Special Report

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

The Institute for Nanobiotechnology & The Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

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Jordan J Green

*Author for correspondence:

E-mail Address: green@jhu.edu

https://orcid.org/0000-0003-4176-3808

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

The Institute for Nanobiotechnology & The Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Department of Ophthalmology & Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Department of Materials Science & Engineering & Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21287, USA

Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

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Eric M Jackson

**Author for correspondence:

E-mail Address: ejackson@jhmi.edu

https://orcid.org/0000-0001-9306-9290

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

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Published Online:23 Jul 2020https://doi.org/10.2217/nnm-2020-0110

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Abstract

Current standard of care for many CNS tumors involves surgical resection followed by chemotherapy and/or radiation. Some pediatric brain tumor types are infiltrative and diffuse in nature, which reduces the role for surgery. Furthermore, children are extremely vulnerable to neurological sequelae from surgery and radiation therapy, thus alternative approaches are in critical need. As molecular targets underlying various cancers become more clearly defined, there is an increasing push for targeted gene therapies. Viral vectors and nonviral nanoparticles have been thoroughly investigated for gene delivery and show promise as vectors for gene therapy for pediatric brain cancer. Here, we review inorganic and organic materials in development for nanoparticle gene delivery to the brain with a particular focus on safety.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Gondi V, Yock TI, Mehta MP. Proton therapy for paediatric CNS tumours – improving treatment-related outcomes. Nat. Rev. Neurol. 12(6), 334–345 (2016).
Medline CASGoogle Scholar
2. Johnson KJ, Cullen J, Barnholtz-Sloan JS et al. Cchildhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol. Biomarkers Prev. 23(12), 2716–2736 (2014).
MedlineGoogle Scholar
3. Ward E, Desantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J. Clin. 64(2), 83–103 (2014).
MedlineGoogle Scholar
4. Warren KE. Diffuse intrinsic pontine glioma: poised for progress. Front. Oncol. 2, 205 (2012).
MedlineGoogle Scholar
5. Park JH, Rivière I, Gonen M et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378(5), 449–459 (2018).
Medline CASGoogle Scholar
6. Hitti FL, Gonzalez-Alegre P, Lucas TH. Gene therapy for neurologic disease: a neurosurgical review. World Neurosurg. 121, 261–273 (2019).
MedlineGoogle Scholar
7. Lentz TB, Gray SJ, Samulski RJ. Viral vectors for gene delivery to the central nervous system. Neurobiol. Dis. 48(2), 179–188 (2012).
Medline CASGoogle Scholar
8. Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat. Rev. Drug Discov. 18(5), 358–378 (2019). • Discusses recent advances in adeno-associated virus therapeutics highlighting advantages and disadvantages of viral gene delivery.
Medline CASGoogle Scholar
9. Li L, Liu S, Han D, Tang B, Ma J. Delivery and biosafety of oncolytic virotherapy. Front. Oncol. 10, 475–475 (2020).
MedlineGoogle Scholar
10. Ding Y, Jiang Z, Saha K et al. Gold nanoparticles for nucleic acid delivery. Mol. Ther. 22(6), 1075–1083 (2014).
