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Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours

Nature Biomedical Engineering volume 6, pages 1148–1166 (2022)Cite this article

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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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Fig. 1: Evaluation of 131I-ELP brachytherapy in combination with paclitaxel nanoparticles (CP-PTX) to treat pancreatic tumours.
Fig. 2: Therapeutic efficacy of brachytherapy and PTX nanoparticle chemotherapy in an s.c. BxPc3-luc2 pancreatic cancer model.
Fig. 3: Effects of substituting current clinical standards of care in combination radiochemotherapy on anti-tumour efficacy in BxPc3-luc2 s.c. xenografts.
Fig. 4: Temporal coordination of radiation delivery with the sensitization effects of PTX is important to achieve synergy between brachytherapy and systemic chemotherapy.
Fig. 5: IHC of orthotopic BxPc3-luc2 tumours after 12 d of treatment revealed differential effects of radiation on the underlying tumour microenvironment.
Fig. 6: The efficacy of optimized 131I-ELP brachytherapy and i.v. CP-PTX chemotherapy in multiple pancreatic tumour xenografts.
Fig. 7: The efficacy and safety of 131I-ELP combination therapy assessed in BxPc3-luc2 tumours grafted orthotopically in the pancreas of male athymic mice.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding author on reasonable request. Source data are provided with this paper.

References

  1. American Cancer Society. Cancer Facts & Figures 2022. Atlanta: American Cancer Society; 2022.

  2. Hidalgo, M. Pancreatic cancer. N. Engl. J. Med. 362, 1605–1617 (2010).

    Article  CAS  Google Scholar 

  3. Li, D., Xie, K., Wolff, R. & Abbruzzese, J. L. Pancreatic cancer. Lancet 363, 1049–1057 (2004).

    Article  CAS  Google Scholar 

  4. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    Article  CAS  Google Scholar 

  5. Michl, P. & Gress, T. M. Current concepts and novel targets in advanced pancreatic cancer. Gut 62, 317–326 (2013).

    Article  CAS  Google Scholar 

  6. Hamada, S., Masamune, A. & Shimosegawa, T. Novel therapeutic strategies targeting tumor-stromal interactions in pancreatic cancer. Front. Physiol. 4, 331 (2013).

    Article  Google Scholar 

  7. Neoptolemos, J. et al. Comparison of adjuvant gemictabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 389, 1011–1024 (2017).

    Article  CAS  Google Scholar 

  8. Regine, W. et al. Fluorouracil-based chemoradiation with either gemictabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: a 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Ann. Surg. Oncol. 18, 1319–1326 (2011).

    Article  Google Scholar 

  9. Tienhoven, G. V. et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial. J. Clin. Oncol. 36, LBA4002 (2018).

    Article  Google Scholar 

  10. Hammel, P. et al. Effect of chemoradiotherapy vs chemotherapy on survival on patients with locally adanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 315, 1844–1853 (2016).

    Article  CAS  Google Scholar 

  11. Reyngold, M., Parikh, P. & Crane, C. H. Ablative radiation therapy for locally advanced pancreatic cancer: techniques and results. Radiat. Oncol. 14, 95 (2019).

    Article  Google Scholar 

  12. Zhong, J. et al. Outcomes for patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiation therapy versus conventionally fractionated radiation. Cancer 123, 3486–3493 (2017).

    Article  Google Scholar 

  13. Tempero, M.A. et al. Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 15, 1028–1061 (2017).

    Article  Google Scholar 

  14. NCI. Surveillance, Epidemiology, and End Results (SEER) Database. (NCI’s Division of Cancer Control and Population Sciences, 2007-2013.

  15. Kamisawa, T., Wood, L. D., Itoi, T. & Takaori, K. Pancreatic cancer. Lancet 388, 73–85 (2016).

    Article  CAS  Google Scholar 

  16. Palta, M. et al. Interim acute toxicity analysis and surgical outcomes of neoadjuvant gemcitabine/nab-paclitaxel and hypofractionated image guided intensity modulated radiation therapy in resectable and borderline resectable pancreatic cancer (ANCHOR) study. Int. J. Radiat. Oncol. Biol. Phys. 96, S204–S205 (2016).

