Overcoming the Blood–Brain Barrier: Successes and Challenges in Developing Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours

Figures & data

Table 1 Advantages and Disadvantages of Experimental Drugs Against High-Grade Gliomas

	Advantages	Disadvantages
Cytotoxic agents	Complete oral bioavailability of TMZ^Citation149 Capacity of nitrosoureas and temozolomide to cross the BBB Clinical efficacy of nitrosoureas chemotherapy combined with radiotherapy^Citation150 Clinical efficacy of the combination of etoposide and platinum salts^Citation149 Availability of newer platinum derivatives (eg oxaliplatin) with activity against resistant tumors^Citation10	Important side effects: nausea, myelosuppression, hepatotoxicity, DOX cardiotoxicity, cisplatin nephrotoxicity, etc Generally i.v. administered
VEGFR inhibitors	Orally administered Potential availability of biomarkers indicative of tumour responsiveness to VEGF inhibition^Citation151 Vascular normalization induced may reduce interstitial fluid pressure and allow better drug penetration^Citation16 Reduced tumour hypoxia^Citation16 Well tolerated	Continued tumour growth in monotherapy^Citation152
Anti-VEGF antibodies	Size reduction in xenograft models^Citation153 Good clinical efficacy also in monotherapy^Citation154	Severe toxicities, especially in combination with irinotecan^Citation71 i.v. administration
EGFR inhibitors	Potential identification of EGFR inhibition sensitive phenotypes^Citation155	Limited efficacy both as mono and combination therapy, or radiotherapy^Citation9 Severe toxicities^Citation9
Anti-EGFR antibodies	Orally administered Binding to both wild-type and EGFRvIII receptors^Citation18 Increased survival in combination with radiotherapy in mouse models^Citation157 Responsiveness as monotherapy in EGFR overexpressing patients refractory to standard chemotherapy^Citation158 Well tolerated	No difference in survival between normal and EGFR overexpressing patients^Citation156 i.v. administration
PDGFR inhibitors	Orally administered Promising direct antitumor activity in preclinical models^Citation159 Sensitize glioma cells to radiation^Citation159 Through vascular normalization, it facilitates the tumor penetration of cytotoxic drugs^Citation159 Well tolerated	Poor clinical efficacy as monotherapy^Citation9
Ras/MAPK inhibitors	Orally administered Safety and efficacy of tipifarnib in combination therapy^Citation9	No clinical efficacy of tipifarnib monotherapy^Citation160
PKC inhibitors	Orally administered Well tolerated and promising efficacy in highly pretreated patients^Citation161	High doses are poorly tolerated with cardiovascular side effects^Citation162
PI3K/Akt/mTOR inhibitors	Everolimus and sirolimus orally administered Tumor growth was retarded in some patients^Citation34 Well tolerated	Significant activation of Akt, potentially resulting in a reduced time to progression^Citation34 No clinical efficacy as monotherapy^Citation163
Multi target inhibitors	Multiple target inhibition with a single agent Pazopanib, sorafenib, sunitinib, tandutinib, vandetanib orally administered Sorafenib overcomes BBB^Citation164	No clinical benefit as monotherapy^Citation9
MMP inhibitors	MMP overexpression in gliomas	Negligible clinical efficacy^Citation165 Severe toxicities^Citation165
Integrin inhibitors	Minimal toxicity also at high doses^Citation166	Limited clinical efficacy as monotherapy^Citation166

Abbreviations: Akt, protein kinase B; BBB, blood–brain barrier; DOX, doxorubicin; EGFR, epidermal growth factor receptor; EGFRvIII, mutant EGFR; MMP, matrix metalloproteinase; PDGFR, platelet-derived growth factor receptor; PI3K/Akt/mTOR, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; PKC, protein kinase C; Ras/MAPK, Ras mitogen-activated protein kinase; TMZ, temozolomide; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 1 Main mechanisms of experimental drugs used against high-grade gliomas.

Abbreviations: avß3/avß5, avß3/avß5 heterodimers; EGFR, epidermal growth factor receptor; EGFRvIII, mutant EGFR; MMP, matrix metalloproteinase; PDGFR, platelet-derived growth factor receptor; PI3K/Akt/mTOR, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; PKC, protein kinase C; PTEN, phosphatase and tensin homolog; Ras/MAPK, Ras mitogen-activated protein kinase; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 2 Rationale of employing nanomedicines for glioma treatment.

Abbreviations: BBB, blood–brain barrier; BBTB, blood–brain tumour barrier; CMT, carrier-mediated transport; EPR, enhanced permeation and retention; HIF, hypoxia-induced factors; P-gp, P-glycoprotein; RMT, receptor-mediated transport.

