Advertisement

Journal of Neuro-Oncology

, Volume 135, Issue 3, pp 497–506 | Cite as

Targeting brain tumors by intra-arterial delivery of cell-penetrating peptides: a novel approach for primary and metastatic brain malignancy

  • Shailendra JoshiEmail author
  • Johann R. N. Cooke
  • Jason A. Ellis
  • Charles W. Emala
  • Jeffrey N. Bruce
Laboratory Investigation

Abstract

Computational modeling shows that intra-arterial delivery is most efficient when the delivered drugs rapidly and avidly bind to the target site. The cell-penetrating peptide trans-activator of transcription (TAT) is a candidate carrier molecule that could mediate such specificity for brain tumor chemotherapeutics. To test this hypothesis we first performed in vitro studies testing the uptake of TAT by one primary and three potentially metastatic brain cancer cell lines (9L, 4T-1, LLC, SKOV-3). Then we performed in vivo studies in a rat model where TAT was delivered either intra-arterially (IA) or intravenously (IV) to 9L brain tumors. We observed robust uptake of TAT by all tumor cell lines in vitro. Flow cytometry and confocal microscopy revealed a rapid uptake of fluorescein-labeled TAT within 5 min of exposure to the cancer cells. IA injections done under transient cerebral hypoperfusion (TCH) generated a four-fold greater tumor TAT concentration compared to conventional IV injections. We conclude that it is feasible to selectively target brain tumors with TAT-linked chemotherapy by the IA-TCH method.

Keywords

Adjuvant therapy Chemotherapy Glioblastoma Glioma Targeted therapy 

Notes

Funding

The funding was provided by National Cancer Institute at the National Institutes of Health (Grant No. RO1-CA-138643).