    Article  Google Scholar 

  17. Schellenberg, D. et al. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 81, 181–188 (2011).

    Article  Google Scholar 

  18. Trakul, N., Koong, A. C. & Chang, D. T. Stereotactic body radiotherapy in the treatment of pancreatic cancer. Semin. Radiat. Oncol. 24, 140–147 (2014).

    Article  Google Scholar 

  19. Koong, A. C. et al. Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 63, 320–323 (2005).

    Article  Google Scholar 

  20. Schellenberg, D. et al. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 72, 678–686 (2008).

    Article  CAS  Google Scholar 

  21. Hoyer, M. et al. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother. Oncol. 76, 48–53 (2005).

    Article  Google Scholar 

  22. Herman, J. M. et al. Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer 121, 1128–1137 (2014).

    Article  Google Scholar 

  23. Park, J. J. et al. Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer. Acta Oncol. 56, 1746–1753 (2017).

    Article  Google Scholar 

  24. Reyngold, M. et al. Association of ablative radiation therapy with survival among patients with inoperable pancreatic cancer. JAMA Oncol. 7, 735–738 (2021).

    Article  Google Scholar 

  25. Ryerson, A. B. et al. Annual report to the nation on the status of cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer 122, 1312–1337 (2016).

    Article  Google Scholar 

  26. Liu, W. et al. Brachytherapy using injectable seeds that are self-assembled from genetically encoded polypeptides in situ. Cancer Res. 72, 5956–5965 (2012).

    Article  CAS  Google Scholar 

  27. Schaal, J. L. et al. Injectable polypeptide micelles that form radiation crosslinked hydrogels in situ for intratumoral radiotherapy. J. Control. Release 228, 58–66 (2016).

    Article  CAS  Google Scholar 

  28. Han, Q., Deng, M., Lv, Y. & Dai, G. Survival of patients with advanced pancreatic cancer after iodine(125) seeds implantation brachytherapy: a meta-analysis. Medicine 96, e5719 (2017).

    Article  CAS  Google Scholar 

  29. Du, Y.-Q., Li, Z.-S. & Jin, Z.-D. Endoscope-assisted brachytherapy for pancreatic cancer: from tumor killing to pain relief and drainage. J. Interv. Gastroenterol. 1, 23–27 (2011).

    Article  Google Scholar 

  30. Urry, D. W. Protein elasticity based on conformations of sequential polypeptides: the biological elastic fiber. J. Protein Chem. 3, 403–436 (1984).

    Article  CAS  Google Scholar 

  31. McDaniel, J. R., Callahan, D. J. & Chilkoti, A. Drug delivery to solid tumors by elastin-like polypeptides. Adv. Drug Deliv. Rev. 62, 1456–1467 (2010).

    Article  CAS  Google Scholar 

  32. Chilkoti, A., Dreher, M. R. & Meyer, D. E. Design of thermally responsive, recombinant polypeptide carriers for targeted drug delivery. Adv. Drug Deliv. Rev. 54, 1093–1111 (2002).

    Article  CAS  Google Scholar 

  33. McDaniel, J. R., Radford, D. C. & Chilkoti, A. A unified model for de novo design of elastin-like polypeptides with tunable inverse transition temperatures. Biomacromolecules 14, 2866–2872 (2013).

    Article  CAS  Google Scholar 

  34. Du, Y.-Q., Li, Z.-S. & Jin, Z.-D. Endoscope-assisted brachytherapy for pancreatic cancer: from tumor killing to pain relief and drainage. J. Interv. Gastroenterol. 1, 23–27 (2011).

    Article  Google Scholar 

  35. Liu, W. et al. Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice. J. Control. Release 116, 170–178 (2006).

    Article  CAS  Google Scholar 

  36. Barbuti, A. M. & Chen, Z.-S. Paclitaxel through the ages of anticancer therapy: exploring its role in chemoresistance and radiation therapy. Cancers 7, 2360–2371 (2015).

