Translational Development of a Silk-Elastinlike Protein Polymer Embolic for Transcatheter Arterial Embolization

Abstract

Locally blocking blood flow to tumors with embolic materials is the key to transcatheter arterial embolization for treating hepatocellular carcinoma. Current microparticle agents do not deeply penetrate target tissues and are compatible with a very limited selection of therapeutic agents. Silk-elastinlike protein polymers (SELPs) combine the solubility of elastin and the strength of silk to create an easily injected liquid embolic that transition into a solid depot amenable to loading with drugs, gene therapy agents, or biologics. SELP, injected as liquid solution, penetrates the vasculature before transitioning to a solid hydrogel. The objective of this manuscript is to evaluate SELP embolization, stability, and biocompatibility at 7-, 30-, and 90-day survival intervals in a porcine model. SELP embolics selectively block blood flow in the kidneys and livers, with no off-target infarctions. As assessed with angiography, SELP renal embolization exhibits decreasing persistence for the duration of the 90-day study period. There is an increased presence of microscopic SELP emboli in the renal setting, compared to Embosphere. Histologically scored inflammatory reactions to SELP are decreased in both the renal and hepatic implantations compared to Embosphere. In conclusion, a bioresorbable SELP liquid embolic system deeply penetrates target tissue and selectively embolizes blood vessels in vivo.

Keywords: hepatocellular carcinoma; liquid embolic; recombinant polymers; transarterial embolization.

Figure 1.

Structural assembly of SELPs and sequence of the SELP used within this investigation (SELP-815K).

Figure 2.. Angiographic evaluation of SELP and Embosphere® (EMBO) implantations within the kidney.

A) SELP and EMBO implantations at the cranial liver pole immediately following implantation (0 Days), and at before animal sacrifice (7 Days, 30 Days, 90 Days). The flat top of the cranial pole in EMBO 90 day is a physical deformation in the kidney. Post necropsy picture of this kidney can be seen in Figure 5. B) Percent of vessel occlusion immediately after implantation (0 Days) as estimated by angiography. (Cr: Cranial pole)

Figure 3.

Angiographic evidence of SELP and Embosphere® (EMBO) occlusion of vessels within the liver. Arrow indicates occluded vessel pre- and post-implantations.

Figure 4.. Secondary animal measures for health and toxicities.

A) Body weight of animals throughout duration of study. B) Body weight of animals at sacrifice represented as a percent change from baseline (Day 0) weight. C) Alanine aminotransferase and D) creatinine concentrations within the blood, represented as a percent change from baseline.

Figure 5.

Gross analysis of porcine kidneys receiving either SELP or Embosphere® (EMBO) implantations after 7, 30, and 90 days. Implantations occurred at the cranial (Cr) pole. Scale bar is 1 cm. (Ca: caudal)

Figure 6.

Gross analysis of porcine livers receiving either SELP or Embosphere® (EMBO) implantations after 7, 30, and 90 days. No signs of infarction were evident in the 7 and 90 day survivial intervals. At the 30 day survival interval tissue discoloration may indicate secondary signs of infarctions. Arrows indicate observed pale or white foci. Scale bar is 1 cm. (Cr: cranial, Ca: caudal, L: left)

Figure 7:. Histological analysis of SELP and Embosphere® (EMBO) implantation sites at 7, 30, and 90 days.

A) H&E staining of kidney implant sites. Arrows indicate calcifications. Filled arrowheads indicate tissue necrosis. Open arrowheads indicate foreign body giant cell. (*: embolic material) B) H&E staining of liver implant sites. Arrows indicate portal inflammation composed of lymphocytes, plasma cells, and admixed eosinophils. Arrowheads indicate foreign body giant cells around Embosphere®. (*: embolic material) C) Scoring of kidney implant reactivity. D) Scoring of liver implant reactivity. E) Scoring of kidney embolization from microscopic analysis. F) Scoring of liver embolization from microscopic analysis. Scale bars indicate 50 µm.