Angiopep-2 modified lipid-coated mesoporous silica nanoparticles for glioma targeting therapy overcoming BBB

https://doi.org/10.1016/j.bbrc.2020.10.076Get rights and content

Highlights

  • LP-MSNs decrease the burst release of loading drugs and enhance biocompatibility and in vivo circulation.

  • With the modification of angiopep-2, LP-MSNs have the ability of crossing the BBB, and further targeting glioma cells.

  • Microdialysis was used to monitor the dynamics of different formulations in blood and intracerebral in vivo.

Abstract

Glioma is the most typical malignant brain tumor, and the chemotherapy to glioma is limited by poor permeability for crossing blood-brain-barrier (BBB) and insufficient availability. In this study, angiopep-2 modified lipid-coated mesoporous silica nanoparticle loading paclitaxel (ANG-LP-MSN-PTX) was developed to transport paclitaxel (PTX) across BBB mediated by low-density lipoprotein receptor-related protein 1 (LRP1), which is over-expressed on both BBB and glioma cells. ANG-LP-MSN-PTX was characterized with homogeneous hydrodynamic size, high drug loading capacity (11.08%) and a sustained release. In vitro experiments demonstrated that the targeting efficiency of PTX was enhanced by ANG-LP-MSN-PTX with higher penetration ability (10.74%) and causing more C6 cell apoptosis. ANG-LP-MSN-PTX (20.6%) revealed higher targeting efficiency compared with LP-MSN-PTX (10.6%) via blood and intracerebral microdialysis method in the pharmacokinetic study. The therapy of intracranial C6 glioma bearing rats was increasingly efficient, and ANG-LP-MSN-PTX could prolong the survival time of model rats. Taken together, ANG-LP-MSN-PTX might hold great promise as a targeting delivery system for glioma treatment.

Graphical abstract

Angiopep-2 modified lipid-coated mesoporous silica nanoparticle loading paclitaxel (ANG-LP-MSN-PTX) was developed to promote PTX transport BBB and cause more glioma cell apoptosis, which could be a promising targeting delivery system for glioma treatment.

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Introduction

As the most frequent and invasive primary intracranial neoplasm in central nervous system (CNS), glioma is the second leading cause of cancer-associated death in adolescents, accounting for 81% of malignant brain tumors [[1], [2], [3]]. Glioma is characterized by high morbidity and mortality and poor prognosis with a limited mean overall survival time of about 15 months [4]. Chemotherapy is a clinically adopted treating method against glioma due to incomplete prevention of glioma invasion into the surrounding normal tissue of traditional surgical resection [2,5]. Nevertheless, the chemotherapeutic efficacy is hampered by its low permeability across the blood-brain-barrier (BBB) and low availability in glioma [[6], [7], [8]].

Paclitaxel (PTX), an Food and Drug Administration (FDA) approved antineoplastic agent, has demonstrated potent anti-tumor activities in glioma cell lines and xenograft models [[9], [10], [11]]. However, PTX has been suffering from poor aqueous solubility, severe side effects, and low therapeutic index [[11], [12], [13], [14]]. Furthermore, the results of PTX on phase II clinical trials against brain tumors were unsatisfactory, primarily as a result of its poor penetration across BBB [15,16]. Therefore, it is imperative to develop a novel drug carrier to enable its permeability across BBB and high accumulation at the tumor site.

Mesoporous silica nanoparticles (MSNs) have been extensively utilized for controlled release of drugs and targeted cancer therapy due to high surface area and pore volume and tunable pore diameters [17,18]. In addition, MSNs also can enhance the dissolution of insolation drug, such as PTX [19]. Nevertheless, the burst release property for loaded drugs, poor stability and biocompatibility in physiological environment, and rapid elimination from the reticuloendothelial system (RES), limited their further applications in drug delivery. Thus, it is crucial to develop a facile and efficient surface modification approaching these drawbacks without adversely affecting the drug loading capacity. Recently, lipid-coated MSNs have been reported, which has combined features of both MSNs and liposomes ideal for the design of a targeted delivery platform for therapeutics with different properties and mechanisms of action [[20], [21], [22]]. Furthermore, lipid coating could enable facile and effective surface functionalization with various ligands to enhance the targeted accumulation of nanocarriers.

The low-density lipoprotein receptor-related protein (LRP) is considered as a potential therapeutic target for glioma, which is highly expressed on both the BBB and the glioma [23,24]. Angiopep-2 (TFFYGGSRGKRNNFKTEEY, 2.4 kDa), a specific ligand to LRP with high brain penetration capability, has been widely used for surface modification of nanoparticles to generate dual-targeting delivery systems to transport chemotherapeutic agents to cross the BBB and subsequently target brain glioma [[25], [26], [27], [28], [29], [30]], exhibiting effective treating efficacy.

Herein, a novel core-shell structured lipid-capped mesoporous silica nanoparticle modified with angiopep-2 was designed as PTX carriers (ANG-LP-MSN-PTX) for glioma treatment. The abilities and properties of targeting nanoparticles in terms of BBB permeability were investigated in vitro. Importantly, their pharmacokinetics and free drug availability in the brain were evaluated simultaneously via blood and intracerebral microdialysis. As a result, ANG-LP-MSN-PTX exhibited the superior permeability across BBB and the favorable therapeutic effects both in vitro and in vivo.

Section snippets

Characterization of MSN, LP-MSN and ANG-LP-MSN

As depicted in Fig. 1, ANG-LP-MSN-PTX was designed and synthesized to deliver PTX across BBB to treat glioma. The PTX was entrapped within the nanopores of MSNs, and the lipid bilayer was coated on the surface, sealing the nanopores, preventing a burst release of PTX as well as improving in vivo circulation time and facilitating their accumulation at tumor site via the enhanced permeability and retention (EPR) effect. Further functionalization of angiopep-2 enabled the dual-targeting drug

Conclusions

In summary, core-shell structured lipid-coated mesoporous silica nanoparticles modified with angiopep-2 (ANG-LP-MSN) were successfully developed in this study. Compared to PTX-Sol, MSN-PTX, and LP-MSN-PTX, the enhanced therapeutic efficacy of ANG-LP-MSN-PTX was realized by increasing the drug transport ratio across the BBB and subsequently targeting the glioma via angiopep-2 modification. Notably, the long-circulation feature and high free drug availability of ANG-LP-MSN-PTX in brain were

Author contributions

Fanzhu Li, Zhihong Zhu and Ji-Gang Piao conceived the idea and supervised the project. Jingjing Zhu and Ying Zhang designed the research and carried out most of the experiments. Xiaojie Chen participated in the experiments. Yue Zhang, Ke Zhang discussed the results and drafted the communication. Hongyue Zheng, Yinghui Wei, Hangsheng Zheng, Jiazhen Zhu and Fang Wu provided some suggestions and offered final approval of the version to be submitted.

Declaration of competing interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81873014, 81873018), Zhejiang Chinese Medical University School-level Scientific Research Fund Project (No.2019ZG39), Natural Science Founfation of Zhejiang Province (No.LQ19H280004, LQ18E030003).

References (38)

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These authors contributed equally to this paper.

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