Improved Delivery of a TLR-9 Agonist to Liver Tissue by Intravascular Pressure Enabled Drug Delivery (PEDD) Compared with Direct Needle Injection

Direct injection of the TLR-9 agonist SD-101 oligonucleotide has shown promising results for the treatment of superficial cutaneous melanoma metastatic lesions in combination with checkpoint inhibition. However, this mode of delivery is limited to easily discernable tumors located in superficial locations. Here we compare local infusion of labeled SD-101 into hepatic tissue using the Pressure Enabled Drug Delivery (PEDD) method vs. direct needle injection. PEDD has been shown to increase the concentration and penetration of therapeutics into tumors, while limiting exposure to off-target tissue.^1,2

Materials and Methods:

The study was conducted on female swine (n=8, 45-65kg). The first cohort (n=4) received a hepatic arterial (HA) PEDD infusion of the TLR-9 agonist oligonucleotide ODN 2395 conjugated to an IRD800 nearIR fluorophore (ODN2395F), using a TriNav device (TNV-21120-35, TriSalus Life Sciences). This was followed by needle injection of the TLR-9 agonist oligonucleotide SD-101 conjugated to a Cy5.5 fluorophore (SD-101F). The second cohort (n=4) received HA PEDD infusion of SD-101F followed by injection of ODN2395F. Needle injections and PEDD infusions were delivered to contralateral hepatic lobes. NearIR imaging was performed on 1 cm thick sections of the organ using the Pearl Trilogy Imaging System to quantify the volume and the relative concentration of oligo present in the tissue as determined by magnitude of fluorescence.

Results:

The volume of liver tissue containing the oligo was significantly greater using PEDD (99.0±28.8cm³ SE, n=8)  than that by injection (13.5±2.9cm³ SE, n=8) (p=0.011). PEDD distributed the therapeutic within the targeted vascular network, producing a measurable uptake throughout the infusion zone. Direct injection of the oligos often resulted in a confined 1-2 cm diameter regions of treated tissue. PEDD also resulted in a significantly higher concentration of oligo retained in the tissue relative to direct injection. Quantification of tissue luminous intensity (kiloluminous units, klu) revealed 49.0±10.1 klu SE in PEDD treated tissues vs 19.3±6.35 klu SE for direct injection (p=0.015).

Conclusion:

The results of this study illustrate the advantage of the PEDD method for HA infusion of therapeutics such as SD-101 directly into hepatic tissue. A 7-fold increase in treated tissue volume and a 2.5-fold increase in therapeutic delivery using PEDD in the normal porcine liver relative to direct needle injection suggest that PEDD offers a potentially effective means of treating diffuse intrahepatic disease through targeted delivery.

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References:

1. Pasciak, A. S., McElmurray, J. H., Bourgeois, A. C., Heidel, R. E. & Bradley, Y. C. The Impact of an Antireflux Catheter on Target Volume Particulate Distribution in Liver-Directed Embolotherapy: A Pilot Study. J. Vasc. Interv. Radiol. 26, 660–669 (2015).

2. Titano, J. J. et al. End-hole Versus Microvalve Infusion Catheters in Patients Undergoing Drug-Eluting Microspheres-TACE for Solitary Hepatocellular Carcinoma Tumors: A Retrospective Analysis. Cardiovasc. Intervent. Radiol. 42, 560–568 (2019).