Pharmaceutical Research

, Volume 33, Issue 9, pp 2059–2077 | Cite as

Nanoparticles for Targeting Intratumoral Hypoxia: Exploiting a Potential Weakness of Glioblastoma

  • Mihaela Aldea
  • Ioan Alexandru Florian
  • Gabriel Kacso
  • Lucian Craciun
  • Sanda Boca
  • Olga Soritau
  • Ioan Stefan Florian


Extensive hypoxic regions are the daunting hallmark of glioblastoma, as they host aggressive stem-like cells, hinder drug delivery and shield cancer cells from the effects of radiotherapy. Nanotechnology could address most of these issues, as it employs nanoparticles (NPs) carrying drugs that selectively accumulate and achieve controlled drug release in tumor tissues. Methods overcoming the stiff interstitium and scarce vascularity within hypoxic zones include the incorporation of collagenases to degrade the collagen-rich tumor extracellular matrix, the use of multistage systems that progressively reduce NP size or of NP-loaded cells that display inherent hypoxia-targeting abilities. The unfavorable hypoxia-induced low pH could be converted into a therapeutical advantage by pH-responsive NPs or multilayer NPs, while overexpressed markers of hypoxic cells could be specifically targeted for an enhanced preferential drug delivery. Finally, promising new gene therapeutics could also be incorporated into nanovehicles, which could lead to silencing of hypoxia-specific genes that are overexpressed in cancer cells. In this review, we highlight NPs which have shown promising results in targeting cancer hypoxia and we discuss their applicability in glioblastoma, as well as possible limitations. Novel research directions in this field are also considered.


glioblastoma hypoxia nanoparticles 



Gold nanoparticles


Blood–brain barrier


Bone marrow-derived monocytes


Cancer-associated fibroblast


Carbonic anhydrase IX


Cleavable amphiphilic peptide


Cluster of differentiation


Convection-enhanced delivery




Extracellular matrix


Endothelial growth factor receptor


Enhanced permeation and retention


Fibroblast activation protein-α


Focused ultrasound




Glucose transporter-1


Glioblastoma stem cell




Hypoxia-induced factor


Hypoxia-response elements


Hypoxic tumor zone


Insulin growth factor


Insulin-like growth binding proteins




Low density lipoprotein receptor-related protein 1


Multidrug resistance 1


Multidrug resistance drug 1


Matrix metalloproteinase




Neural stem cell


Leptin receptor


Octamer-binding transcription factor 4


Poly(allylamine hydrochloride)


Poly(ethylene glycol)




Positron emission tomography-computed tomography


pH Low Insertion Peptide






Receptor for advanced glycation end-products


Reticuloendothelial system


Saposin C dioleoylphosphatidylserine


Stromal cell-derived factor 1


Small interfering ribonucleic acid


Tumor associated macrophage


Transferrin receptor


Vascular endothelial growth factor


Von Hippel Lindau



This work was supported by the national fellowship program L’Oréal – Unesco „For Women in Science”, by a research grant of the Iuliu Hatieganu University of Medicine and Pharmacy in accordance to contract 1493/15/28.01.2014 and by two research grants of the Romanian National Authority for Scientific Research and Innovation, CNCS-UEFISCDI, project numbers PNII-RU-TE-2014-4-0225 (ENERGY) and PN-II-RU-TE-2014-4-2426 (NanoMED LeuKemist).


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Mihaela Aldea
    • 1
  • Ioan Alexandru Florian
    • 2
  • Gabriel Kacso
    • 1
  • Lucian Craciun
    • 3
  • Sanda Boca
    • 4
  • Olga Soritau
    • 5
  • Ioan Stefan Florian
    • 2
  1. 1.Department of OncologyIuliu Hatieganu University of Medicine and PharmacyCluj-NapocaRomania
  2. 2.Department of NeurosurgeryIuliu Hatieganu University of Medicine and PharmacyCluj-NapocaRomania
  3. 3.Department of PathologyIuliu Hatieganu University of Medicine and PharmacyCluj-NapocaRomania
  4. 4.Nanobiophotonics and Laser Microspectroscopy Center, Interdisciplinary Research Institute on Bio-Nano-SciencesBabes-Bolyai UniversityCluj-NapocaRomania
  5. 5.Department of Tumor BiologyIon Chiricuta Cancer CenterCluj-NapocaRomania

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