Doxorubicin and NFL-TBS.40-63 peptide loaded gold nanoparticles as a multimodal therapy of glioblastoma
Source abstract
Abstract
Conventional treatments for glioblastoma (GBM) are hindered by systemic toxicity, limited blood-brain barrier penetration, and therapeutic resistance. To address these challenges, we developed dual-functionalized gold nanoparticles (AuNPs) conjugated with a biotinylated NFL-TBS.40-63 peptide and the chemotherapeutic agent doxorubicin. This platform integrates targeted delivery and therapeutic action to enhance efficacy while minimising off-target effects. Our findings reveal superior cellular uptake, dose- and time-dependent cytotoxicity, and apoptosis induction in GBM cells compared to mono-functionalized counterparts. Furthermore, pH-sensitive drug release profiles underscore the system's potential to exploit the tumour microenvironment's acidic conditions for precise drug delivery. Comprehensive characterisation confirmed the stability, biocompatibility, and functional efficacy of the dual-functionalized AuNPs. This study highlights the promise of these nanoconjugates as a multimodal approach to GBM therapy, paving the way for further translational research in nanomedicine.
Source: openalex_inverted_index · Quality: baseline
Research context
OpenAlex topics: Nanoplatforms for cancer theranostics · Nanoparticle-Based Drug Delivery · RNA Interference and Gene Delivery
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (72)
Show source-provided references
1. Alifieris C, Trafalis DT. Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther. 2015;152:63–82.10.1016/j.pharmthera.2015.05.005 ↗
2. Stupp R, Hegi M, Mason W, van den Bent M, Taphoorn M, Janzer R, Ludwin S, Allgeier A, Fisher B, Belanger K, Hau P, Brandes A, Gijtenbeek J, Marosi C, Vecht C, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross J, Mirimanoff R, E.O.R. Treatment, C.B.T. Grp, R.O. Grp, N.C.I.C.C. Trials, E.O.R. Treatment, C.B.T. Grp, R.O. Grp, N.C.I.C.C. Trials, Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial, Lancet Oncol. 2009;10(5):459–66.10.1016/S1470-2045(09)70025-7 ↗
3. Cagel M, Grotz E, Bernabeu E, Moretton MA, Chiappetta DA. Doxorubicin: nanotechnological overviews from bench to bedside. Drug Discov Today. 2017;22(2):270–81.10.1016/j.drudis.2016.11.005 ↗
4. Fan D, Cao Y, Cao M, Wang Y, Gong T. Nanomedicine in cancer therapy. Signal Transduct Target Ther. 2023;8(1):293.10.1038/s41392-023-01536-y ↗
5. Shergalis A, Bankhead A, Luesakul U, Muangsin N, Neamati N. Current challenges and opportunities in treating glioblastoma. Pharmacol Rev. 2018;70(3):412–45.10.1124/pr.117.014944 ↗
6. Allen NC, Chauhan R, Bates PJ, O’Toole MG. Optimization of tumor targeting gold nanoparticles for glioblastoma applications. Nanomaterials (Basel). 2022;12(21):3869.10.3390/nano12213869 ↗
7. Norouzi M. Gold nanoparticles in glioma theranostics. Pharmacol Res. 2020;156: 104753.10.1016/j.phrs.2020.104753 ↗
8. Heo DN, Yang DH, Moon HJ, Lee JB, Bae MS, Lee SC, Lee WJ, Sun IC, Kwon IK. Gold nanoparticles surface-functionalized with paclitaxel drug and biotin receptor as theranostic agents for cancer therapy. Biomaterials. 2012;33(3):856–66.10.1016/j.biomaterials.2011.09.064 ↗
