Poly(lactide-co-glycolide) microspheres for MRI-monitored transcatheter delivery of sorafenib to liver tumors

Abstract

The multi-kinase inhibitor (MKI) sorafenib can be an effective palliative therapy for patients with hepatocellular carcinoma (HCC). However, patient tolerance is often poor due to common systemic side effects following oral administration. Local transcatheter delivery of sorafenib to liver tumors has the potential to reduce systemic toxicities while increasing the dose delivered to targeted tumors. We developed sorafenib-eluting PLG microspheres for delivery by intra-hepatic transcatheter infusion in an orthotropic rodent HCC model. The particles also encapsulated iron-oxide nanoparticles permitting magnetic resonance imaging (MRI) of intra-hepatic biodistributions. The PLG microspheres (diameter ≈1 μm) were loaded with 18.6% (w/w) sorafenib and 0.54% (w/w) ferrofluid and 65.2% of the sorafenib was released within 72 hours of media exposure. In vitro studies demonstrated significant reductions in HCC cell proliferation with increasing doses of the sorafenib-eluting microspheres, where the estimated IC50 was a 29 ug/mL dose of microspheres. During in vivo studies, MRI permitted intra-procedural visualization of intra-hepatic microsphere delivery. At 72 hours after microsphere infusion, microvessel density was significantly reduced in tumors treated with the sorafenib-eluting microspheres compared to both sham control tumors (by 35%) and controls (by 30%). These PLG microspheres offer the potential to increase the efficacy of molecularly targeted MKI therapies while reducing systemic exposures via selective catheter-directed delivery to HCC.

Pharmacokinetic study of conventional sorafenib chemoembolization in a rabbit VX2 liver tumor model

“…Another promising avenue for potential investigation includes drug-eluting beads, an embolic platform associated with reduced systemic drug release as compared to ethiodized oil when applied for TACE (24). To this end, the feasibility of targeted delivery of sorafenib loaded poly(lactide-co-glycolide) microspheres has been recently demonstrated (25). As a final note, anatomic characteristics, such as tumor size and presence of arteriovenous communications, may also impact drug pharmacokinetics after TACE.…”

Sulfamethazine-based pH-sensitive hydrogels with potential application for transcatheter arterial chemoembolization therapy

“…However, the efficacy of the Lipiodol ® -based system is limited by its inconsistent persistence time and lack of ability to control release [16][17]. Recently, to overcome these drawbacks of Lipiodol ® -based systems, a variety of strategies were introduced, including a combination of therapies, stabilized Lipiodol ® emulsion, polymeric microspheres or drug eluting bead (DEB) [18][19][20][21]. Among them, DEB-based TACE was proved as an emerging system that provides favorable pharmacokinetic profile and lower peak plasma concentration, which lead to lower systemic toxicity and higher clinical outcome in comparison to conventional Lipiodol ® -based TACE [22][23][24].…”

Alginate microgels loaded with temperature sensitive liposomes for magnetic resonance imageable drug release and microgel visualization

“…Examples of polymers used for the preparation of DEBs are chitosan [27,28], PLGA (poly(lactide-co-glycolide)) [29] and alginate [30]. Clinically used DEBs are based on polyvinyl alcohol modified with a sulfonic acid group to obtain negatively charged microspheres (DC beads).…”