Figure 3 Scheme of brain delivery of nanoparticles with focused ultrasound (FUS) technique.

Abbreviation: SF₆, sulfur hexafluoride.

Table 2 Plain Nanocarriers Aiming to Glioma Therapy Employed in Preclinical Studies

Nanocarriers	Drug	Experimental in vivo Model	Achievements in vivo	References
AgNPs combined with MNPH	Ag^+	Efficacy in glioma rat model	Enhanced Bcl-2-associated X protein expression	[^Citation104]
Cationic SLN	PEGylated c-Met siRNA	Efficacy in U87 xenografts	Enhanced accumulation in brain tumour and down-regulation of c-Met levels	[^Citation93]
Liposomes	Oxaliplatin	Biodistribution and survival analysis in F98/Fischer glioma model	Increased brain oxaliplatin concentration and median survival time of glioma models	[^Citation167]
NLC	TMZ; GFP encoding pDNA	Efficacy in U87 xenografts	Gene transfection and enhanced antitumor activity	[^Citation96]
PLGA nanoparticles, SLN, NLC	TMZ	Efficacy in U87 xenografts	Best efficacy obtained with NLC formulation	[^Citation168]
Polymer nanogel	miRNA miR.34a	Efficacy in U87 xenografts	Significant tumor growth inhibition	[^Citation169]
Polysorbate 80 coated PBCA nanoparticles	DOX	Biodistribution in glioma models	Increased accumulation of DOX in brain tumour	[^Citation170]
Polysorbate 80 coated PBCA nanoparticles	TMZ	Biodistribution in healthy rats	Increased brain uptake of TMZ	[^Citation171]
Polysorbate 80 coated PBCA nanoparticles	Gemcitabine	Survival analysis in C6/Sprague Dawley rat glioma models	Prolonged survival of glioma models	[^Citation172]
Polysorbate 80 coated PLA nanoparticles	TMZ	Pharmacokinetic and biodistribution in rats	Enhancement in half-life of TMZ with higher deposition in the brain	[^Citation173]
Polysorbate 80 coated SLN	CPT	Pharmacokinetic and biodistribution in rats	Increased brain accumulation of CPT	[^Citation108]
Polysorbate 80 coated SPION	DOX	Biodistribution and efficacy in C6/Sprague Dawley glioma model	Enhanced brain accumulation of SPION and increased anti- tumour efficacy under magnetic field	[^Citation174]
SLN	PTX	Rat brain perfusion experiment after intra-carotid administration	Enhanced PTX accumulation in brain; P-gp overcoming	[^Citation100]
SLN	EDF	Biodistribution and efficacy in subcutaneous mouse model	Good drug accumulation in brain after oral administration; P-gp overcoming	[^Citation101]
SLN	DOX	Pharmacokinetic and biodistribution in rats and rabbits	Enhanced DOX accumulation in brain	[^Citation175,Citation176]
SLN	Idarubicin	Pharmacokinetic and biodistribution in rats	Enhanced idarubicin accumulation in brain after SLN oral administration	[^Citation103]
SLN, NLC	TMZ; vincristine	Efficacy in U87 xenografts	Improved glioma inhibition with NLC and drug co-delivery	[^Citation97]

Abbreviations: AgNPs, silver nanoparticles; Bcl-2, B-cell lymphoma 2; c-Met, tyrosine-protein kinase Met; C6, C6 cells; CPT, camptothecin; DOX, doxorubicin; EDF, edelfosine; GFP, green fluorescent protein; miRNA, microRNA; MNPH, magnetic nanoparticle hyperthermia; NLC, nanostructured lipid carriers, PBCA, poly(butyl cyanoacrylate); pDNA, plasmid DNA; PEG, polyethylenglycol; P-gp, P-glycoprotein; PLA, poly-lactide; PLGA, poly-lactide-glycolide; PTX, paclitaxel; siRNA, small interfering RNA; SLN, solid lipid nanoparticles; SPION, superparamagnetic iron oxide nanoparticles; U87, U87 cells; TMZ, temozolomide.