    Article  CAS  Google Scholar 

  37. Adiseshaiah, P. P., Crist, R. M., Hook, S. S. & McNeil, S. E. Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat. Rev. Clin. Oncol. 13, 750–765 (2016).

    Article  CAS  Google Scholar 

  38. Bley, C. R. et al. Microtubule stabilising agents and ionising radiation: multiple exploitable mechanisms for combined treatment. Eur. J. Cancer 49, 245–253 (2013).

    Article  Google Scholar 

  39. Choy, H., Rodriguez, F. F., Koester, S., Hilsenbeck, S. & Hoff, D. D. V. Investigation of taxol as a potential radiation sensitizer. Cancer 71, 3774–3778 (1993).

    Article  CAS  Google Scholar 

  40. Miller, M. A. et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci. Transl. Med. 9, eaal0225 (2017).

    Article  Google Scholar 

  41. Bhattacharyya, J. et al. A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models. Nat. Commun. 6, 7939 (2015).

    Article  CAS  Google Scholar 

  42. Greco, W., Bravo, G. & Parson, J. The search for synergy: a critical review from a response surface perspective. Pharmacol. Rev. 24, 331–385 (1995).

    Google Scholar 

  43. McConkey, D. J. et al. in Neoptolemos, J. P. et al. (eds) Pancreatic Cancer 457–469 (Springer, 2010).

  44. Deer, E. L. et al. Phenotype and genotype of pancreatic cancer cell lines. Pancreas 39, 425–435 (2010).

    Article  CAS  Google Scholar 

  45. Trieu, V., Hsu, J., Choi, M. & Hwang, L. P0157 Preclinical evaluation of NBN-paclitaxel in pancreatic cancer xenograft models. Eur. J. Cancer 50, e53 (2014).

    Article  Google Scholar 

  46. Sun, J. D. et al. Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer. Cancer Biol. Ther. 16, 438–449 (2015).

    Article  CAS  Google Scholar 

  47. Ragupathi, G. et al. Abstract A73: antitumor activity of MVT-5873, a monoclonal antibody targeting sialyl Lewisa, alone and in combination with gemcitabine/nab-paclitaxel in a BxPC3 human pancreatic cancer xenograft model. Cancer Res. 76, A73 (2016).

    Article  Google Scholar 

  48. Morgan, M. A. et al. The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer. Clin. Cancer Res. 14, 5142–5419 (2008).

    Article  CAS  Google Scholar 

  49. Cao, N. et al. Monitoring the effects of anti-angiogenesis on the radiation sensitivity of pancreatic cancer xenografts using dynamic contrast-enhanced computed tomography. Int. J. Radiat. Oncol. Biol. Phys. 88, 412–418 (2014).

    Article  Google Scholar 

  50. Zimmer, S. M., Liu, J., Clayton, J. L., Stephens, D. S. & Snyder, J. P. Paclitaxel binding to human and murine MD-2. J. Biol. Chem. 283, 27916–27926 (2008).

    Article  CAS  Google Scholar 

  51. Kolby, L. et al. Successful receptor-mediated radiation therapy of xenografted human midgut carcinoid tumor. Br. J. Cancer 93, 1144–1151 (2005).

    Article  CAS  Google Scholar 

  52. Nicolas, G. P. et al. Biodistribution, pharmacokinetics, and dosimetry of 177Lu-, 90Y, and 111In-labeled somatostatin receptor antagonist OPS201 in comparison to the agonist 177Lu-DOTATATE: the mass effect. J. Nucl. Med. 58, 1435–1441 (2017).

    Article  CAS  Google Scholar 

  53. Barrett, J. A. et al. Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution. Cancer Biother. Radiopharm. 25, 299–308 (2010).

