Lactoferrin-modified poly(ethylene glycol)-grafted BSA nanoparticles as a dual-targeting carrier for treating brain gliomas.

Lactoferrin-modified poly(ethylene glycol)-grafted BSA nanoparticles as a dual-targeting carrier for treating brain gliomas.

Molecular pharmaceutics (2014-05-02)

Zhigui Su, Lei Xing, Yinan Chen, Yurui Xu, Feifei Yang, Can Zhang, Qineng Ping, Yanyu Xiao

ABSTRACT

In this study, a dual-targeting drug delivery system based on bovine serum albumin nanoparticles (BSA-NPs) modified with both lactoferrin (Lf) and mPEG2000 loading doxorubicin (DOX) was designed, and its blood-brain barrier (BBB) penetration and brain glioma cells targeting properties were explored. BSA-NPs were prepared by a desolvation technique, and mPEG2000 was incorporated onto the surface of BSA-NPs by reacting with the free amino-group of BSA to form mPEG2000-modified BSA-NPs (P2000-NPs). Finally, Lf-modified P2000-NPs (Lf-NPs) was obtained by absorbing Lf onto the surface of P2000-NPs via the positive and negative charges interaction at physiological pH. Three levels of mPEG2000 and Lf-modified NPs were prepared and characterized, respectively. The uptake and potential cytotoxicity of different DOX preparations in vitro by the primary brain capillary endothelial cells (BCECs) and glioma cells (C6) were investigated. The dual-targeting effects were studied on the BBB model in vitro, BCECs/C6 glioma coculture model in vitro, and C6 glioma-bearing rats in vivo, respectively. The results exhibited that, with the increase of the amount of both mPEG2000 and Lf, the particle size of NPs increased and its zeta potential decreased. The in vivo pharmacokinetics study in healthy rats exhibited that P2000-NPs with a high level of mPEG2000 (P2000H-NPs) had longer circulation time in vivo. Compared to other NPs, Lf-NPs with high level of both Lf and mPEG2000 (LfH-NPs) showed the strongest cytotoxicity and the highest effectiveness in the uptake both in BCECs and C6 as well as improved the dual-targeting effects. Body distribution of DOX in different formulations revealed that LfH-NPs could significantly increase the accumulation of DOX in the brain, especially at 2 h postinjection (P < 0.05). In conclusion, Lf-NPs were a prospective dual-targeting drug delivery system for effective targeting therapy of brain gliomas.

MATERIALS

Product Number

Brand

Product Description

38912

Sigma-Aldrich

Dimethyl ether, puriss., ≥99.9% (GC)

38914

Sigma-Aldrich

Dimethyl ether, puriss., ≥99.9% (GC)

451045

Sigma-Aldrich

Iodine, anhydrous, beads, −10 mesh, 99.999% trace metals basis

229695

Sigma-Aldrich

Iodine, 99.999% trace metals basis

326143

Sigma-Aldrich

Iodine, ≥99.99% trace metals basis

743925

Sigma-Aldrich

Dimethyl ether, ≥99.9%

207772

Sigma-Aldrich

Iodine, ACS reagent, ≥99.8%, solid

I3380

Supelco

Iodine, ReagentPlus^®, ≥99.8% (titration)

266426

Sigma-Aldrich

Iodine, ReagentPlus^®, 99.7% trace metals basis, beads, 1-3 mm

376558

Sigma-Aldrich

Iodine, flakes, ReagentPlus^®, ≥99%

P8166

Sigma-Aldrich

Potassium iodide, suitable for plant cell culture

P2963

Sigma-Aldrich

Potassium iodide, BioXtra, ≥99.0%

G6403

Sigma-Aldrich

Glutaraldehyde solution, 50% in H₂O, suitable for photographic applications

G5882

Sigma-Aldrich

Glutaraldehyde solution, Grade I, 25% in H₂O, specially purified for use as an electron microscopy fixative

G7651

Sigma-Aldrich

Glutaraldehyde solution, Grade I, 50% in H₂O, specially purified for use as an electron microscopy fixative or other sophisticated use

G7526

Sigma-Aldrich

Glutaraldehyde solution, Grade I, 8% in H₂O, specially purified for use as an electron microscopy fixative or other sophisticated use

G7776

Sigma-Aldrich

Glutaraldehyde solution, Grade I, 70% in H₂O, specially purified for use as an electron microscopy fixative or other sophisticated use

429422

Sigma-Aldrich

Potassium iodide, AnhydroBeads^™, −10 mesh, 99.998% trace metals basis

60399

Sigma-Aldrich

Potassium iodide, BioUltra, ≥99.5% (AT)

60422

Sigma-Aldrich

Potassium iodide, tested according to Ph. Eur.

49629

Sigma-Aldrich

Glutaraldehyde solution, technical, ~50% in H₂O (5.6 M)

G6257

Sigma-Aldrich

Glutaraldehyde solution, Grade II, 25% in H₂O

340855

Sigma-Aldrich

Glutaraldehyde solution, 50 wt. % in H₂O

204102

Sigma-Aldrich

Potassium iodide, ≥99.99% trace metals basis

W512303

Sigma-Aldrich

Glutaric dialdehyde solution, 50 wt. % in H₂O, FCC

160210

Sigma-Aldrich

4-Nitrophenyl chloroformate, 96%

746428

Sigma-Aldrich

Potassium iodide, anhydrous, free-flowing, Redi-Dri^™, ACS reagent, ≥99%

221945

Sigma-Aldrich

Potassium iodide, ACS reagent, ≥99.0%

793582

Sigma-Aldrich

Potassium iodide, anhydrous, free-flowing, Redi-Dri^™, ReagentPlus^®, 99%

207969

Sigma-Aldrich

Potassium iodide, ReagentPlus^®, 99%