Skip to main content

Advertisement

SpringerLink
Log in

Non-adhesive and highly stable biodegradable nanoparticles that provide widespread and safe transgene expression in orthotopic brain tumors

  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Several generations of poly(β-amino ester) (PBAE) polymers have been developed for efficient cellular transfection. However, PBAE-based gene vectors, similar to other cationic materials, cannot readily provide widespread gene transfer in the brain due to adhesive interactions with the extracellular matrix (ECM). We thus engineered eight vector candidates using previously identified lead PBAE polymer variants but endowed them with non-adhesive surface coatings to facilitate their spread through brain ECM. Specifically, we screened for the ability to provide widespread gene transfer in tumor spheroids and healthy mouse brains. We then confirmed that a lead formulation provided widespread transgene expression in orthotopically established brain tumor models with an excellent in vivo safety profile. Lastly, we developed a method to store it long-term while fully retaining its brain-penetrating property. This new platform provides a broad utility in evaluating novel genetic targets for gene therapy of brain tumors and neurological disorders in preclinical and clinical settings.

We engineered biodegradable DNA-loaded brain-penetrating nanoparticles (DNA-BPN) possessing small particle diameters (< 70 nm) and non-adhesive surface coatings to facilitate their spread through brain tumor extracellular matrix (ECM). These DNA-BPN provide widespread gene transfer in models recapitulating the ECM barrier, including three-dimensional multicellular tumor spheroids and mice with orthotopically established brain tumor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bowers WJ, Breakefield XO, Sena-Esteves M. Genetic therapy for the nervous system. Hum Mol Genet. 2011;20(R1):R28–41.

    Article  CAS  Google Scholar 

  2. Mastorakos P, Zhang C, Berry S, Oh Y, Lee S, Eberhart CG, et al. Highly PEGylated DNA nanoparticles provide uniform and widespread gene transfer in the brain. Adv Healthc Mater. 2015;4(7):1023–33.

    Article  CAS  Google Scholar 

  3. Mastorakos P, Song E, Zhang C, Berry S, Park HW, Kim YE, et al. Biodegradable DNA nanoparticles that provide widespread gene delivery in the brain. Small. 2016;12(5):678–85.

    Article  CAS  Google Scholar 

  4. A.T.I. Ltd, Phase 2b, trial of Intravesical DTA-H19/PEI in patients with intermediate-risk superficial bladder Cancer, NCT00595088 (2008-2014).

  5. A.T.I. Ltd., Phase 1/2a study of DTA-H19 in advanced stage ovarian Cancer, NCT00826150 (2009-2012).

  6. A.T.I. Ltd., Phase 1/2a DTA-H19 in patients with Unresectable pancreatic Cancer, NCT00711997 (2008-2013).

  7. G.O. Group, EGEN-001 in treating patients with persistent or recurrent ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer, NCT01118052 (2010-present).

  8. I. EGEN, Safety and efficacy of EGEN-001 combined with carboplatin and Docetaxel in recurrent, platinum-sensitive, ovarian cancer, NCT00473954 (2007-2013).

  9. Chen J, Guo Z, Tian H, Chen X. Production and clinical development of nanoparticles for gene delivery. Mol Ther Methods Clin Dev. 2016;3:16023.

    Article  Google Scholar 

  10. Konstan MW, Davis PB, Wagener JS, Hilliard KA, Stern RC, Milgram LJ, et al. Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Hum Gene Ther. 2004;15(12):1255–69.

    Article  CAS  Google Scholar 

  11. Berry S, Mastorakos P, Zhang C, Song E, Patel H, Suk JS, et al. Enhancing intracranial delivery of clinically relevant non-viral gene vectors. RSC Adv. 2016;48(6):41665–74.

    Article  Google Scholar 

  12. Mead BP, Mastorakos P, Suk JS, Klibanov AL, Hanes J, Price RJ. Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. J Control Release. 2016;223:109–17.

    Article  CAS  Google Scholar 

  13. Anderson DG, Lynn DM, Langer R. Semi-automated synthesis and screening of a large library of degradable cationic polymers for gene delivery. Angew Chem Int Ed Engl. 2003;42(27):3153–8.

