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

Aldea, Mihaela; Florian, Ioan Alexandru; Kacsó, Gabriel; Craciun, Lucian; Boca, Sanda; Şoriţău, Olga

doi:10.1007/s11095-016-1947-8

Cited by 23 publications

(20 citation statements)

References 171 publications

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“…As a hypoxia-specific molecular marker, increased expression of phosphatidylserine, a phenomenon normally associated with apoptosis, is observed on the external layer of hypoxic tumor cells and tumor-associated endothelial cell membranes. For example, Saposin C, a lysosomal protein that binds to phosphatidylserine, has been utilized to build NPs that bind to the hypoxic TME 50, 51. The resulting NPs showed impressive therapeutic efficacy in the glioblastoma model, crossing the blood-brain barrier, exhibiting specific retention in the tumor tissue, and sensitizing the hypoxic cells.…”

Section: Utilization Of Tme-specific Molecular Markersmentioning

confidence: 99%

Alliance with EPR Effect: Combined Strategies to Improve the EPR Effect in the Tumor Microenvironment

et al. 2019

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The use of nanomedicine for cancer treatment takes advantage of its preferential accumulation in tumors owing to the enhanced permeability and retention (EPR) effect. The development of cancer nanomedicine has promised highly effective treatment options unprecedented by standard therapeutics. However, the therapeutic efficacy of passively targeted nanomedicine is not always satisfactory because it is largely influenced by the heterogeneity of the intensity of the EPR effect exhibited within a tumor, at different stages of a tumor, and among individual tumors. In addition, limited data on EPR effectiveness in human hinders further clinical translation of nanomedicine. This unsatisfactory therapeutic outcome in mice and humans necessitates novel approaches to improve the EPR effect. This review focuses on current attempts at overcoming the limitations of traditional EPR-dependent nanomedicine by incorporating supplementary strategies, such as additional molecular targeting, physical alteration, or physiological remodeling of the tumor microenvironment. This review will provide valuable insight to researchers who seek to overcome the limitations of relying on the EPR effect alone in cancer nanomedicine and go “beyond the EPR effect”.

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Section: Utilization Of Tme-specific Molecular Markersmentioning

confidence: 99%

Alliance with EPR Effect: Combined Strategies to Improve the EPR Effect in the Tumor Microenvironment

et al. 2019

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“…Possible biodegradable NPs are more desirable for this purpose. Also, another strategy to increase drug concentrations would be the intratumoral administration of MET or within the tumoral cavity after surgical resection (Aldea et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Metformin delivery using chitosan-capped gold nanoparticles in glioblastoma cell lines

Aldea¹,

Florian²,

Potara³

et al. 2018

Romanian Neurosurgery

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Introduction: Metformin (MET), an old anti-diabetic drug, has proven unexpected anti-glioblastoma effects, by impacting cell proliferation, migration and invasion. However, its remarkable anti-cancer efficacy is mainly limited to the use of high millimolar concentrations in in vitro studies, which are hard to be attained in the clinical setting. Aim: The aim of this paper was to synthetize gold nanoparticles loaded with MET and to test if an enhanced drug delivery via nanotechnology could overcome the limitations of small drug concentrations. Materials and Methods: Gold nanoparticles were functionalized with chitosan (GNPc) and loaded with 80 μM of MET. Their size, zeta potential and stability were characterized and their internalization within tumor cells was assayed through dark field microscopy. Three primary glioblastoma stem cell lines were treated with 5, 10 and 20 μg/mL concentrations of nanoparticles and irradiated. The anti-tumoral effect was evaluated through the MTT cell viability assay. Results: MET-GNPc are easily synthetized and have a positive zeta potential, spherical shape and a median size of 26 nm. MET-GNPc have an increased cell internalization and affect the viability of all three glioblastoma cell lines used compared to control and free MET. However, their anti-cancer effect is not statistically different when compared to GNPc, although a slight tendency to a better response may be observed. Conclusion:Despite an increased cell internalization, the small micromolar concentrations of metformin does not bring an additional benefit to chitosan-based GNPs. Novel delivery methods being able to carry a higher drug concentration of metformin should be tested.

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“…In successful cases, nano-formulations of anticancer drugs have shown to extend their blood circulation time leading to improved accumulation of the drug in solid tumors mostly by the enhanced permeability and retention (EPR) effect and/or decrease drug exposure and toxicity to normal tissues [9,45]. However, owing to their nanoscopic size and slow drug release, nano-formulations of the anticancer drugs are also speculated to provide limited access of the drug to hypoxic cancer cells that are located in areas of tumor away from blood vessels [46].…”

Section: Discussionmentioning

confidence: 99%

Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance

et al. 2018

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Hypoxia can induce chemoresistance, which is a significant clinical obstacle in cancer therapy. Here, we assessed development of hypoxia-induced chemoresistance (HICR) against free versus polymeric cisplatin micelles in a triple negative breast cancer cell line, MDA-MB-231. We then explored two strategies for the modulation of HICR against cisplatin micelles: a) the development of actively targeted micelles; and b) combination therapy with modulators of HICR in MDA-MB-231 cells. Actively targeted cisplatin micelles were prepared through surface modification of acetal-poly(ethylene oxide)-poly(α-carboxyl-ε-caprolactone) (acetal-PEO-PCCL) micelles with epidermal growth factor receptor (EGFR)-targeting peptide, GE11 (YHWYGYTPQNVI). Our results showed that hypoxia induced resistance against free and cisplatin micelles in MDA-MB-231 cells. A significant increase in micellar cisplatin uptake was observed in MDA-MB-231 cells that overexpress EGFR, following surface modification of micelles with GE11. This did not lead to increased cytotoxicity of micellar cisplatin, however. On the other hand, the addition of pharmacological inhibitors of key molecules involved in HICR in MDA-MB-231 cells, i.e., inhibitors of hypoxia inducing factor-1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), substantially enhanced the cytotoxicity of free and cisplatin micelles. The results indicated the potential benefit of combination therapy with HIF-1 and STAT3 inhibitors in overcoming HICR to free or micellar cisplatin.

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

Cited by 23 publications

References 171 publications

Alliance with EPR Effect: Combined Strategies to Improve the EPR Effect in the Tumor Microenvironment

Alliance with EPR Effect: Combined Strategies to Improve the EPR Effect in the Tumor Microenvironment

Metformin delivery using chitosan-capped gold nanoparticles in glioblastoma cell lines

Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance

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