References

  1. 1.
    Dobrzynska I, Skrzydlewska E, Figaszewski ZA (2013) Changes in electric properties of human breast cancer cells. J Membr Biol 246(2):161–166. doi: 10.1007/s00232-012-9516-5 CrossRefPubMedGoogle Scholar
  2. 2.
    Dobrzynska I, Szachowicz-Petelska B, Darewicz B, Figaszewski ZA (2015) Characterization of human bladder cell membrane during cancer transformation. J Membr Biol 248(2):301–307. doi: 10.1007/s00232-015-9770-4 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Dobrzynska I, Szachowicz-Petelska B, Sulkowski S, Figaszewski Z (2005) Changes in electric charge and phospholipids composition in human colorectal cancer cells. Mol Cell Biochem 276(1–2):113–119. doi: 10.1007/s11010-005-3557-3 CrossRefPubMedGoogle Scholar
  4. 4.
    Klahn M, Zacharias M (2013) Transformations in plasma membranes of cancerous cells and resulting consequences for cation insertion studied with molecular dynamics. Phys Chem Chem Phys 15(34):14427–14441. doi: 10.1039/c3cp52085d CrossRefPubMedGoogle Scholar
  5. 5.
    Ran S, Downes A, Thorpe PE (2002) Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res 62(21):6132–6140PubMedGoogle Scholar
  6. 6.
    Szachowicz-Petelska B, Dobrzynska I, Skrodzka M, Darewicz B, Figaszewski ZA, Kudelski J (2013) Phospholipid composition and electric charge in healthy and cancerous parts of human kidneys. J Membr Biol 246(5):421–425. doi: 10.1007/s00232-013-9554-7 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chen B, Le W, Wang Y, Li Z, Wang D, Ren L, Lin L, Cui S, Hu JJ, Hu Y, Yang P, Ewing RC, Shi D, Cui Z (2016) Targeting negative surface charges of cancer cells by multifunctional nanoprobes. Theranostics 6(11):1887–1898. doi: 10.7150/thno.16358 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Abbasi S, Paul A, Shao W, Prakash S (2012) Cationic albumin nanoparticles for enhanced drug delivery to treat breast cancer: preparation and in vitro assessment. J Drug Deliv 2012:686108. doi: 10.1155/2012/686108 CrossRefPubMedGoogle Scholar
  9. 9.
    Bilensoy E, Sarisozen C, Esendagli G, Dogan AL, Aktas Y, Sen M, Mungan NA (2009) Intravesical cationic nanoparticles of chitosan and polycaprolactone for the delivery of Mitomycin C to bladder tumors. Int J Pharm 371(1–2):170–176. doi: 10.1016/j.ijpharm.2008.12.015 CrossRefPubMedGoogle Scholar
  10. 10.
    Eichhorn ME, Becker S, Strieth S, Werner A, Sauer B, Teifel M, Ruhstorfer H, Michaelis U, Griebel J, Brix G, Jauch KW, Dellian M (2006) Paclitaxel encapsulated in cationic lipid complexes (MBT-0206) impairs functional tumor vascular properties as detected by dynamic contrast enhanced magnetic resonance imaging. Cancer Biol Ther 5(1):89–96CrossRefPubMedGoogle Scholar
  11. 11.
    Lu W, Wan J, Zhang Q, She Z, Jiang X (2007) Aclarubicin-loaded cationic albumin-conjugated pegylated nanoparticle for glioma chemotherapy in rats. Int J Cancer 120(2):420–431CrossRefPubMedGoogle Scholar
  12. 12.
    Xu F, Lu W, Wu H, Fan L, Gao X, Jiang X (2009) Brain delivery and systemic effect of cationic albumin conjugated PLGA nanoparticles. J Drug Target 17(6):423–434CrossRefPubMedGoogle Scholar
  13. 13.
    Zhao M, Chang J, Fu X, Liang C, Liang S, Yan R, Li A (2012) Nano-sized cationic polymeric magnetic liposomes significantly improves drug delivery to the brain in rats. J Drug Target 20(5):416–421CrossRefPubMedGoogle Scholar
  14. 14.
    Gupta B, Levchenko TS, Torchilin VP (2007) TAT peptide-modified liposomes provide enhanced gene delivery to intracranial human brain tumor xenografts in nude mice. Oncol Res 16(8):351–359PubMedGoogle Scholar
  15. 15.
    Liu L, Venkatraman SS, Yang YY, Guo K, Lu J, He B, Moochhala S, Kan L (2008) Polymeric micelles anchored with TAT for delivery of antibiotics across the blood–brain barrier. Biopolymers 90(5):617–623. doi: 10.1002/bip.20998 CrossRefPubMedGoogle Scholar
  16. 16.
    Zelphati O, Uyechi LS, Barron LG, Szoka FC Jr (1998) Effect of serum components on the physico-chemical properties of cationic lipid/oligonucleotide complexes and on their interactions with cells. Biochim Biophys Acta 1390(2):119–133CrossRefPubMedGoogle Scholar