Medline CASGoogle Scholar
11. Shen L, Li B, Qiao Y. Fe₃O₄ nanoparticles in targeted drug/gene delivery systems. Materials 11(2), 324–324 (2018).
Google Scholar
12. Soenen SJH, Himmelreich U, Nuytten N, De Cuyper M. Cytotoxic effects of iron oxide nanoparticles and implications for safety in cell labelling. Biomaterials 32(1), 195–205 (2011).
Medline CASGoogle Scholar
13. Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (Lond.) 3(5), 703–717 (2008). • Describes clearance mechanisms of various types of nanoparticles.
CASGoogle Scholar
14. Bulbake U, Doppalapudi S, Kommineni N, Khan W. Liposomal formulations in clinical use: an updated review. Pharmaceutics 9(4), 12–12 (2017).
Google Scholar
15. Huo T, Barth RF, Yang W et al. Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats. PLoS One 7(11), e48752 (2012).
Medline CASGoogle Scholar
16. Huang J-Y, Lu Y-M, Wang H et al. The effect of lipid nanoparticle PEGylation on neuroinflammatory response in mouse brain. Biomaterials 34(32), 7960–7970 (2013).
Medline CASGoogle Scholar
17. Buck J, Grossen P, Cullis PR, Huwyler J, Witzigmann D. Lipid-based DNA therapeutics: hallmarks of non-viral gene delivery. ACS Nano 13(4), 3754–3782 (2019).
Medline CASGoogle Scholar
18. Ciolkowski M, Petersen JF, Ficker M et al. Surface modification of PAMAM dendrimer improves its biocompatibility. Nanomedicine 8(6), 815–817 (2012).
Medline CASGoogle Scholar
19. Wang S, Li Y, Fan J et al. The role of autophagy in the neurotoxicity of cationic PAMAM dendrimers. Biomaterials 35(26), 7588–7597 (2014).
Medline CASGoogle Scholar
20. Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers 3(3), 1377–1397 (2011).
Medline CASGoogle Scholar
21. Lee Y, Mo H, Koo H et al. Visualization of the degradation of a disulfide polymer, linear poly(ethylenimine sulfide), for gene delivery. Bioconjug. Chem. 18(1), 13–18 (2007).
Medline CASGoogle Scholar
22. Moghimi SM, Symonds P, Murray JC, Hunter AC, Debska G, Szewczyk A. A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy. Mol. Ther. 11(6), 990–995 (2005).
Medline CASGoogle Scholar
23. Liu Y, Li Y, Keskin D, Shi L. Poly(β-amino esters): synthesis, formulations, and their biomedical applications. Adv. Healthc. Mater. 8(2), 1801359–1801359 (2018).
Google Scholar
24. Udaka YT, Packer RJ. Pediatric brain tumors. Neurol. Clin. 36(3), 533–556 (2018). • Overview of pediatric brain tumors describe incidence and classification systems of various tumor types.
MedlineGoogle Scholar
25. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. World Health Organization Histological System, Revised Classification of Tumours of the Central Nervous System. International Agency for Research on Cancer, France (2016).
Google Scholar
26. Taylor MD, Northcott PA, Korshunov A et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 123(4), 465–472 (2012).
Medline CASGoogle Scholar
27. Packer RJ, Gajjar A, Vezina G et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J. Clin. Oncol. 24(25), 4202–4208 (2006).
Medline CASGoogle Scholar
28. Biegel JA. Molecular genetics of atypical teratoid/rhabdoid tumors. Neurosurg. Focus 20(1), E11 (2006).
MedlineGoogle Scholar
29. Chi SN, Zimmerman MA, Yao X et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J. Clin. Oncol. 27(3), 385–389 (2009).
MedlineGoogle Scholar
30. Braunstein S, Raleigh D, Bindra R, Mueller S, Haas-Kogan D. Pediatric high-grade glioma: current molecular landscape and therapeutic approaches. J. Neuro Oncol. 134(3), 541–549 (2017).
Medline CASGoogle Scholar