9. Yu Y, Wang A, Wang S, Sun Y, Chu L, Zhou L, Yang X, Liu X, Sha C, Sun K, Xu L. Efficacy of temozolomide-conjugated gold nanoparticle photothermal therapy of drug-resistant glioblastoma and its mechanism study. Mol Pharm. 2022;19(4):1219–29.10.1021/acs.molpharmaceut.2c00083 ↗
10. Chinnaiyan SK, Soloman AM, Perumal RK, Gopinath A, Balaraman M. 5 Fluorouracil-loaded biosynthesised gold nanoparticles for the in vitro treatment of human pancreatic cancer cell. IET Nanobiotechnol. 2019;13(8):824–8.10.1049/iet-nbt.2019.0007 ↗
11. Ruan S, Yuan M, Zhang L, Hu G, Chen J, Cun X, Zhang Q, Yang Y, He Q, Gao H. Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles. Biomaterials. 2015;37:425–35.10.1016/j.biomaterials.2014.10.007 ↗
12. Yang Y, Zheng X, Chen L, Gong X, Yang H, Duan X, Zhu Y. Multifunctional gold nanoparticles in cancer diagnosis and treatment. Int J Nanomed. 2022;17:2041–67.10.2147/IJN.S355142 ↗
13. Qureshi S, Anjum S, Hussain M, Sheikh A, Gupta G, Almoyad MAA, Wahab S, Kesharwani P. A recent insight of applications of gold nanoparticles in glioblastoma multiforme therapy. Int J Pharm. 2024;660: 124301.10.1016/j.ijpharm.2024.124301 ↗
14. Raucher D. Tumor targeting peptides: novel therapeutic strategies in glioblastoma. Curr Opin Pharmacol. 2019;47:14–9.10.1016/j.coph.2019.01.006 ↗
15. Lépinoux-Chambaud C, Eyer J. The NFL-TBS.40-63 peptide targets and kills glioblastoma stem cells derived from human patients and also targets nanocapsules into these cells. Int J Pharm. 2019;566:218–28.10.1016/j.ijpharm.2019.05.060 ↗
16. Balzeau J, Pinier M, Berges R, Saulnier P, Benoit JP, Eyer J. The effect of functionalizing lipid nanocapsules with NFL-TBS.40-63 peptide on their uptake by glioblastoma cells. Biomaterials. 2013;34(13):3381–9.10.1016/j.biomaterials.2013.01.068 ↗
17. Bocquet A, Berges R, Frank R, Robert P, Peterson AC, Eyer J. Neurofilaments bind tubulin and modulate its polymerization. J Neurosci. 2009;29(35):11043–54.10.1523/JNEUROSCI.1924-09.2009 ↗
18. Rivalin R, Lepinoux-Chambaud C, Eyer J, Savagner F. The NFL-TBS.40-63 anti-glioblastoma peptide disrupts microtubule and mitochondrial networks in the T98G glioma cell line. PLoS ONE. 2014;9(6):e98473.10.1371/journal.pone.0098473 ↗
19. Alnemeh-Al Ali H, Griveau A, Artzner F, Dupont A, Lautram N, Jourdain MA, Eyer J. Investigation on the self-assembly of the NFL-TBS.40-63 peptide and its interaction with gold nanoparticles as a delivery agent for glioblastoma. Int J Pharm X. 2022;4:100128.
20. Arib C, Griveau A, Eyer J, Spadavecchia J. Cell penetrating peptide (CPP) gold(iii)–complex–bioconjugates: from chemical design to interaction with cancer cells for nanomedicine applications. Nanoscale Adv. 2022;4(14):3010–22.10.1039/D2NA00096B ↗
21. Liu Q, Liu H, Griveau A, Li X, Eyer J, Arib C, Spadavecchia J. NFL-TBS.40-63 peptide gold complex nanovector: a novel therapeutic approach to increase anticancer activity by breakdown of microtubules in pancreatic adenocarcinoma (PDAC). ACS Pharmacol Transl Sci. 2022;5(12):1267–78.10.1021/acsptsci.2c00159 ↗
22. Griveau A, Arib C, Spadavecchia J, Eyer J. Biological activity of gold nanoparticles combined with the NFL-TBS.40-63 peptide, or with other cell penetrating peptides, on rat glioblastoma cells. Int J Pharm X. 2022;4:100129.