    CAS  Google Scholar 

  54. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    Article  CAS  Google Scholar 

  55. Litiere, S., Collette, S., de Vries, E. G. E., Seymour, L. & Bogaerts, J. RECIST - learning from the past to build the future. Nat. Rev. Clin. Oncol. 14, 187–192 (2017).

    Article  CAS  Google Scholar 

  56. Hong, T. & Mamon, H. Short-course versus standard chemoradiation in T3 rectal cancer. Oncologist 16, 717–721 (2011).

    Article  Google Scholar 

  57. Newton, J. et al. Commissioning a small-field biological irradiator using point, 2D, and 3D dosimetry techniques. Med. Phys. 38, 6754–6762 (2011).

    Article  Google Scholar 

  58. Rankine, L. et al. Investigating end-to-end accuracy of image guided radiation treatment delivery using a micro-irradiator. Phys. Med. Biol. 58, 7791–7801 (2013).

    Article  CAS  Google Scholar 

  59. Rios-Doria, J. et al. Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models. Neoplasia 17, 661–670 (2015).

    Article  CAS  Google Scholar 

  60. Darzynkiewicz, Z. & Juan, G. DNA content measurement for DNA ploidy and cell cycle analysis. Curr. Protoc. Cytom. 7, 7.5 (2001).

  61. Mao, Z., Bozzella, M., Seluanov, A. & Gorbunova, V. DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell Cycle 7, 2902–2906 (2008).

    Article  CAS  Google Scholar 

  62. Mjelle, R. et al. Cell cycle regulation of human DNA repair and chromatin remodeling genes. DNA Repair 30, 53–67 (2015).

    Article  CAS  Google Scholar 

  63. Weber, D. A., Eckerman, K. F., Dillman, L. T. & Ryman, J. C. MIRD: Radionuclide Data and Decay Schemes (Society of Nuclear Medicine, 1989).

  64. Siegel, J. A. & Stabin, M. G. Absorbed fractions for electrons and beta particles in spheres of various sizes. J. Nucl. Med. 35, 152–156 (1994).

    CAS  Google Scholar 

  65. Provenzano, P. P. & Hingorani, S. R. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br. J. Cancer 108, 1–8 (2013).

    Article  CAS  Google Scholar 

  66. Roy, F. V. Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat. Rev. Cancer 14, 121–134 (2014).

    Article  Google Scholar 

  67. Krause, G. et al. Structure and function of claudins. Biochim. Biophys. Acta 1778, 631–645 (2008).

    Article  CAS  Google Scholar 

  68. Nichols, L. S., Ashfaq, R. & Iacobuzio-Donahue, C. A. Claudin 4 protein expression in primary and metastatic pancreatic cancer. Am. J. Clin. Pathol. 121, 226–230 (2004).

    Article  CAS  Google Scholar 

  69. Valkenburg, K. C., de Groot, A. E. & Pienta, K. J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 15, 366–381 (2018).

    Article  Google Scholar 

  70. Privratsky, J. R. & Newman, P. J. PECAM-1: regulator of endothelial junctional integrity. Cell Tissue Res. 355, 607–619 (2014).

    Article  CAS  Google Scholar 

  71. DeLisser, H. et al. Vascular endothelial platelet endothelial cell adhesion molecule 1 (PECAM-1) regulates advanced metastatic progression. Proc. Natl Acad. Sci. USA 107, 18616–18621 (2010).

    Article  CAS  Google Scholar 

  72. Diana, A. et al. Prognostic role and correlation of CA9, CD31, CD68 and CD20 with the desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget 7, 72819–72832 (2016).

    Article  Google Scholar 

  73. Quarmby, S. et al. Irradiation induces upregulation of CD31 in human endothelial cells. Arterioscler. Thromb. Vasc. Biol. 19, 588–597 (1999).

    Article  CAS  Google Scholar 

  74. Karamanolis, G. et al. Increased expression of VEGF and CD31 in postradiation rectal tissue: implications for radiation proctitis. Mediators Inflamm. 2013, 515048 (2013).