    Article  CAS  Google Scholar 

  14. Anderson DG, Akinc A, Hossain N, Langer R. Structure/property studies of polymeric gene delivery using a library of poly(beta-amino esters). Mol Ther. 2005;11(3):426–34.

    Article  CAS  Google Scholar 

  15. Guerrero-Cazares H, Tzeng SY, Young NP, Abutaleb AO, Quinones-Hinojosa A, Green JJ. Biodegradable polymeric nanoparticles show high efficacy and specificity at DNA delivery to human glioblastoma in vitro and in vivo. ACS Nano. 2014;8(5):5141–53.

    Article  CAS  Google Scholar 

  16. Keeney M, Ong SG, Padilla A, Yao Z, Goodman S, Wu JC, et al. Development of poly(beta-amino ester)-based biodegradable nanoparticles for nonviral delivery of minicircle DNA. ACS Nano. 2013;7(8):7241–50.

    Article  CAS  Google Scholar 

  17. Park HJ, Lee J, Kim MJ, Kang TJ, Jeong Y, Um SH, et al. Sonic hedgehog intradermal gene therapy using a biodegradable poly(beta-amino esters) nanoparticle to enhance wound healing. Biomaterials. 2012;33(35):9148–56.

    Article  CAS  Google Scholar 

  18. Zugates GT, Tedford NC, Zumbuehl A, Jhunjhunwala S, Kang CS, Griffith LG, et al. Gene delivery properties of end-modified poly(beta-amino ester)s. Bioconjug Chem. 2007;18(6):1887–96.

    Article  CAS  Google Scholar 

  19. Edmondson R, Broglie JJ, Adcock AF, Yang L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol. 2014;12(4):207–18.

    Article  CAS  Google Scholar 

  20. Mastorakos P, da Silva AL, Chisholm J, Song E, Choi WK, Boyle MP, et al. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc Natl Acad Sci U S A. 2015;112(28):8720–5.

    Article  CAS  Google Scholar 

  21. Paunovska K, Sago CD, Monaco CM, Hudson WH, Castro MG, Rudoltz TG, et al. A direct comparison of in vitro and in vivo nucleic acid delivery mediated by hundreds of nanoparticles reveals a weak correlation. Nano Lett. 2018;18(3):2148–57.

    Article  CAS  Google Scholar 

  22. Negron K, Khalasawi N, Lu B, Ho CY, Lee J, Shenoy S, et al. Widespread gene transfer to malignant gliomas with in vitro-to-in vivo correlation. J Control Release. 2019;303:1–11.

    Article  CAS  Google Scholar 

  23. Mastorakos P, Zhang C, Song E, Kim YE, Park HW, Berry S, et al. Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors. J Control Release. 2017;262:37–46.

    Article  CAS  Google Scholar 

  24. Weingart MF, Roth JJ, Hutt-Cabezas M, Busse TM, Kaur H, Price A, et al. Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target. Oncotarget. 2015;6(5):3165–77.

    Article  Google Scholar 

  25. Erdreich-Epstein A, Robison N, Ren X, Zhou H, Xu J, Davidson TB, et al. PID1 (NYGGF4), a new growth-inhibitory gene in embryonal brain tumors and gliomas. Clin Cancer Res. 2014;20(4):827–36.

    Article  CAS  Google Scholar 

  26. Recinos VR, Tyler BM, Bekelis K, Sunshine SB, Vellimana A, Li KW, et al. Combination of intracranial temozolomide with intracranial carmustine improves survival when compared with either treatment alone in a rodent glioma model. Neurosurgery. 2010;66(3):530–7 discussion 537.

    Article  Google Scholar 

  27. Mao XG, Hutt-Cabezas M, Orr BA, Weingart M, Taylor I, Rajan AK, et al. LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program. Oncotarget. 2013;4(7):1050–64.

    Article  Google Scholar 

  28. Song E, Gaudin A, King AR, Seo YE, Suh HW, Deng Y, et al. Surface chemistry governs cellular tropism of nanoparticles in the brain. Nat Commun. 2017;8:15322.

    Article  CAS  Google Scholar 

  29. Greensted A. Otsu thresholding. In: The lab book pages; 2010.

    Google Scholar 

  30. Weiner NE, Pyles RB, Chalk CL, Balko MG, Miller MA, Dyer CA, et al. A syngeneic mouse glioma model for study of glioblastoma therapy. J Neuropathol Exp Neurol. 1999;58(1):54–60.