31. Roujeau T, Machado G, Garnett MR et al. Stereotactic biopsy of diffuse pontine lesions in children. J. Neurosurg. 107(Suppl. 1), 1–4 (2007).
MedlineGoogle Scholar
32. Dang M, Phillips PC. Pediatric brain tumors. Continuum (Minneap. Minn.) 23(6), 1727–1757 (2017).
MedlineGoogle Scholar
33. Liu K-W, Pajtler KW, Worst BC, Pfister SM, Wechsler-Reya RJ. Molecular mechanisms and therapeutic targets in pediatric brain tumors. Sci. Signal. 10(470), eaaf7593 (2017). •• Overview of the molecular basis of common pediatric tumors give insight into potential therapeutic targets.
MedlineGoogle Scholar
34. Puget S, Philippe C, Bax DA et al. Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 7(2), e30313–e30313 (2012).
Medline CASGoogle Scholar
35. Wetmore C, Boyett J, Li S et al. Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. Neuro Oncol. 17(6), 882–888 (2015).
Medline CASGoogle Scholar
36. Bavle A, Jones J, Lin FY, Malphrus A, Adesina A, Su J. Dramatic clinical and radiographic response to BRAF inhibition in a patient with progressive disseminated optic pathway glioma refractory to MEK inhibition. Pediatr. Hematol. Oncol. 34(4), 254–259 (2017).
MedlineGoogle Scholar
37. Smalley E. First AAV gene therapy poised for landmark approval. Nat. Biotechnol. 35(11), 998–999 (2017).
Medline CASGoogle Scholar
38. Hoy SM. Onasemnogene abeparvovec: first global approval. Drugs 79(11), 1255–1262 (2019).
Medline CASGoogle Scholar
39. Clinicaltrials.Gov. Search of: Gene Therapy | Brain Cancer (2020). https://clinicaltrials.gov/ct2/results?cond=Brain+Cancer&term=gene+therapy&cntry=&state=&city=&dist=
Google Scholar
40. Kramm CM, Rainov NG, Sena-Esteves M et al. Long-term survival in a rodent model of disseminated brain tumors by combined intrathecal delivery of herpes vectors and ganciclovir treatment. Human Gene Ther. 7(16), 1989–1994 (1996).
Medline CASGoogle Scholar
41. Studebaker AW, Hutzen B, Pierson CR, Russell SJ, Galanis E, Raffel C. Oncolytic measles virus prolongs survival in a murine model of cerebral spinal fluid-disseminated medulloblastoma. Neuro Oncol. 14(4), 459–470 (2012).
MedlineGoogle Scholar
42. Studebaker AW, Hutzen B, Pierson CR, Shaffer TA, Raffel C, Jackson EM. Oncolytic measles virus efficacy in murine xenograft models of atypical teratoid rhabdoid tumors. Neuro Oncol. 17(12), 1568–1577 (2015).
Medline CASGoogle Scholar
43. Studebaker AW, Hutzen BJ, Pierson CR et al. Oncolytic herpes virus rRp450 shows efficacy in orthotopic xenograft group 3/4 medulloblastomas and atypical teratoid/rhabdoid tumors. Mol. Ther. Oncolytics 6, 22–30 (2017).
Medline CASGoogle Scholar
44. Varela-Guruceaga M, Tejada-Solís S, García-Moure M et al. Oncolytic viruses as therapeutic tools for pediatric brain tumors. Cancers 10(7), 226 (2018).
Google Scholar
45. Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348(3), 255–256 (2003).
MedlineGoogle Scholar
46. Akinc A, Maier MA, Manoharan M et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 14(12), 1084–1087 (2019).
Medline CASGoogle Scholar
47. Jensen SA, Day ES, Ko CH et al. Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. Sci. Transl. Med. 5(209), 209ra152 (2013).
MedlineGoogle Scholar
48. Dufes C, Uchegbu I, Schatzlein A. Dendrimers in gene delivery. Adv. Drug Deliv. Rev. 57(15), 2177–2202 (2005).
Medline CASGoogle Scholar
49. Kukowska-Latallo JF, Bielinska AU, Johnson J, Spindler R, Tomalia DA, Baker JR. Efficient transfer of genetic material into mammalian cells using Starburst polyamidoamine dendrimers. Proc. Natl Acad. Sci. USA 93(10), 4897–4902 (1996).
Medline CASGoogle Scholar