Table 3 Functionalized Nanocarriers Aiming to Glioma Therapy Employed in Preclinical Studies

Nanocarriers	Drug	Functionalization	Experimental in vivo Model	Achievements in vivo	References
Polymeric nanoparticles	TMZ	Angiopep-2	Biodistribution of liposomes and efficacy in C6/ICR mouse glioma models	Enhanced brain distribution of DOX and promising efficacy in glioma models	[^Citation177]
Dendrimers	TRAIL DNA	Angiopep-2	Biodistribution of dendrimers and survival analysis in C6 mouse xenografts	Increased survival of xenografts	[^Citation106]
PCL nanoparticles	DOX	Angiopep-2	Pharmacokinetics, biodistribution and survival analysis in C6/Wistar rat glioma models	Enhanced brain uptake of DOX, prolonged survival of glioma models	[^Citation178]
PLGA nanoparticles	IP10	Angiopep-2; EGFRvIII scFv	Efficacy in U87-EGFRvIII cells xenografts	Reduced tumour growth, prolonged survival of glioma models	[^Citation179]
Liposomes	Daunomycin	Anti Tf Receptor antibody	Pharmacokinetic & biodistribution in rats	Increased daunomycin accumulation in brain	[^Citation180]
Calcium phosphate nanoparticles	ATF5 siRNA	Apo E	Glioma distribution, ATF5 expression and survival analysis in C6 mouse xenografts	Efficient tumour targeting and increased survival of xenografts	[^Citation181]
Polymersomes	Saporin	Apo E	Biodistribution and efficacy in U87 mouse xenografts	Specific brain accumulation of polymersomes, encouraging efficacy towards brain tumours	[^Citation182]
SLN	MTX prodrug	Apo E chimera peptide	Biodistribution and survival analysis in F98/Fischer rat glioma model	Increased brain accumulation of MTX; encouraging efficacy	[^Citation50]
Lipid nanoparticles	Porphyrin	Apo E3	Pharmacokinetics and biodistribution in mice, efficacy in U87 mouse xenografts	Selective drug accumulation in brain tumour compared to healthy parenchyma	[^Citation183]
Liposomes	–	Cetuximab	Biodistribution in U87 mouse xenografts	Increased brain accumulation of liposomes	[^Citation113]
Liposomes	DOX	Chlorotoxin	Biodistribution of liposomes and efficacy in U87 mouse xenografts	Brain accumulation of liposomes, reduced tumour growth	[^Citation117]
Polyionic micelles	Cilengitide	Cilengitide	Survival analysis in C6/Wistar rat glioma models	Prolonged survival of glioma models	[^Citation184]
Polymeric micelles	DACHPt	Cilengitide	Efficacy in U87 mouse xenografts	Reduced tumour growth	[^Citation185]
Liposomes	DOX	Cilengitide and Peptide 22 (LDL receptor)	Biodistribution and survival analysis in intracranial glioma-bearing mice	Prolonged survival time of glioma models	[^Citation114]
PEG−PLA micelles	PTX	EGFR/EGFRvIII targeting peptide	Pharmacokinetics in healthy rats, biodistribution and efficacy in U87 mouse xenografts	Specific micelles distribution to the brain, reduced tumour growth in glioma models	[^Citation186]
PEG-PLA nanoparticles	PTX	F3 peptide (targeting nucleolin) and tLyp-1 peptide (targeting neuropilin)	Pharmacokinetics in rats; biodistribution and survival analysis in C6 mouse xenografts	Enhanced PTX accumulation and deep penetration at the tumour location; prolonged survival in xenografts	[^Citation115]
PEGilated liposomes	DOX	GSH	Pharmacokinetics, biodistribution and efficacy in U87 mouse xenografts	Enhanced brain retention of DOX; strong inhibition of brain tumour growth	[^Citation110]
Liposomes	DOX	IL-13	Efficacy in U251 mouse xenografts	Reduced tumour growth in glioma models	[^Citation187]
BSA nanoparticles	DOX	Lf	Pharmacokinetics in rats, biodistribution in C6/Wistar rat glioma model	Increased brain uptake of DOX	[^Citation188]
Cationic liposomes	DOX	Lf	Biodistribution and survival analysis in C6/Wistar rat glioma models	Increased accumulation of DOX in brain and prolonged survival time of glioma models	[^Citation109]
Liposomes	^99mTc-BMEDA	Lf	Pharmacokinetic & biodistribution in mice	Increased brain accumulation	[^Citation189]
Olive oil nanoparticles	TMZ	Lf	Pharmacokinetic & biodistribution in healthy mice; biodistribution and efficacy in GL261/C57BL/6 mouse models	Enhanced brain distribution of TMZ and promising efficacy towards glioma	[^Citation190]
Olive oil nanoparticles	Aurora Kinase B siRNA	Lf	Gene silencing and survival analysis in GL261/C57BL/6 mouse models	Survival improvement of glioma models treated with nanoparticles and TMZ simultaneously	[^Citation191]
PEG-PCL polymersomes	DOX and tetrandrine	Lf	Pharmacokinetics, biodistribution and efficacy in C6/Wistar rat glioma model	Improved DOX distribution in brain, reduced tumour growth and increased survival in glioma models	[^Citation192]
PEG-PLA nanoparticles	PTX	Lf and tLyp-1 peptide (targeting neuropilin)	Pharmacokinetics in healthy rats, biodistribution and efficacy in C6 mouse xenografts	Enhanced tumour accumulation of PTX and increased survival of glioma models	[^Citation53]
NLC	TMZ and vincristine	Lf, RGD	Biodistribution and efficacy in U87 xenografts	Specific brain distribution of the drugs, promising efficacy in glioma models	[^Citation193]
Liposomes	DOX and vincristine	T7 and ^DA7R	Biodistribution of liposomes and efficacy in C6/ICR mouse glioma models	Enhanced brain distribution of liposomes and promising efficacy in glioma models	[^Citation194]
Liposomes	5-fluorouracil	Tf	Biodistribution of radiolabelled liposomes in healthy rats	Increased brain uptake of liposomes	[^Citation195]
Liposomes	TMZ and bromodomain inhibitor	Tf	Biodistribution in mice and efficacy in U87 mouse xenografts and C57BL/6 mouse models	Improved liposomes distribution to the brain; promising efficacy in glioma models	[^Citation196]
SLN	MTX prodrug	Tf, Insulin	Biodistribution in healthy rats	Increased brain accumulation of MTX	[^Citation51]
Liposomes	DOX	Tf, Octaarginin	Biodistribution of liposomes and efficacy in U87 mouse xenografts	Prolonged survival of glioma models	[^Citation197]
SLN	Docetaxel	HBA	Pharmacokinetics and biodistribution in healthy rats	Enhanced drug brain uptake	[^Citation111]
SLN	Docetaxel ketoconazole	Folic acid	Pharmacokinetics and biodistribution in healthy rats	Enhanced drug brain uptake; P-gp overcoming	[^Citation61]
PEG-co-PCL nanoparticles	PTX	Activatable LMWP coupled to a MMP-2/9-cleavable peptide sequence	Pharmacokinetics in rats; biodistribution and efficacy in C6 mouse xenografts	Specific PTX accumulation in glioma; enhanced efficacy in xenografts	[^Citation116]