  17. 17.
    Campbell RB, Fukumura D, Brown EB, Mazzola LM, Izumi Y, Jain RK, Torchilin VP, Munn LL (2002) Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. Cancer Res 62(23):6831–6836PubMedGoogle Scholar
  18. 18.
    Mickan A, Sarko D, Haberkorn U, Mier W (2014) Rational design of CPP-based drug delivery systems: considerations from pharmacokinetics. Curr Pharm Biotechnol 15(3):200–209CrossRefPubMedGoogle Scholar
  19. 19.
    Riina HA, Knopman J, Greenfield JP, Fralin S, Gobin YP, Tsiouris AJ, Souweidane MM, Boockvar JA (2010) Balloon-assisted superselective intra-arterial cerebral infusion of bevacizumab for malignant brainstem glioma. A technical note. Intervent Neuroradiol 16(1):71–76CrossRefGoogle Scholar
  20. 20.
    Pile-Spellman J, Young WL, Joshi S, Duong DH, Vang MC, Hartmann A, Kahn RA, Rubin DA, Prestigiacomo CJ, Ostapkovich ND (1999) Adenosine-induced cardiac pause for endovascular embolization of cerebral arteriovenous malformations: technical case report. Neurosurgery 44(4):881–886 (discussion 886–887)CrossRefPubMedGoogle Scholar
  21. 21.
    Hashimoto T, Young WL, Aagaard BD, Joshi S, Ostapkovich ND, Pile-Spellman J (2000) Adenosine-induced ventricular asystole to induce transient profound systemic hypotension in patients undergoing endovascular therapy: dose-response characteristics [In Process Citation]. Anesthesiology 93(4):998–1001CrossRefPubMedGoogle Scholar
  22. 22.
    Joshi S, Wang M, Etu JJ, Suckow RF, Cooper TB, Feinmark SJ, Bruce JN, Fine RL (2007) Transient cerebral hypoperfusion enhances intraarterial carmustine deposition into brain tissue. J Neurooncol 86(2):123–132CrossRefPubMedGoogle Scholar
  23. 23.
    Klopp CT, Alford TC, Bateman J, Berry GN, Winship T (1950) Fractionated intra-arterial cancer; chemotherapy with methyl bis amine hydrochloride; a preliminary report. Ann Surg 132(4):811–832CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wilson CB (1976) Chemotherapy of brain tumors. Adv Neurol 15:361–367PubMedGoogle Scholar
  25. 25.
    Wilson CB (1964) Chemotherapy of brain tumors by continuous arterial infusion. Surgery 55:640–653PubMedGoogle Scholar
  26. 26.
    Levin VA, Wilson CB (1976) Nitrosourea chemotherapy for primary malignant gliomas. Cancer Treat Rep 60(6):719–724PubMedGoogle Scholar
  27. 27.
    Wilson CB, Gutin P, Boldrey EB, Drafts D, Levin VA, Enot KJ (1976) Single-agent chemotherapy of brain tumors. A five-year review. Arch Neurol 33(11):739–744CrossRefPubMedGoogle Scholar
  28. 28.
    Mitsuki S, Diksic M, Conway T, Yamamoto YL, Villemure JG, Feindel W (1991) Pharmacokinetics of 11C-labelled BCNU and SarCNU in gliomas studied by PET. J Neurooncol 10(1):47–55CrossRefPubMedGoogle Scholar
  29. 29.
    Tyler JL, Yamamoto YL, Diksic M, Theron J, Villemure JG, Worthington C, Evans AC, Feindel W (1986) Pharmacokinetics of superselective intra-arterial and intravenous [11C]BCNU evaluated by PET. J Nucl Med 27(6):775–780PubMedGoogle Scholar
  30. 30.
    Rosenblum MK, Delattre JY, Walker RW, Shapiro WR (1989) Fatal necrotizing encephalopathy complicating treatment of malignant gliomas with intra-arterial BCNU and irradiation: a pathological study. J Neurooncol 7(3):269–281CrossRefPubMedGoogle Scholar
  31. 31.
    Tonn JC, Roosen K, Schachenmayr W (1991) Brain necroses after intraarterial chemotherapy and irradiation of malignant gliomas–a complication of both ACNU and BCNU? J Neurooncol 11(3):241–242CrossRefPubMedGoogle Scholar
  32. 32.
    Kroll RA, Neuwelt EA (1998) Outwitting the blood-brain barrier for therapeutic purposes: Osmotic opening and other means [Comments by Paul. Kornblith L, Pollay Michael, Pierre-Yves Dietrich and Nicolas de Tribolet, Berislav Zlokovic]. Neurosurgery 42(5):1083–1100CrossRefPubMedGoogle Scholar
  33. 33.