50. Cui Y, Zhang M, Zeng F, Jin H, Xu Q, Huang Y. Dual-targeting magnetic PLGA nanoparticles for codelivery of paclitaxel and curcumin for brain tumor therapy. ACS Appl. Mater. Interfaces 8(47), 32159–32169 (2016).
Medline CASGoogle Scholar
51. Li H, Tong Y, Bai L et al. Lactoferrin functionalized PEG-PLGA nanoparticles of shikonin for brain targeting therapy of glioma. Int. J. Biol. Macromol. 107(PartA), 204–211 (2018).
Medline CASGoogle Scholar
52. Bi C, Wang A, Chu Y et al. Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG–PLGA nanoparticles for Parkinson's disease treatment. Int. J. Nanomedicine 11, 6547–6559 (2016).
Medline CASGoogle Scholar
53. Zhou J, Patel TR, Fu M, Bertram JP, Saltzman WM. Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors. Biomaterials 33(2), 583–591 (2012).
Medline CASGoogle Scholar
54. Boussif O, Lezoualc'h F, Zanta MA et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc. Natl Acad. Sci. USA 92(16), 7297–7301 (1995).
Medline CASGoogle Scholar
55. Hu Y, He Z, Hao Y et al. Kinetic control in assembly of plasmid DNA/polycation complex nanoparticles. ACS Nano 13(9), 10161–10178 (2019).
Medline CASGoogle Scholar
56. Karlsson J, Rui Y, Kozielski KL et al. Engineered nanoparticles for systemic siRNA delivery to malignant brain tumours. Nanoscale 11(42), 20045–20057 (2019). • Emphasizes the safety profile of poly(beta-amino) esters in an in vivo glioblastoma model.
Medline CASGoogle Scholar
57. Lopez-Bertoni H, Kozielski KL, Rui Y et al. Bioreducible polymeric nanoparticles containing multiplexed cancer stem cell regulating miRNAs inhibit glioblastoma growth and prolong survival. Nano Lett. 18(7), 4086–4094 (2018).
Medline CASGoogle Scholar
58. Ebrahimkhani S, Vafaee F, Hallal S et al. Deep sequencing of circulating exosomal microRNA allows non-invasive glioblastoma diagnosis. NPJ Precis. Oncol. 2(1), 28 (2018).
Medline CASGoogle Scholar
59. Lopez-Bertoni H, Kotchetkov IS, Mihelson N et al. A Sox2:miR-486-5p axis regulates survival of GBM cells by inhibiting tumor suppressor networks. Cancer Res. 80(8), 1644 (2020).
Medline CASGoogle Scholar
60. Mangraviti A, Tzeng SY, Kozielski KL et al. Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo. ACS Nano 9(2), 1236–1249 (2015).
Medline CASGoogle Scholar
61. Choi J, Rui Y, Kim J et al. Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies. Nanomedicine 23, 102115 (2020). •• Highlights the potential utility of poly(beta-amino) esters in the context of pediatric brain tumors.
Medline CASGoogle Scholar
62. Tam VH, Sosa C, Liu R, Yao N, Priestley RD. Nanomedicine as a non-invasive strategy for drug delivery across the blood brain barrier. Int. J. Pharm. 515(1–2), 331–342 (2016).
Medline CASGoogle Scholar
63. Hynynen K, Mcdannold N, Vykhodtseva N, Jolesz FA. Noninvasive MR imaging-guided focal opening of the blood–brain barrier in rabbits. Radiology 220(3), 640–646 (2001).
Medline CASGoogle Scholar
64. Nance E, Timbie K, Miller GW et al. Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood−brain barrier using MRI-guided focused ultrasound. J. Control. Rel. 189, 123–132 (2014).
Medline CASGoogle Scholar
65. Airan RD, Meyer RA, Ellens NPK et al. Noninvasive targeted transcranial neuromodulation via focused ultrasound gated drug release from nanoemulsions. Nano Lett. 17(2), 652–659 (2017).
Medline CASGoogle Scholar
66. Brem H, Piantadosi S, Burger PC et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345(8956), 1008–1012 (1995).
Medline CASGoogle Scholar
67. Segovia N, Pont M, Oliva N, Ramos V, Borrós S, Artzi N. Hydrogel doped with nanoparticles for local sustained release of siRNA in breast cancer. Adv. Healthc. Mater. 4(2), 271–280 (2015).
