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Subcutaneous Delivery of Diagnostics and RNAi to Primary and Metastatic Tumors via Actively-targeted sub-50 nm (s50) Capsules
Poster Title: Subcutaneous Delivery of Diagnostics and RNAi to Primary and Metastatic Tumors via Actively-targeted sub-50 nm (s50) Capsules
Submitted on 05 Jun 2017
Author(s): Vicci L. Korman1, Lucas Nacusi1, Alex J. Pretti1, Diane L. Tobolt1, J. David Robertson2, Gretchen M. Unger1
Affiliations: 1GeneSegues Therapeutics, Eden Prairie, MN 55347; 2University of Missouri, Columbia, MO 65211
This poster was presented at AAPS National Biotechnology Conference 2015-521 W3006
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Poster Information
Abstract: Title: Subcutaneous Delivery of Diagnostics and RNAi to Primary and Metatstatic Tumors via Actively-targeted sub-50 nm (s50) Capsules.

Purpose: To investigate targeting and efficacy of s50 capsules for delivery of biotherapeutics to primary and distant tumors by subcutaneous (SQ) injection.

Methods: s50 capsules comprised of a tumor-targeting Tenfibgen (TBG) shell and bearing either Dysprosium (TBGDy) or a mixture of RNAi oligonucleotides against Casein Kinase 2 (CK2) α and α’ kinase subunits (GS-10), were synthesized by dispersion atomization (Fig.1). Two metastatic head and neck cancer (HNC) xenograft models, FaDu and SCC-47, were flank-injected into nude mice to test s50 targeting and efficacy. Specific targeting was assayed by delivering TBGDy via IV or SQ administration and measuring biodistribution. Mice were dissected and Dy content was quantitated in blood and tissues by neutron activation analysis for the isotope Dy163m . Capsule localization in tissue was documented by direct far-red fluorescence of Dy and indirect immunofluorescence of a Fab fragment “spiked” into the capsule shell. GS-10 efficacy in xenograft models was assayed by measuring growth inhibition via primary tumor weights and CK2 mRNA transcript levels by qPCR. GS-10 efficacy on distant brain and lung tumors was determined by cytokeratin-14 (K-14) expression.

Results: Biodistribution studies showed higher Dy concentration in tumor than liver for SQ routes (Fig. 2). Dy accumulation in primary tumors peaked at 48hrs post-SQ administration and was comparable to 4hrs post-IV administration (28% vs. 16% ID/g). Dy colocalization with capsule shell was confirmed by confocal microscopy supporting interpretation of Dy163m as capsule signal (Fig. 3). In the 30-day FaDu efficacy study, a 100 ug/kg daily (tumor-remote) SQ dose, decreased K-14, 47 and 79% in brains and lungs, respectively (n=5). In the 21-day SCC-47 model, significant growth inhibition of was observed in primary tumor weights relative to diluent and sugar capsule treatment respectively (92.8, 89.8%). CK2 RNA levels were reduced relative to sugar capsule-treated tumors (α and α’: 25.4%, 24.4%, n=3) while further anti-CK2 transcript activity by translational blockade, and CK2 protein downregulation was found by microscopy.

Conclusion: Subcutaneous administration of s50-delivered RNAi is a viable strategy for treatment of metastatic cancer.
Summary: Poster describes nanoparticle method for biodistribution using Dy163m neutron activation analysis while illustrating the excellent tumor-targeting of the sub-50 nm (aka CUSP) nanoparticle.References: (1) Unger GM, Kren BT, Korman VL, Kimbrough TG, Vogel R, Ondrey FG, Trembley JH, Ahmed K. Mechanism and Efficacy of Sub-50-nm Tenfibgen Nanocapsules for Cancer Cell-Directed Delivery of Anti-CK2 RNAi to Primary and Metastatic Squamous Cell Carcinoma. Mol Can Ther Aug 13(3): 2018-29
(2) Ahmed K, et. al., Joining the cell survival squad: An emerging role for protein kinase CK2. Trend in Cell Biology 12: 226-230, 2002.
(3) Koukoulis, G., et al., Tenascin in normal, reactive, hyperplastic and neoplastic tissues: biologic and pathologic implications. Hu. Pathol, 1991. 22: p. 636-643.
(4) Huhtinen, P, et al., Synthesis, characterization, and application of Eu(III), and Dy(III) lanthanide chelate nanoparticle labels. Anal Chem., 2005. Apr 15;77(8): 2643-8.
(5) Kattumuri V, Katti KK, Robertson JD, Kannan R, Katti KK: Gum arabic as a phytochemical construct for the stabilization of gold nanoparticles: in vivo pharmacokinetics and X-ray-contrast-imaging. Small 3(2):333-41Report abuse »
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