23. Liu Q, Liu H, Sacco P, Djaker N, Lamy de la Chapelle M, Marsich E, Li X, Spadavecchia J. CTL-doxorubicin (DOX)-gold complex nanoparticles (DOX-AuGCs): from synthesis to enhancement of therapeutic effect on liver cancer model. Nanoscale Adv. 2020;2(11):5231–41.10.1039/D0NA00758G ↗
24. Markoutsa E, Papadia K, Giannou AD, Spella M, Cagnotto A, Salmona M, Stathopoulos GT, Antimisiaris SG. Mono and dually decorated nanoliposomes for brain targeting, in vitro and in vivo studies. Pharm Res. 2014;31(5):1275–89.10.1007/s11095-013-1249-3 ↗
25. Xin H, Jiang X, Gu J, Sha X, Chen L, Law K, Chen Y, Wang X, Jiang Y, Fang X. Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles as dual-targeting drug delivery system for brain glioma. Biomaterials. 2011;32(18):4293–305.10.1016/j.biomaterials.2011.02.044 ↗
26. Xin H, Sha X, Jiang X, Zhang W, Chen L, Fang X. Anti-glioblastoma efficacy and safety of paclitaxel-loading Angiopep-conjugated dual targeting PEG-PCL nanoparticles. Biomaterials. 2012;33(32):8167–76.10.1016/j.biomaterials.2012.07.046 ↗
27. Jiang X, Xin H, Ren Q, Gu J, Zhu L, Du F, Feng C, Xie Y, Sha X, Fang X. Nanoparticles of 2-deoxy-D-glucose functionalized poly(ethylene glycol)-co-poly(trimethylene carbonate) for dual-targeted drug delivery in glioma treatment. Biomaterials. 2014;35(1):518–29.10.1016/j.biomaterials.2013.09.094 ↗
28. Li Y, Wen G, Wang D, Zhang X, Lu Y, Wang J, Zhong L, Cai H, Wang Y. A complementary strategy for enhancement of nanoparticle intracellular uptake. Pharm Res. 2014;31(8):2054–64.10.1007/s11095-014-1307-5 ↗
29. Liu Y, Ren Z, Zhang X, Zhao Z, Ma G, Pei Y, Zhao W, Wan D, Pan J. Dual-triggered peptide-based polymeric micelles enhance doxorubicin delivery for targeted cancer therapy. Acs Appl Nano Mater. 2024;7(12):14380–91.10.1021/acsanm.4c01874 ↗
30. Lakkadwala S, Dos Santos Rodrigues B, Sun C, Singh J. Dual functionalized liposomes for efficient co-delivery of anti-cancer chemotherapeutics for the treatment of glioblastoma. J Control Release. 2019;307:247–60.10.1016/j.jconrel.2019.06.033 ↗
31. Chen WH, Xu XD, Jia HZ, Lei Q, Luo GF, Cheng SX, Zhuo RX, Zhang XZ. Therapeutic nanomedicine based on dual-intelligent functionalized gold nanoparticles for cancer imaging and therapy in vivo. Biomaterials. 2013;34(34):8798–807.10.1016/j.biomaterials.2013.07.084 ↗
32. Zhan R, Xu X, Cui Y, Ma J, Liu H, Wang Y, Zhang G, Tian G. Dual-functional nano-carrier system based on NIR-laser-triggered dynamic Au-Se interaction for chemo-photothermal synergistic tumor therapy. Colloid Interface Sci Commun. 2024;59:100774.10.1016/j.colcom.2024.100774 ↗
33. Moustaoui H, Movia D, Dupont N, Bouchemal N, Casale S, Djaker N, Savarin P, Prina-Mello A, de la Chapelle ML, Spadavecchia J. Tunable design of gold(III)-doxorubicin complex-PEGylated nanocarrier. The golden doxorubicin for oncological applications. ACS Appl Mater Interfaces. 2016;8(31):19946–57.10.1021/acsami.6b07250 ↗