    Article  CAS  Google Scholar 

  75. Dejana, E., Orsenigo, F. & Lampugnani, M. G. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J. Cell Sci. 121, 2115–2122 (2008).

    Article  CAS  Google Scholar 

  76. Bamford, S. et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 91, 355–358 (2004).

    Article  CAS  Google Scholar 

  77. Lee, C. J., Spalding, A. C., Ben-Josef, E., Wang, L. & Siemone, D. M. In vivo bioluminescent imaging of irradiated orthotopic pancreatic cancer xenografts in nonobese diabetic-severe combined immunodeficient mice: a novel method for targeting and assaying efficacy of ionizing radiation. Transl. Oncol. 3, 153–159 (2010).

    Article  Google Scholar 

  78. Chang, Q., Folz, W. D., Chaudary, N., Hill, R. P. & Hedley, D. W. Tumor-stroma interaction in orthotopic primary pancreatic cancer xenografts during hedgehog pathway inhibition. Int. J. Cancer 133, 225–235 (2013).

    Article  CAS  Google Scholar 

  79. Clavé, P. et al. Amylase, lipase, pancreatic isoamylase, and phospholipase A in diagnosis of acute pancreatitis. Clin. Chem. 41, 1129–1134 (1995).

    Article  Google Scholar 

  80. Alvarez, R. D. et al. A phase I study of combined modality 90Yttrium-CC49 intraperitoneal radioimmunotherapy for ovarian cancer. Clin. Cancer Res. 8, 2806–2811 (2002).

    CAS  Google Scholar 

  81. Kelly, M. P., Lee, F. T., Smyth, F. E., Brechbiel, M. W. & Scott, A. M. Enhanced efficacy of 90Y-radiolabeled anti-Lewis Y humanized monoclonal antibody hu3S193 and paclitaxel combined-modality radioimmunotherapy in a breast cancer model. J. Nucl. Med. 47, 716–725 (2006).

    CAS  Google Scholar 

  82. Liu, Q. et al. The combined therapeutic effects of 131iodine-labeled multifunctional copper sulfide-loaded microspheres in treating breast cancer. Acta Pharm. Sin. B 8, 371–380 (2018).

    Article  Google Scholar 

  83. Awasthi, N. et al. Comparative benefits of Nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer. Carcinogenesis 34, 2361–2369 (2013).

    Article  CAS  Google Scholar 

  84. Awasthi, N., Ostapoff, K., Zhang, C., Schwarz, M. A. & Schwarz, R. Evaluation of combination treatment benefits of nab-paclitaxel in experimental pancreatic cancer. J. Clin. Oncol. 30, 170 (2012).

    Article  Google Scholar 

  85. Ito, D. et al. In vivo antitumor effect of the mTOR inhibitor CCI‐779 and gemcitabine in xenograft models of human pancreatic cancer. Int. J. Cancer 118, 2337–2343 (2006).

    Article  CAS  Google Scholar 

  86. Fujiwara, M. et al. Modulating effect of the PI3-kinase inhibitor LY294002 on cisplatin in human pancreatic cancer cells. J. Exp. Clin. Cancer Res. 27, 76 (2008).

    Article  Google Scholar 

  87. Therapeutics, H. Halozyme provides update on SWOG Collaborative Group clinical study. (Halozyme Therapeutics, 2017).

  88. Hingorani, S. R. et al. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin. Cancer Res. 22, 2848–2854 (2016).

    Article  CAS  Google Scholar 

  89. Golden, E. & Apetoh, L. Radiotherapy and immunogenic cell death. Semin. Radiat. Oncol. 25, 11–17 (2015).

    Article  Google Scholar 

  90. Silberstein, E. B. et al. The SNMMI practice guideline for therapy of thyroid disease with 131I 3.0. J. Nucl. Med. 53, 1633–1651 (2012).

    Article  Google Scholar 

  91. Agah, R. & RenovoRX. Intra-Arterial Treatment of Pancreatic Cancer Using the RenovoCath™ RC120 Catheter NCT02591082 (ClinicalTrials.gov, 2018).

