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Optimizing the Design of Blood–Brain Barrier-Penetrating Polymer-Lipid-Hybrid Nanoparticles for Delivering Anticancer Drugs to Glioblastoma

Abstract

Purpose

Chemotherapy for glioblastoma multiforme (GBM) remains ineffective due to insufficient penetration of therapeutic agents across the blood–brain barrier (BBB) and into the GBM tumor. Herein, is described, the optimization of the lipid composition and fabrication conditions for a BBB- and tumor penetrating terpolymer-lipid-hybrid nanoparticle (TPLN) for delivering doxorubicin (DOX) to GBM.

Methods

The composition of TPLNs was first screened using different lipids based on nanoparticle properties and in vitro cytotoxicity by using 23 full factorial experimental design. The leading DOX loaded TPLNs (DOX-TPLN) were prepared by further optimization of conditions and used to study cellular uptake mechanisms, in vitro cytotoxicity, three-dimensional (3D) glioma spheroid penetration, and in vivo biodistribution in a murine orthotopic GBM model.

Results

Among various lipids studied, ethyl arachidate (EA) was found to provide excellent nanoparticle properties e.g., size, polydispersity index (PDI), zeta potential, encapsulation efficiency, drug loading, and colloidal stability, and highest anticancer efficacy for DOX-TPLN. Further optimized EA-based TPLNs were prepared with an optimal particle size (103.8 ± 33.4 nm) and PDI (0.208 ± 0.02). The resultant DOX-TPLNs showed ~ sevenfold higher efficacy than free DOX against human GBM U87-MG-RED-FLuc cells in vitro. The interaction between the TPLNs and the low-density lipoprotein receptors also facilitated cellular uptake, deep penetration into 3D glioma spheroids, and accumulation into the in vivo brain tumor regions of DOX-TPLNs.

Conclusion

This work demonstrated that the TPLN system can be optimized by rational selection of lipid type, lipid content, and preparation conditions to obtain DOX-TPLN with enhanced anticancer efficacy and GBM penetration and accumulation.

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Abbreviations

3D:

Three-dimensional

ABCB1:

ATP-binding cassette-1

ANOVA:

Analysis of variance

ApoE:

Apolipoprotein E

BBB:

Blood-brain barrier

BCRP:

Breast cancer resistance protein

CDD:

Central composite design

CI:

Confidence intervals

CNS:

Central nervous system

Cy5:

Cyanine 5

DAPI:

Hoechst 33,342

DL:

Drug loading

DLS:

Dynamic light scattering

DOE:

Design of experiment

DOX:

Doxorubicin

EA:

Ethyl arachidate

EE:

Encapsulation efficiency

EM:

Ethyl myristate

EMEM:

Eagle’s minimum essential medium

FACS:

Fluorescence activated cell sorter

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

FSC-A:

Forward-scattering light

GBM:

Glioblastoma multiforme

GM:

Glycerol monostearate

HER2:

Human epidermal growth receptor 2

HF 750:

HiLyte Fluor ™ 750 hydrazide

HPESO:

Hydrolyzed polymer of epoxidized soybean oil (HPESO)

hRAP:

Human receptor-associated protein

I.V.:

Intravenous

LDL-R:

Low density lipoprotein receptor

MA:

Myristic acid

MFI:

Median fluorescence intensity

MTT:

Thiazolyl blue tetrazolium bromide

M.W.:

Molecular weight

NP:

Nanoparticle

PCC:

Pearson’s correlation coefficients

PDI:

Polydispersity index

PFA:

Paraformaldehyde

PF68:

Pluronic® F-68

P-gp:

P-glycoprotein

PLN:

Polymer-lipid hybrid nanoparticles;

PMAA:

Poly(methacrylic acid)

poly-HEMA:

Poly(2-hydroxyethyl methacrylate

PS 80:

Polysorbate 80

SLN:

Solid lipid nanoparticles

SA:

Stearic acid

SSC-A:

Side-scattered

TEM:

Transmission electron microscopy

TMZ:

Temozolomide

TPLN:

Terpolymer-lipid nanoparticle system

VRP:

Verapamil HCl

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank the Canadian Institutes of Health Research (CIHR) for an Operating Grant to X.Y.W, A.M.R. and J.T.H and the Natural Sciences and Engineering Research Council (NSERC) of Canada for equipment grants to X.Y.W; Connaught International Scholarship for Doctoral students and top up scholarship from the Graduate Department of Pharmaceutical Sciences, University of Toronto to T.A.

The authors declare no competing financial interest.

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Contributions

X.Y.W. conceived the project. T.A., and F–C F.L. designed and conducted the experiments, performed the analysis and interpretations, and wrote the paper. T.A., C.H, P.C. and A.Z.A performed the bio-distribution experiments. A.M.R., J.T.H, and X.Y.W. conceived the hypotheses, designed the experiments, and edited the paper. The manuscript has been revised and read by all authors.

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Correspondence to Xiao Yu Wu.

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Ahmed, T., Liu, FC.F., He, C. et al. Optimizing the Design of Blood–Brain Barrier-Penetrating Polymer-Lipid-Hybrid Nanoparticles for Delivering Anticancer Drugs to Glioblastoma. Pharm Res (2021). https://doi.org/10.1007/s11095-021-03122-9

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Key words

  • 3D tumor spheroids
  • blood–brain barrier
  • design of experiment (DOE)
  • endocytosis
  • glioblastoma multiforme
  • polymer-lipid hybrid nanoparticle