34. von Maltzahn G, Ren Y, Park JH, Min DH, Kotamraju VR, Jayakumar J, Fogal V, Sailor MJ, Ruoslahti E, Bhatia SN. In vivo tumor cell targeting with “click” nanoparticles. Bioconjug Chem. 2008;19(8):1570–8.10.1021/bc800077y ↗
35. Ross AM, Kennedy T, McNulty D, Leahy CI, Walsh DR, Murray P, Grabrucker AM, Mulvihill JJE. Comparing nanoparticles for drug delivery: the effect of physiological dispersion media on nanoparticle properties. Mater Sci Eng C Mater Biol Appl. 2020;113: 110985.10.1016/j.msec.2020.110985 ↗
36. Hirsch V, Kinnear C, Moniatte M, Rothen-Rutishauser B, Clift MJ, Fink A. Surface charge of polymer coated SPIONs influences the serum protein adsorption, colloidal stability and subsequent cell interaction in vitro. Nanoscale. 2013;5(9):3723–32.10.1039/c2nr33134a ↗
37. Doyen M, Goole J, Bartik K, Bruylants G. Amino acid induced fractal aggregation of gold nanoparticles: why and how. J Colloid Interface Sci. 2016;464:160–6.10.1016/j.jcis.2015.11.017 ↗
38. Salesa B, Ferrús-Manzano P, Tuñón-Molina A, Cano-Vicent A, Assis M, Andrés J, Serrano-Aroca A. Study of biological properties of gold nanoparticles: Low toxicity, no proliferative activity, no ability to induce cell gene expression and no antiviral activity. Chemico-Biol Interact. 2023;382:110646.10.1016/j.cbi.2023.110646 ↗
39. Madeo F, Fröhlich E, Ligr M, Grey M, Sigrist SJ, Wolf DH, Fröhlich KU. Oxygen stress: a regulator of apoptosis in yeast. J Cell Biol. 1999;145(4):757–67.10.1083/jcb.145.4.757 ↗
40. Ludovico P, Sousa MJ, Silva MT, Leão CL, Côrte-Real M. Saccharomyces cerevisiae commits to a programmed cell death process in response to acetic acid. Microbiology (Reading). 2001;147(Pt 9):2409–15.10.1099/00221287-147-9-2409 ↗
41. Ruan H, Yao S, Wang S, Wang R, Xie C, Guo H, Lu W. Stapled RAP12 peptide ligand of LRP1 for micelles-based multifunctional glioma-targeted drug delivery. Chem Eng J. 2021;403:126296.10.1016/j.cej.2020.126296 ↗
42. Huo T, Yang Y, Qian M, Jiang H, Du Y, Zhang X, Xie Y, Huang R. Versatile hollow COF nanospheres via manipulating transferrin corona for precise glioma-targeted drug delivery. Biomaterials. 2020;260: 120305.10.1016/j.biomaterials.2020.120305 ↗
43. Kuo YC, Chang YH, Rajesh R. Targeted delivery of etoposide, carmustine and doxorubicin to human glioblastoma cells using methoxy poly(ethylene glycol)-poly(ε-caprolactone) nanoparticles conjugated with wheat germ agglutinin and folic acid. Mater Sci Eng C Mater Biol Appl. 2019;96:114–28.10.1016/j.msec.2018.10.094 ↗
44. Wu S, Lu L, Zhou J, Ran D, Wang S, Xu Q, Xu W, Wang J, Liu Y, Xie C, Luo Z, Lu W. All-stage targeted therapy for glioblastoma based on lipid membrane coated cabazitaxel nanocrystals. J Control Release. 2022;345:685–95.10.1016/j.jconrel.2022.03.047 ↗
45. Hu XY, Gao L, Mosel S, Ehlers M, Zellermann E, Jiang H, Knauer SK, Wang L, Schmuck C. From supramolecular vesicles to micelles: controllable construction of tumor-targeting nanocarriers based on host-guest interaction between a pillar[5]arene-based prodrug and a RGD-sulfonate guest. Small. 2018;14(52): e1803952.10.1002/smll.201803952 ↗