    Neuwelt EA, Frenkel EP, Diehl JT, Maravilla KR, Vu LH, Clark WK, Rapoport SI, Barnett PA, Hill SA, Lewis SE, Ehle AL, Beyer CW Jr, Moore RJ (1979) Osmotic blood-brain barrier disruption: a new means of increasing chemotherapeutic agent delivery. Trans Am Neurol Assoc 104:256–260PubMedGoogle Scholar
  34. 34.
    Stewart DJ, Grahovac Z, Hugenholtz H, DaSilva V, Richard MT, Benoit B, Belanger G, Russell N (1993) Feasibility study of intraarterial vs intravenous cisplatin, BCNU, and teniposide combined with systemic cisplatin, teniposide, cytosine arabinoside, glycerol and mannitol in the treatment of primary and metastatic brain tumors. J Neurooncol 17(1):71–79CrossRefPubMedGoogle Scholar
  35. 35.
    Newton HB, Slivka MA, Volpi C, Bourekas EC, Christoforidis GA, Baujan MA, Slone W, Chakeres DW (2003) Intra-arterial carboplatin and intravenous etoposide for the treatment of metastatic brain tumors. J Neurooncol 61(1):35–44CrossRefPubMedGoogle Scholar
  36. 36.
    Cloughesy TF, Gobin YP, Black KL, Vinuela F, Taft F, Kadkhoda B, Kabbinavar F (1997) Intra-arterial carboplatin chemotherapy for brain tumors: a dose escalation study based on cerebral blood flow. J Neurooncol 35(2):121–131CrossRefPubMedGoogle Scholar
  37. 37.
    Vance RB, Pittisapu J, Kapp JP (1986) Experiences with sodium thiosulfate after intracarotid infusion of cisplatin and BCNU for malignant gliomas. J Neurooncol 4(2):151–154CrossRefPubMedGoogle Scholar
  38. 38.
    Oldfield EH, Dedrick RL, Yeager RL, Clark WC, DeVroom HL, Chatterji DC, Doppman JL (1985) Reduced systemic drug exposure by combining intra-arterial chemotherapy with hemoperfusion of regional venous drainage. J Neurosurg 63(5):726–732CrossRefPubMedGoogle Scholar
  39. 39.
    D’Aliberti G, Talamonti G, Versari PP, Todaro C, Bizzozero L, Arena O, Collice M (1997) Comparison of pediatric and adult cerebral arteriovenous malformations. J Neurosurg Sci 41(4):331–336PubMedGoogle Scholar
  40. 40.
    Boockvar JA, Tsiouris AJ, Hofstetter CP, Kovanlikaya I, Fralin S, Kesavabhotla K, Seedial SM, Pannullo SC, Schwartz TH, Stieg P, Zimmerman RD, Knopman J, Scheff RJ, Christos P, Vallabhajosula S, Riina HA (2011) Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma Clinical article. J Neurosurg 114(3):624–632. doi: 10.3171/2010.9.Jns101223 CrossRefPubMedGoogle Scholar
  41. 41.
    Shin BJ, Burkhardt JK, Riina HA, Boockvar JA (2012) Superselective intra-arterial cerebral infusion of novel agents after blood-brain disruption for the treatment of recurrent glioblastoma multiforme: a technical case series. Neurosurg Clin N Am 23(2):323–329CrossRefPubMedGoogle Scholar
  42. 42.
    Cooke JN, Ellis JA, Hossain S, Nguyen J, Bruce JN, Joshi S (2016) Computational pharmacokinetic rationale for intra-arterial delivery to the brain. Drug Deliv Transl Res. doi: 10.1007/s13346-016-0319-6 PubMedCentralGoogle Scholar
  43. 43.
    Dedrick RL (1988) Arterial drug infusion: pharmacokinetic problems and pitfalls. J Natl Cancer Inst 80(2):84–89CrossRefPubMedGoogle Scholar
  44. 44.
    Joshi S, Wang M, Etu JJ, Nishanian EV, Pile-Spellman J (2006) Cerebral blood flow affects dose requirements of intracarotid propofol for electrocerebral silence. Anesthesiology 104(2):290–298CrossRefPubMedGoogle Scholar
  45. 45.
    Joshi S, Wang M, Etu JJ, Pile-Spellman J (2005) Reducing cerebral blood flow increases the duration of electroencephalographic silence by intracarotid thiopental. Anesthesia Analgesia 101(3):851–858CrossRefPubMedGoogle Scholar
  46. 46.
    Joshi S, Singh-Moon RP, Ellis JA, Chaudhuri DB, Wang M, Reif R, Bruce JN, Bigio IJ, Straubinger RM (2014) Cerebral hypoperfusion-assisted intraarterial deposition of liposomes in normal and glioma-bearing rats. Neurosurgery NIHMS 624641 (in press)Google Scholar
  47. 47.
    Joshi S, Singh-Moon RP, Wang M, Chaudhuri DB, Holcomb M, Straubinger NL, Bruce JN, Bigio IJ, Straubinger RM (2014) Transient cerebral hypoperfusion assisted intraarterial cationic liposome delivery to brain tissue. J Neurooncol. doi: 10.1007/s11060-014-1421-6 Google Scholar
  48. 48.