  92. Meyer, D. E. & Chilkoti, A. Purification of recombinant proteins by fusion with thermally-responsive polypeptides. Nat. Biotechnol. 17, 1112–1115 (1999).

    Article  CAS  Google Scholar 

  93. A Harmonized Standard <85> for Bacterial Endotoxins Test (USP, 2012).

  94. MacKay, J. A. et al. Self-assembling chimeric polypeptide-doxorubicin conjugate nanoparticles that abolish tumours after a single injection. Nat. Mater. 8, 993–999 (2009).

    Article  Google Scholar 

  95. Wood, W., Wachter, C. & Scriba, P. Experiences using chloramine-T and 1, 3, 4, 6-tetrachloro-3 alpha, 6 alpha-diphenylglycoluril (iodogen) for radioiodination of materials for radioimmunoassay. J. Clin. Chem. Clin. Biochem. 19, 1051–1056 (1981).

    CAS  Google Scholar 

  96. Qiu, W. & Su, G. H. Development of orthotopic pancreatic tumor mouse models. Methods Mol. Biol. 980, 215–223 (2013).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Z. Su of the Duke Pathology Department for invaluable assistance in processing and assessing the histological specimens; L. d. S. Campos for expertise in operating the X-RAD CX225 micro-irradiator; and S. Kron of the University of Chicago for early discussions that inspired our investigation of vascular permeability following radiotherapy. The following Duke Shared Facilities provided resources critical to this study: the Duke Cancer Center Isolation Facility for animal housing and husbandry, the DCI Optical Molecular Imaging and Analysis Shared Resource for in vivo imaging methods, the Duke Research Immunohistology Laboratory for tissue pathology, and the Duke Light Microscopy Core Facility. Funding for these studies was provided by the NIH through grant 5R01EB000188 to A.C. and NCI grant R35CA197616 to D.G.K.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Jeffrey L. Schaal, Jayanta Bhattacharyya, Garrett Kelly, Soumen Saha, Joshua Milligan, Samagya Banskota, Xinghai Li, Wenge Liu, Michael R. Zalutsky & Ashutosh Chilkoti

  2. Center for Biomedical Engineering, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, India

    Jayanta Bhattacharyya

  3. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA

    Jeremy Brownstein, David G. Kirsch & Michael R. Zalutsky

  4. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    Kyle C. Strickland

  5. Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA

    David G. Kirsch

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Contributions

J.L.S. and A.C. conceived and designed all studies in the research. J.L.S. performed all experiments and analysed the results. J. Bhattacharyya helped conceive paclitaxel as a radiation-sensitizer, synthesized the CP-PTX and co-designed the dose-escalation studies. K.C.S. performed blinded pathological analysis of the IHC samples. X.L. and S.B. assisted with in vivo experiments and imaging. J. Brownstein and D.G.K provided radiation oncology expertise in designing EBRT experiments, planning IHC staining and reviewing brachytherapy dose calculations. G.K., S.S. and J.M. conducted additional EBRT therapy studies per reviewer request. W.L. supervised in vivo experiment design. M.R.Z. supervised radiochemistry procedures, provided facilities and reviewed MIRD dosimetry calculations. J.L.S. and A.C. wrote the manuscript, and all authors edited it.

Corresponding author

Correspondence to Ashutosh Chilkoti.

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Competing interests

A.C. is a scientific advisor to PhaseBio Pharmaceuticals, which has licensed the ELP technology for drug delivery from Duke University. D.G.K. is a co-founder of XRAD Therapeutics, which develops small-molecule radiosensitizers, and is on the Scientific Advisory Board of Lumicell, Inc., which commercializes intraoperative imaging technology. A provisional patent application (US20220008567A1, United States, 2018) has been filed by Duke University on the basis of this work, with J.L.S., A.C. and W.L. listed as inventors.

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Nature Biomedical Engineering thanks Abraham Wu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Single agent therapy data from 131I-ELP dose escalation trial.

