Brachytherapy via a depot of biopolymer-bound <sup>131</sup>I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours.

Abstract

Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (131I-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours. 131I-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed that 131I-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development of 131I-ELP depots for the synergistic treatment of localized pancreatic cancer.

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Citation

Published Version (Please cite this version)

10.1038/s41551-022-00949-4

Publication Info

Schaal, Jeffrey L, Jayanta Bhattacharyya, Jeremy Brownstein, Kyle C Strickland, Garrett Kelly, Soumen Saha, Joshua Milligan, Samagya Banskota, et al. (2022). Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours. Nature biomedical engineering, 6(10). pp. 1148–1166. 10.1038/s41551-022-00949-4 Retrieved from https://hdl.handle.net/10161/26126.

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Scholars@Duke

Strickland

Kyle C. Strickland

Adjunct Associate Professor of Pathology

Dr. Strickland specializes in cytopathology and women's and perinatal surgical pathology.  His areas of interest include epithelial and mesenchymal gynecologic neoplasia and fine needle aspiration cytology.

Soumen Saha

Research Scientist, Senior
Zalutsky

Michael Rod Zalutsky

Jonathan Spicehandler, M.D. Distinguished Professor of Neuro Oncology, in the School of Medicine

The overall objective of our laboratory is the development of novel radioactive compounds for improving the diagnosis and treatment of cancer. This work primarily involves radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later two being of particular interest because they can be used for the quantification of biochemical and physiological processes in the living human through positron emission tomography. For therapy, astatine-211 decays by the emission of alpha-particles, a type of radiation considerably more cytotoxic that the beta-particles used in conventional endoradiotherapy. The range of At-211 alpha particles is only a few cell diameters, offering the possibility of extremely focal irradiation of malignant cells while leaving neighboring cells intact. Highlights of recent work include: a)
development of reagents for protein and peptide radioiodination that decrease deiodination in vivo by up to 100-fold, b) demonstration that At-211 labeled monoclonal antibodies are effective in the treatment of a rat model of neoplastic meningitis, c) synthesis of a thymidine analogue labeled with At-211 and the demonstration that this molecule is taken up in cellular DNA with highly cytotoxicity even at levels of only one atom bound per cell and d) development of
radiohalobenzylguanidines which are specifically cytotoxic for human neuroblastoma cells.

Chilkoti

Ashutosh Chilkoti

Alan L. Kaganov Distinguished Professor of Biomedical Engineering

Ashutosh Chilkoti is the Alan L. Kaganov Professor of Biomedical Engineering and Chair of the Department of Biomedical Engineering at Duke University.

My research in biomolecular engineering and biointerface science focuses on the development of new molecular tools and technologies that borrow from molecular biology, protein engineering, polymer chemistry and surface science that we then exploit for the development of applications that span the range from bioseparations, plasmonic biosensors, low-cost clinical diagnostics, and drug delivery.


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