Medline CASGoogle Scholar
68. Conde J, Oliva N, Zhang Y, Artzi N. Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model. Nat. Mater. 15(10), 1128–1138 (2016).
Medline CASGoogle Scholar
69. Triarico S, Maurizi P, Mastrangelo S, Attinà G, Capozza MA, Ruggiero A. Improving the brain delivery of chemotherapeutic drugs in childhood brain tumors. Cancers 11(6), 824–824 (2019).
CASGoogle Scholar
70. Zhou Z, Singh R, Souweidane M. Convection-enhanced delivery for diffuse intrinsic pontine glioma treatment. Curr. Neuropharmacol. 15(1), 116–128 (2016). •• Overview of convection-enhanced delivery as a delivery mechanism for drugs to the brain with a perspective on obstacles that need to be addressed for improved delivery for diffuse intrinsic pontine glioma.
Google Scholar
71. Syková E, Nicholson C. Diffusion in brain extracellular space. Physiol. Rev. 88(4), 1277–1340 (2008).
Medline CASGoogle Scholar
72. Thorne RG, Lakkaraju A, Rodriguez-Boulan E, Nicholson C. In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate. Proc. Natl Acad. Sci. USA 105(24), 8416 (2008).
Medline CASGoogle Scholar
73. Thorne RG, Nicholson C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc. Natl Acad. Sci. USA 103(14), 5567–5572 (2006).
Medline CASGoogle Scholar
74. Nance EA, Woodworth GF, Sailor KA et al. A Dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci. Transl. Med. 4(149), 149ra119 (2012).
MedlineGoogle Scholar
75. Demeule M, Currie J-C, Bertrand Y et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector Angiopep-2. J. Neurochem. 106(4), 1534–1544 (2008).
Medline CASGoogle Scholar
76. Dumont MF, Yadavilli S, Sze RW, Nazarian J, Fernandes R. Manganese-containing Prussian blue nanoparticles for imaging of pediatric brain tumors. Int. J. Nanomed. 9, 2581–2595 (2014).
Medline CASGoogle Scholar
77. Veiseh O, Sun C, Fang C et al. Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood–brain barrier. Cancer Res. 69(15), 6200–6207 (2009).
Medline CASGoogle Scholar
78. Jansen MHA, Van Vuurden DG, Vandertop WP, Kaspers GJL. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat. Rev. 38(1), 27–35 (2012).
Medline CASGoogle Scholar
79. Menyhárt O, Giangaspero F, Győrffy B. Molecular markers and potential therapeutic targets in non-WNT/non-SHH (group 3 and group 4) medulloblastomas. J. Hematol. Oncol. 12(1), 29–29 (2019).
MedlineGoogle Scholar
80. Inakoshi H, Kayamori R, Tsuchida E et al. Multivariate analysis of dissemination relapse of medulloblastoma and estimation of its time parameter for craniospinal irradiation. Radiat. Med. 21(1), 37–45 (2003).
MedlineGoogle Scholar
81. Song E, Mao T, Dong H et al. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature 577(7792), 689–694 (2020).
Medline CASGoogle Scholar
82. Mathios D, Kim JE, Mangraviti A et al. Anti–PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Sci. Transl. Med. 8(370), 370ra180–370ra180 (2016).
MedlineGoogle Scholar

Vol. 15, No. 18

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Received 15 March 2020

Accepted 1 June 2020

Published online 23 July 2020

Published in print August 2020

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Financial & competing interests disclosure

The authors thank the NIH for support (R01CA228133 and P41EB028239). J Green and Y Rui are inventors on patents related to polymeric gene therapy that are owned by Johns Hopkins University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Safety considerations for nanoparticle gene delivery in pediatric brain tumors

Abstract

References