Single agent therapy data from the 131I-ELP dose escalation trial. (a) 3.3 µCi/mm3 treatment group showed no improvement over untreated tumors (p > 0.05, 2-way ANOVA), nor (b) was there any significant survival advantage (p > 0.05, Mantel Cox log-rank). (c) The 6.6 µCi/mm3 treatment group showed improved single agent efficacy (p = 0.047, 2-way ANOVA) but combination therapy was still superior (p = 0.037, 2-way ANOVA). (d) Median survival for the 6.6 µCi/mm3 monotherapy group did increase to 33d, compared to 24d and 19d for the 3.3 µCi/mm3 and PBS control groups, respectively (p = 0.005, Mantel Cox log-rank). (e) The 10.0 µCi/mm3 treatment group exhibited improved tumor regression trends, but benefits were insignificant compared with previous 131I-ELP doses (p = 0.762, 2-way ANOVA). (f) As a monotherapy, the 10.0 µCi/mm3 monotherapy provided significant benefit over CP-PTX only and untreated tumors (p = 0.005), but the combination group significantly outperformed the monotherapy (p < 0.004, Mantel Cox log-rank).

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Extended Data Fig. 2 Single agent therapy data from CP-PTX dose escalation trial.

Single agent therapy data from CP-PTX dose escalation study. (a) Tumor response to for the single agent CP-PTX group dosed at 50 mg/kg was insignificant compared to PBS control mice (p = 0.063, 2-way ANOVA) (b) 50 mg/kg CP-PTX also conferred no survival advantage over unless combined with 131I-ELP (p = 0.333 Mantel Cox log-rank). (c) The 25 mg/kg treatment group also demonstrated no improvement in tumor response compared to untreated tumors (p = 0.129, 2-way ANOVA). (d) The 25 mg/kg group median survival was 25d compared to 21d for the PBS controls (p = 0.127, Mantel Cox log-rank). (e) Similarly, the 12.5 mg/kg CP-PTX group showed no improvement in tumor response and (f) had an identical median survival of 21d as PBS treated control mice. At all doses, CP-PTX required the combination of 131I-ELP to significantly improve tumor responses.

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Extended Data Fig. 3 Bliss Independence isobolograms of combination therapy trials.

Bliss Independence isobolograms were constructed to evaluate if combination therapy responses were synergistic or merely the result of additive effects. Trials analyzed included: (a) 131I-ELP with single i.v. dose of CP-PTX, (b) 131I-ELP with two i.v. doses of CP-PTX, (c) 131I-ELP with four i.v. doses of nab-paclitaxel, (d) 10 Gy x5 fractions EBRT with four i.v. doses of CP-PTX., (e) 5 Gy x5 fraction EBRT with four i.v. doses of CP-PTX, and (f) 3 Gy x15 fractions EBRT with four i.v. doses of CP-PTX. Mathematical synergy is indicated when the actual tumor regression (solid line) is lower than the Bliss prediction (dashed line) and exceeds the 95% confidence interval (shaded). All data are shown as mean ± SEM, with significance determined using 2-way ANOVA.

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Extended Data Fig. 4 H&E stained images of treated BxPc3-luc2 tumors.

Hematoxylin and eosin histology images of treated tumor specimens representing (a) normal murine pancreas, (b) untreated BxPc3-luc2 tumors, (c) CP-PTX treated tumors, (d) 25 Gy EBRT monotherapy, (e) 131I-ELP monotherapy, (f) EBRT combination therapy, and (g) 131I-ELP combination therapy treated tumors. Full panels show representative pathological patterning, while insets emphasize cellular characteristics.

Extended Data Fig. 5 Masson Trichrome stained images of treated BxPc3-luc2 tumors.