Abbreviations: ^99mTc-labeled N,N-bis(2-mercaptoethyl)-N’,N’-diethylethylenediamine (^99mTc-BMEDA); Apo, apolipoprotein; ATF5, activating transcription factor-5; C6, C6 cells; ^DA7R, ^DA^DT^DW^DL^DP^DP^DR sequence, which has a high affinity for VEGFR 2; DACHPt, (1,2-diaminocyclohexane)platinum(II); DOX, doxorubicin; EGFR, epidermal growth factor receptor; EGFRvIII, mutant EGFR; F98, F98 cells; GL261, GL261 cells; GSH, glutathione; HBA, β-hydroxybutyric acid; IP10, Interferon-γ-inducible protein; LDL, low density lipoprotein; Lf, lactoferrin; LMWP, low-molecular-weight protein; MMP, matrix metalloproteinase; MTX, methotrexate; NLC, nanostructured lipid carriers; PCL, poly(ε-caprolactone); PEG, polyethylenglycol; P-gp, P-glycoprotein; PLA, poly-lactide; PLGA, poly-lactide-glycolide; PTX, paclitaxel; RGD, arginine-glycine-aspartic acid; scFv, single-chain Fv fragments; siRNA, small interfering RNA; SLN, solid lipid nanoparticles; T7, HAIYPRH sequence, which can bind to Tf receptors; Tf, transferrin; TMZ, temozolomide; TRAIL, tumor necrosis factor (TNF) related apoptosis-inducing ligand; U251, U251 cells; U87, U87 cells.

Figure 4 Scheme of the main mechanism used for active targeting of nanocarriers in glioma therapy. Blue: endogenous ligands; red: exogenous ligands.

Abbreviations: avß3/avß5, avß3/avß5 heterodimers; CTX, chlorotoxin; EGFR, epidermal growth factor receptor; GSH, glutathione; HFE, homeostatic iron regulator protein; IL 13, interleukin 13; LDL, low-density lipoprotein; Lf, lactoferrin; MCT-1, monocarboxylic acid transporter 1; MMP, matrix metalloproteinase; Tf, transferrin.

Figure 5 Scheme of nanocarrier mesenchymal stem cells (MSC) combined therapy of gliomas.

Figure 6 Scheme of homotypic targeting of glioma cell membrane-coated nanoparticles.

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