46. Qi N, Zhang S, Zhou X, Duan W, Gao D, Feng J, Li A. Combined integrin α. J Nanobiotechnol. 2021;19(1):446.10.1186/s12951-021-01180-0 ↗
47. Cui Y, Xu Q, Chow PK, Wang D, Wang CH. Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment. Biomaterials. 2013;34(33):8511–20.10.1016/j.biomaterials.2013.07.075 ↗
48. Ali O, Bekhit A, Khattab S, Helmy M, Abdel-Ghany Y, Teleb M, Elzoghby A. Synthesis of lactoferrin mesoporous silica nanoparticles for pemetrexed/ellagic acid synergistic breast cancer therapy. Colloids Surfaces B-Biointerfaces. 2020;188:110824.10.1016/j.colsurfb.2020.110824 ↗
49. Lesniak MS, Upadhyay U, Goodwin R, Tyler B, Brem H. Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. Anticancer Res. 2005;25(6B):3825–31.
50. Imantay A, Mashurov N, Zhaisanbayeva BA, Mun EA. Doxorubicin-conjugated nanoparticles for potential use as drug delivery systems. Nanomaterials (Basel). 2025;15(2):133.10.3390/nano15020133 ↗
51. Wang JX, Choi SYC, Niu X, Kang N, Xue H, Killam J, Wang Y. Lactic acid and an acidic tumor microenvironment suppress anticancer immunity. Int J Mol Sci. 2020;21(21):8363.10.3390/ijms21218363 ↗
52. Asokan A, Cho MJ. Exploitation of intracellular pH gradients in the cellular delivery of macromolecules. J Pharm Sci. 2002;91(4):903–13.10.1002/jps.10095 ↗
53. Gerweck LE, Vijayappa S, Kozin S. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Ther. 2006;5(5):1275–9.10.1158/1535-7163.MCT-06-0024 ↗
54. Evans TG, Somero GN. A microarray-based transcriptomic time-course of hyper- and hypo-osmotic stress signaling events in the euryhaline fish Gillichthys mirabilis: osmosensors to effectors. J Exp Biol. 2008;211(Pt 22):3636–49.10.1242/jeb.022160 ↗
55. Pagani F, Paolicelli RC, Murana E, Cortese B, Di Angelantonio S, Zurolo E, Guiducci E, Ferreira TA, Garofalo S, Catalano M, D’Alessandro G, Porzia A, Peruzzi G, Mainiero F, Limatola C, Gross CT, Ragozzino D. Defective microglial development in the hippocampus of Cx3cr1 deficient mice. Front Cell Neurosci. 2015;9:111.10.3389/fncel.2015.00111 ↗
56. Pu W, Qiu J, Riggins GJ, Parat MO. Matrix protease production, epithelial-to-mesenchymal transition marker expression and invasion of glioblastoma cells in response to osmotic or hydrostatic pressure. Sci Rep. 2020;10(1):2634.10.1038/s41598-020-59462-w ↗
57. Mellinger A, Lubitz LJ, Gazaille C, Leneweit G, Bastiat G, Lépinoux-Chambaud C, Eyer J. The use of liposomes functionalized with the NFL-TBS.40-63 peptide as a targeting agent to cross the in vitro blood-brain barrier and target glioblastoma cells. Int J Pharm. 2023;646:123421.10.1016/j.ijpharm.2023.123421 ↗
58. Audrey G, Claire LC, Joel E. Effect of the NFL-TBS.40-63 peptide on canine glioblastoma cells. Int J Pharm. 2021;605:120811.10.1016/j.ijpharm.2021.120811 ↗
59. Fathi-karkan S, Sargazi S, Shojaei S, Far B, Mirinejad S, Cordani M, Khosravi A, Zarrabi A, Ghavami S. Biotin-functionalized nanoparticles: an overview of recent trends in cancer detection. Nanoscale. 2024;16(27):12750–92.10.1039/D4NR00634H ↗