Masson Trichrome staining of treated tumors for detection of stromal collagen (cyan), cytoplasm (pink), and nuclei (purple). Tissue samples represented are taken from (a) normal murine pancreatic tissue and (b) an untreated s.c. BxPc3-luc2 tumor xenograft specimen, and (c) an orthotopic BxPc3-luc2 pancreatic tumor. Stromal differentiation was analyzed following tumor treatment with (d) CP-PTX monotherapy, (e) EBRT monotherapy, (f) 131I-ELP monotherapy, (g) EBRT combination therapy, and (h) 131I-ELP combination therapy. Tumor samples were collected 12 days after treatment. Insets emphasize cellular features.

Extended Data Fig. 6 Pathological analysis of treated BxPc3-luc2 tumors with immunohistochemistry staining.

Pathological analysis of treated BxPc3-luc2 tumors after immunohistochemistry staining. (a) Qualitative analysis of tumor stromal collagen after Masson Trichrome staining. Relative abundance was ranked by abundance: 0-normal collagen, 1-minimal stroma, 2-light stroma, 3-moderate stroma, 4-dense stroma. EBRT was found to induce a dense phenotype while 131I-ELP combination therapy significantly reduced stromal collagen into the light-moderate range (p = 0.005, ANOVA). (b) Claudin-4 cell membrane intensity staining was quantified after cell membrane IHC staining: 3-intense, 2-moderate, 1-light, and 0-no staining. (c) The relative area of Claudin-4 coverage was quantified by converting to a binary mask. Significant (p = 0.005, ANOVA) reduction in staining was observed for CP-PTX, 131I-ELP monotherapy, and 131I-ELP combination therapy treatments. (d) CD-31 (PECAM-1) staining of tumor cell cytoplasm, as evaluated by a blinded qualitative intensity scaling, showed no differences between treatments. (e) The relative area of CD-31 staining coverage also showed comparable expression amongst treatment groups. (f) Tumor tissue was next issued a CD-144 (VE-Cadherin) histology score (H-Score) that combined the intensity and frequency of nuclear staining within cells. Results showed a significant reduction in CD-144 for 131I-ELP groups over other single monotherapies and untreated tumor specimens (p = 0.040, ANOVA). (g) Area of expression showed a trend of reduced VE-Cadherin expression for 131I-ELP treatment groups but was not statistically significant.

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Extended Data Fig. 7 Claudin-4 immunohistochemistry images of treated BxPc3-luc2 tumors.

Claudin-4 immunohistochemistry images for treated tumors, including (a) a normal murine pancreatic tissue and (b) an untreated orthotopic BxPc3-luc2 tumor. Claudin-4 expression was then assessed after treatment with (c) CP-PTX only, (d) EBRT (25 Gy) only, (e) 131I-ELP only, (f) EBRT combination therapy with CP-PTX, and (g) 131I-ELP combination therapy.

Extended Data Fig. 8 CD-31 immunohistochemistry images of treated BxPc3-luc2 tumors.

CD-31 immunohistochemistry staining for treated tumor specimens, consisting of (a) a normal murine prostate and (b) an untreated BxPc3-luc2 tumor, (c) CP-PTX only, (d) EBRT (25 Gy) only, (e) 131I-ELP only, (f) EBRT combination therapy with CP-PTX, and (g) 131I-ELP combination therapy with CP-PTX. No significant difference in expression was observed amongst treatments.

Extended Data Fig. 9 CD-144 immunohistochemistry images of treated BxPc3-luc2 tumors.

CD-144 immunohistochemistry staining of VE-Cadherin for treated tumor specimens, consisting of (a) a normal murine prostate and (b) an untreated BxPc3-luc2 tumor, (c) CP-PTX only, (d) EBRT (25 Gy) only, (e) 131I-ELP only, (f) EBRT combination therapy with CP-PTX, and (g) 131I-ELP combination therapy.

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Summary of a literature review of the outcomes of over 1,100 therapies used to treat animal models of pancreatic tumours.

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Schaal, J.L., Bhattacharyya, J., Brownstein, J. et al. Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours. Nat. Biomed. Eng 6, 1148–1166 (2022). https://doi.org/10.1038/s41551-022-00949-4

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