    Ellis JA, Cooke J, Singh-Moon RP, Wang M, Bruce JN, Emala CW, Bigio IJ, Joshi S (2016) Safety, feasibility, and optimization of intra-arterial mitoxantrone delivery to gliomas. J Neurooncol 130(3):449–454. doi: 10.1007/s11060-016-2253-3 CrossRefPubMedGoogle Scholar
  49. 49.
    Joshi S, Cooke JR, Chan DK, Ellis JA, Hossain SS, Singh-Moon RP, Wang M, Bigio IJ, Bruce JN, Straubinger RM (2016) Liposome size and charge optimization for intraarterial delivery to gliomas. Drug Deliv Transl Res 6(3):225–233. doi: 10.1007/s13346-016-0294-y CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Nguyen J, Cooke JR, Ellis JA, Deci M, Emala CW, Bruce JN, Bigio IJ, Straubinger RM, Joshi S (2016) Cationizable lipid micelles as vehicles for intraarterial glioma treatment. J Neurooncol. doi: 10.1007/s11060-016-2088-y PubMedCentralGoogle Scholar
  51. 51.
    Joshi S, Singh-Moon RP, Ellis JA, Chaudhuri DB, Wang M, Reif R, Bruce JN, Bigio IJ, Straubinger RM (2015) Cerebral hypoperfusion-assisted intra-arterial deposition of liposomes in normal and glioma-bearing rats. Neurosurgery 76(1):92–100. doi: 10.1227/NEU.0000000000000552 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Pile-Spellman J, Young WL, Joshi S, Duong H, Vang MC, Hartmann A, Kahn RA, Rubin DA, Prestigiacomo CJ, Ostapkovich ND (1999) Adenosine-induced cardiac pause for endovascular embolization of cerebral arteriovenous malformations: technical case report. Neurosurgery 44(4):881–886 (discussion 886–887)CrossRefPubMedGoogle Scholar
  53. 53.
    Hashimoto T YW, Davis CC, Joshi S, Ostapkovich ND (1999) Dose-response characteristics of adenosine when used for cardiac pause for deliberate systemic hypotension (Abstract #807). J Neurosurg Anesthesiol 11:327CrossRefGoogle Scholar
  54. 54.
    Hashimoto T, Young WL, Aagaard BD, Joshi S, Ostapkovich ND, Pile-Spellman J (2000) Adenosine-induced ventricular asystole to induce transient profound systemic hypotension in patients undergoing endovascular therapy. Dose-response characteristics. Anesthesiology 93(4):998–1001CrossRefPubMedGoogle Scholar
  55. 55.
    Yang X, Page M (1995) P-glycoprotein expression in ovarian cancer cell line following treatment with cisplatin. Oncol Res 7(12):619–624PubMedGoogle Scholar
  56. 56.
    Wang RH, Bai J, Deng J, Fang CJ, Chen X (2017) TAT-modified gold nanoparticle carrier with enhanced anticancer activity and size effect on overcoming multidrug resistance. ACS Appl Mater Interfaces 9(7):5828–5837. doi: 10.1021/acsami.6b15200 CrossRefPubMedGoogle Scholar
  57. 57.
    Banks WA, Robinson SM, Nath A (2005) Permeability of the blood–brain barrier to HIV-1 Tat. Exp Neurol 193(1):218–227. doi: 10.1016/j.expneurol.2004.11.019 CrossRefPubMedGoogle Scholar
  58. 58.
    Nguyen J, Hossain SS, Cooke JRN, Ellis JA, Deci MB, Emala CW, Bruce JN, Bigio IJ, Straubinger RM, Joshi S (2017) Flow arrest intra-arterial delivery of small TAT-decorated and neutral micelles to gliomas. J Neurooncol 133(1):77–85. doi: 10.1007/s11060-017-2429-5 CrossRefPubMedGoogle Scholar
  59. 59.
    Aziz HA, Boutrid H, Murray TG, Berrocal A, Wolfe SQ, Pina Y, Dorfman M, Moftakhar R, Fernandes CE, Reichbach J, Aziz-Sultan MA (2010) Supraselective injection of intraarterial melphalan as the primary treatment for late presentation unilateral multifocal stage Vb retinoblastoma. Retina 30(4 Suppl):S63-65. doi: 10.1097/IAE.0b013e3181cbda0f Google Scholar
  60. 60.
    Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP (2008) A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology 115(8):1398–1404. doi: 10.1016/j.ophtha.2007.12.014 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Shailendra Joshi
    • 1
    Email author
  • Johann R. N. Cooke
    • 1
  • Jason A. Ellis
    • 2
  • Charles W. Emala
    • 1
  • Jeffrey N. Bruce
    • 2
  1. 1.Department of Anesthesiology, College of Physicians and SurgeonsColumbia University Medical CenterNew YorkUSA
  2. 2.Department of Neurological SurgeryColumbia University Medical CenterNew YorkUSA

Personalised recommendations