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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
EXPERT REVIEW

ABSTRACT

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.

KEY WORDS

glioblastoma hypoxia nanoparticles 

ABBREVIATIONS

Au-NPs

Gold nanoparticles

BBB

Blood–brain barrier

BMDMs

Bone marrow-derived monocytes

CAF

Cancer-associated fibroblast

CAIX

Carbonic anhydrase IX

CAP

Cleavable amphiphilic peptide

CD

Cluster of differentiation

CED

Convection-enhanced delivery

DOPE

1,2-dioleyl-sn-glycero-3-phosphoethanolamine

ECM

Extracellular matrix

EGFR

Endothelial growth factor receptor

EPR

Enhanced permeation and retention

FAP-α

Fibroblast activation protein-α

FUS

Focused ultrasound

GBM

Glioblastoma

GLUT-1

Glucose transporter-1

GSC

Glioblastoma stem cell

HA

Hyaluronan

HIF

Hypoxia-induced factor

HRE

Hypoxia-response elements

HZ

Hypoxic tumor zone

IGF

Insulin growth factor

IGFBP

Insulin-like growth binding proteins

LbL

Layer-by-layer

LRP1

Low density lipoprotein receptor-related protein 1

MDR1

Multidrug resistance 1

MDR1

Multidrug resistance drug 1

MMP

Matrix metalloproteinase

NP

Nanoparticle

NSC

Neural stem cell

ObR

Leptin receptor

Oct4

Octamer-binding transcription factor 4

PAH

Poly(allylamine hydrochloride)

PEG

Poly(ethylene glycol)

PEI

Polyethyleneimine

PET- CT

Positron emission tomography-computed tomography

pHLIP

pH Low Insertion Peptide

PLL

Poly-L-lysine

PS

Phosphatydilserine

RAGE

Receptor for advanced glycation end-products

RES

Reticuloendothelial system

SapC DOPS

Saposin C dioleoylphosphatidylserine

SDF-1

Stromal cell-derived factor 1

siRNA

Small interfering ribonucleic acid

TAM

Tumor associated macrophage

TfR

Transferrin receptor

VEGF

Vascular endothelial growth factor

VHL

Von Hippel Lindau

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

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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