60. Freese C, Gibson MI, Klok HA, Unger RE, Kirkpatrick CJ. Size- and coating-dependent uptake of polymer-coated gold nanoparticles in primary human dermal microvascular endothelial cells. Biomacromol. 2012;13(5):1533–43.10.1021/bm300248u ↗
61. Panzarini E, Mariano S, Carata E, Mura F, Rossi M, Dini L. Intracellular transport of silver and gold nanoparticles and biological responses: an update. Int J Mol Sci. 2018;19(5):1305.10.3390/ijms19051305 ↗
62. Lépinoux-Chambaud C, Eyer J. The NFL-TBS.40-63 anti-glioblastoma peptide enters selectively in glioma cells by endocytosis. Int J Pharm. 2013;454(2):738–47.10.1016/j.ijpharm.2013.04.004 ↗
63. Manke A, Wang L, Rojanasakul Y. Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed Res Int. 2013;2013: 942916.10.1155/2013/942916 ↗
64. Xuan L, Ju Z, Skonieczna M, Zhou PK, Huang R. Nanoparticles-induced potential toxicity on human health: applications, toxicity mechanisms, and evaluation models. MedComm. 2023;4(4):e327.10.1002/mco2.327 ↗
65. Jawaid P, Rehman MU, Zhao QL, Misawa M, Ishikawa K, Hori M, Shimizu T, Saitoh JI, Noguchi K, Kondo T. Small size gold nanoparticles enhance apoptosis-induced by cold atmospheric plasma via depletion of intracellular GSH and modification of oxidative stress. Cell Death Discov. 2020;6:83.10.1038/s41420-020-00314-x ↗
66. Brenner C, Kroemer G. Apoptosis. Mitochondria–the death signal integrators. Science. 2000;289(5482):1150–1.10.1126/science.289.5482.1150 ↗
67. Li LS, Ren B, Yang X, Cai ZC, Zhao XJ, Zhao MX. Hyaluronic acid-modified and doxorubicin-loaded gold nanoparticles and evaluation of their bioactivity. Pharmaceuticals (Basel). 2021;14(2):101.10.3390/ph14020101 ↗
68. Long TC, Tajuba J, Sama P, Saleh N, Swartz C, Parker J, Hester S, Lowry GV, Veronesi B. Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro. Environ Health Perspect. 2007;115(11):1631–7.10.1289/ehp.10216 ↗
69. Valdés-Rives SA, Casique-Aguirre D, Germán-Castelán L, Velasco-Velázquez MA, González-Arenas A. Apoptotic signaling pathways in glioblastoma and therapeutic implications. Biomed Res Int. 2017;2017:7403747.10.1155/2017/7403747 ↗
70. Khan M, Cherni K, Dekhili R, Spadavecchia J. Spectroscopic assessment of doxorubicin (DOX)-gemcitabine (GEM) gold complex nanovector as diagnostic tool of galectin-1 biomarker. Nanotechnol Sci Appl. 2024;17:95–105.10.2147/NSA.S448883 ↗
71. Svitkova B, Selc M, Nemethova V, Razga F, Gabelova A, Ursinyova M, Babelova A. Plate reader spectroscopy as an alternative to atomic absorption spectroscopy for the assessment of nanoparticle cellular uptake. Heliyon. 2022;8(11): e11595.10.1016/j.heliyon.2022.e11595 ↗
72. Christie C, Madsen SJ, Peng Q, Hirschberg H. Photothermal therapy employing gold nanoparticle- loaded macrophages as delivery vehicles: comparing the efficiency of nanoshells versus nanorods. J Environ Pathol Toxicol Oncol. 2017;36(3):229–35.10.1615/JEnvironPatholToxicolOncol.2017021545 ↗