225-AuNPs) resulted in appreciably reduced cell viability, after a 2-h incubation. After intravenous injection of immuno gold nanoparticles in A549 tumor-bearing mice, microSPECT/CT imaging revealed a high tumor-to-muscle ratio of 5.5 at 4 h post injection. Our studies suggested that 111In/131I-C225-AuNPs may provide a new approach of targeted imaging and therapy towards high EGFR-expression cancers. Self-assembly polymeric micelle was developed as a water-soluble biocompatible vehicle for delivering hydrophobic chemotherapeutic agents to tumor site with reduced toxicity and prolonged systemic circulation. A copolymer of poly(ethylene glycol)-b-poly(caprolactone) (PEG-PCL) was modified with a benzyl moiety and labeled with I-131 to give 131I-benzyl-PEG-PCL. 131I-benzyl-PEG-PCL and PEG-PCL-PC self-assembled in aqueous solution to form 131I-benzyl-micelles. The biodistribution and the pharmacokinetic study of radiolabeled micelles were characterized in a colon carcinoma-bearing mouse model. Administration of 131I-benzyl-micelles to a tumor-bearing mouse model gives a 4.9-fold higher tumor-to-muscle ratio at 48 h post-injection than that of the unimer 131I-benzyl-PEG-PCL. This study demonstrated that 131I-benzyl-micelles are a plausible radioactive surrogate for PEG-PCL copolymer micelles. Modifying the amphiphilic copolymer with a benzyl moiety and labeling it with iodine-131 would make possible the real-time and noninvasive evaluation of the pharmacokinetics of copolymer micelles in vivo. The preclinical studies illuminated that radiotracer application is not only a helpful method in clarifying some bioprocesses, such as the pathways of metabolism, body clearance and active targeting of a drug or a drug carrier, but also a useful approach for evaluation of the therapeutic efficacy of various biomaterial systems in the personalization of cancer therapy.