    Article  CAS  Google Scholar 

  31. Szatmari T, Lumniczky K, Desaknai S, Trajcevski S, Hidvegi EJ, Hamada H, et al. Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy. Cancer Sci. 2006;97(6):546–53.

    Article  CAS  Google Scholar 

  32. Kaur H, Hutt-Cabezas M, Weingart MF, Xu J, Kuwahara Y, Erdreich-Epstein A, et al. The chromatin-modifying protein HMGA2 promotes atypical teratoid/rhabdoid cell tumorigenicity. J Neuropathol Exp Neurol. 2015;74(2):177–85.

    Article  CAS  Google Scholar 

  33. Burger PC, Yu IT, Tihan T, Friedman HS, Strother DR, Kepner JL, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a pediatric oncology group study. Am J Surg Pathol. 1998;22(9):1083–92.

    Article  CAS  Google Scholar 

  34. Biswas A, Kashyap L, Kakkar A, Sarkar C, Julka PK. Atypical teratoid/rhabdoid tumors: challenges and search for solutions. Cancer Manag Res. 2016;8:115–25.

    Article  CAS  Google Scholar 

  35. Lostalé-Seijo I, Montenegro J. Synthetic materials at the forefront of gene delivery. Nat Rev Chem. 2018;2(10):258–77.

    Article  Google Scholar 

  36. Greenland JR, Liu H, Berry D, Anderson DG, Kim WK, Irvine DJ, et al. Beta-amino ester polymers facilitate in vivo DNA transfection and adjuvant plasmid DNA immunization. Mol Ther. 2005;12(1):164–70.

    Article  CAS  Google Scholar 

  37. Bhise NS, Gray RS, Sunshine JC, Htet S, Ewald AJ, Green JJ. The relationship between terminal functionalization and molecular weight of a gene delivery polymer and transfection efficacy in mammary epithelial 2-D cultures and 3-D organotypic cultures. Biomaterials. 2010;31(31):8088–96.

    Article  CAS  Google Scholar 

  38. Zhang C, Mastorakos P, Sobral M, Berry S, Song E, Nance E, et al. Strategies to enhance the distribution of nanotherapeutics in the brain. J Control Release. 2017;267:232–9.

    Article  CAS  Google Scholar 

  39. Arshad A, Yang B, Bienemann AS, Barua NU, Wyatt MJ, Woolley M, et al. Convection-enhanced delivery of carboplatin PLGA nanoparticles for the treatment of Glioblastoma. PLoS One. 2015;10(7):e0132266.

    Article  Google Scholar 

Download references

Funding

The funding was provided by the National Institutes of Health (R01EB020147, R01CA220841, R01CA204968, R01NS111102, and P30EY001765), Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship F31 (K.N.), and W.W. Smith Charitable Trust (J.S.S.).

Author information

Authors and Affiliations

  1. Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Karina Negron, Divya Rao, Justin Hanes & Jung Soo Suk

  2. Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Karina Negron & Justin Hanes

  3. Brain Trauma Neuroprotection Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA

    Karina Negron

  4. Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA

    Casey Zhu, Shun-Wen Chen, Divya Rao, Justin Hanes & Jung Soo Suk

  5. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Shubin Shahab & Eric H. Raabe

  6. Department of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Shubin Shahab

  7. Department of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Eric H. Raabe & Charles G. Eberhart

  8. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Charles G. Eberhart, Justin Hanes & Jung Soo Suk

Authors
  1. Karina Negron
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Casey Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shun-Wen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shubin Shahab
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Divya Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric H. Raabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles G. Eberhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Justin Hanes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jung Soo Suk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jung Soo Suk.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Data availability

The raw/processed data required to reproduce these findings cannot be shared at this time due to technical or time limitations.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 34.6 kb)

ESM 2

(DOCX 3.53 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Negron, K., Zhu, C., Chen, SW. et al. Non-adhesive and highly stable biodegradable nanoparticles that provide widespread and safe transgene expression in orthotopic brain tumors. Drug Deliv. and Transl. Res. 10, 572–581 (2020). https://doi.org/10.1007/s13346-020-00759-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-020-00759-8

Keywords

Search

Navigation