Sorafenib is a potent multi-kinase inhibitor for the treatment of patients with unresectable hepatocellular carcinoma (HCC). However, systemic exposures can lead to severe toxicities. Sorafenib dose often must be reduced or administration discontinued altogether. Microsphere drug delivery platforms offer the potential to significantly increase the efficacy of sorafenib therapy for HCC while reducing systemic exposures via targeted image-guided transcatheter delivery. Quantitative approaches for imaging sorafenib-eluting microsphere delivery may be critical to permit early prediction of response thus prompting adjustments to treatment regimens as needed (additional infusions or adoption of alternative therapies). During this pre-clinical project we seek to develop a powerful new approach for image-guided catheter-directed delivery of sorafenib to liver tumors. We will address the following Specific Aims in a well-established VX-2 rabbit model of liver cancer:
Aim 1 : Characterize the relationship between poly(D,L-lactide-co-glycolide) (PLG) microsphere fabrication methods, sorafenib and contrast agent loading, size distribution, release kinetics, and MRI properties.
Aim 2 : Optimize methods for in vivo MRI of SPIO-labeled sorafenib-eluting PLG microspheres and validate that these methods permit accurate quantification of transcatheter delivery to liver tumors.
Aim 3 : Validate that sorafenib-eluting microspheres inhibit angiogenesis and tumor growth, compare outcomes in liver tumors treated with sorafenib-eluting microspheres, bland embolization, and sorafenib chemo- embolization (drug infusion without microsphere encapsulation), and finally compare MRI measurements of transcatheter microsphere delivery to the elicited therapeutic responses.
Sorafenib is a potent therapy for liver cancer but administered orally thus often leading to toxic side-effects. Selective delivery to liver tumors by direct injection into the feeding blood vessels should enhance efficacy while reducing toxicity. For this purpose, sorafenib will be encapsulated in small drug carriers, visible with non- invasive imaging methods and able to be infused through a catheter into the tumor's blood supply. Imaging will permit immediate confirmation of drug carrier delivery to the targeted liver tumors.
|Deschamps, Frederic; Harris, Kathleen R; Moine, Laurence et al. (2018) Pickering-Emulsion for Liver Trans-Arterial Chemo-Embolization with Oxaliplatin. Cardiovasc Intervent Radiol 41:781-788|
|Park, Wooram; Gordon, Andrew C; Cho, Soojeong et al. (2017) Immunomodulatory Magnetic Microspheres for Augmenting Tumor-Specific Infiltration of Natural Killer (NK) Cells. ACS Appl Mater Interfaces 9:13819-13824|
|Li, Weiguo; Wang, Xifu; Miller, Frank H et al. (2017) Chemical Shift magnetization transfer magnetic resonance imaging. Magn Reson Med 78:656-663|
|Park, Wooram; Cho, Soojeong; Huang, Xiaoke et al. (2017) Branched Gold Nanoparticle Coating of Clostridium novyi-NT Spores for CT-Guided Intratumoral Injection. Small 13:|
|Jeon, Min Jeong; Gordon, Andrew C; Larson, Andrew C et al. (2016) Transcatheter intra-arterial infusion of doxorubicin loaded porous magnetic nano-clusters with iodinated oil for the treatment of liver cancer. Biomaterials 88:25-33|
|Park, Wooram; Chen, Jeane; Cho, Soojeong et al. (2016) Acidic pH-Triggered Drug-Eluting Nanocomposites for Magnetic Resonance Imaging-Monitored Intra-arterial Drug Delivery to Hepatocellular Carcinoma. ACS Appl Mater Interfaces 8:12711-9|
|Kim, Dong-Hyun; Li, Weiguo; Chen, Jeane et al. (2016) Multimodal Imaging of Nanocomposite Microspheres for Transcatheter Intra-Arterial Drug Delivery to Liver Tumors. Sci Rep 6:29653|
|Li, Weiguo; Zhang, Zhuoli; Gordon, Andrew C et al. (2016) SPIO-labeled Yttrium Microspheres for MR Imaging Quantification of Transcatheter Intrahepatic Delivery in a Rodent Model. Radiology 278:405-12|
|Chen, Jeane; White, Sarah B; Harris, Kathleen R et al. (2015) Poly(lactide-co-glycolide) microspheres for MRI-monitored delivery of sorafenib in a rabbit VX2 model. Biomaterials 61:299-306|
|White, Sarah B; Chen, Jeane; Gordon, Andrew C et al. (2015) Percutaneous ultrasound guided implantation of VX2 for creation of a rabbit hepatic tumor model. PLoS One 10:e0123888|
Showing the most recent 10 out of 13 publications