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

Pharmaceutical Research volume 33, pages 2059–2077 (2016)Cite this article

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.

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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

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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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    1. Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Victor Babes Str, Cluj-Napoca, Romania, 400012

      Mihaela Aldea & Gabriel Kacso

    2. Department of Neurosurgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

      Ioan Alexandru Florian & Ioan Stefan Florian

    3. Department of Pathology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

      Lucian Craciun

    4. Nanobiophotonics and Laser Microspectroscopy Center, Interdisciplinary Research Institute on Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania

      Sanda Boca

    5. Department of Tumor Biology, Ion Chiricuta Cancer Center, Cluj-Napoca, Romania

      Olga Soritau

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    1. Mihaela Aldea
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    The authors Mihaela Aldea and Ioan Alexandru Florian contributed equally to this work.

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    Aldea, M., Florian, I.A., Kacso, G. et al. Nanoparticles for Targeting Intratumoral Hypoxia: Exploiting a Potential Weakness of Glioblastoma. Pharm Res 33, 2059–2077 (2016). https://doi.org/10.1007/s11095-016-1947-8

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    KEY WORDS

    • glioblastoma
    • hypoxia
    • nanoparticles