Abstract 5695: PLGA microspheres for MRI-guided localized transcatheter delivery of sorafenib: development and preclinical feasibility studies

Purpose: Sorafenib is a multi-kinase inhibitor with efficacy for the palliative treatment of hepatocellular carcinoma (HCC). However, oral administration limits the dose that ultimately reaches tumors and many patients cannot tolerate associated systemic toxicities such as hand-foot syndrome and cardiac ischemia. Local delivery of sorafenib-eluting microspheres via intra-arterial transcather infusion should increase the dose supplied to tumors while limiting the harsh side-effects. The purpose of this study was to design and characterize sorafenib-eluting microspheres that also permit MRI of the intra-hepatic biodistribution post-infusion. Methods: Polylactide-co-glycolide (PLGA) microspheres encapsulating sorafenib and an iron-oxide ferrofluid were synthesized via a double emulsion solvent evaporation method. Microsphere encapsulation properties were characterized using high performance liquid chromatography (HPLC) for sorafenib encapsulation, and inductively coupled plasma mass spectrometry (ICP-MS) for ferrofluid encapsulation. A cell viability study was performed to investigate the therapeutic efficacy of the microspheres (cell proliferation in McA-RH7777 HCC cell line). An in vitro imaging study was then performed where the microspheres were embedded in agar gels and imaged with MRI. Lastly, six Sprague Dawley rats were catheterized and infused with 4-6 mgs of the microspheres via the proper hepatic artery and imaged with MRI to visualize the biodistribution of the microspheres. Prussian blue staining was used to identify microsphere positions within hepatic tissue specimens at necropsy. The agar phantom and rat MRI studies were performed using a 7T Bruker Clinscan system. Results: The characterization studies indicated that the Sorafenib-eluting PLGA microspheres (roughly 10 microns in diameter) included 16.4% (w/w) sorafenib and 0.81% (w/w) ferrofluid. Cell viability studies showed an 84% decrease in cell number compared to the control (50% compared to the initial amount plated) after treatment of the McA-RH7777 cells with the microspheres at a concentration of 36.6 μg/mL for 72 hours. MRI phantom studies demonstrated that T2* relaxation times decreased from 6.9 ms −1 to 2.8 ms −1 when microsphere concentrations increased from 0 to 2 mg/mL. For rat studies, the intra-hepatic distribution of the microspheres was clearly depicted in follow-up T2-weighted MRI images. Prussian blue slides confirmed hepatic microsphere delivery. Conclusion: The designed PLGA microspheres with sorafenib and ferrofluid permitted transcatheter delivery to rodent livers and MRI visualization of the resulting intra-hepatic biodistribution. This design allows for local delivery that may ultimately reduce systemic toxicities and increase therapeutic efficacy of sorafenib and other similar MKIs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5695. doi:1538-7445.AM2012-5695