Angiopep-2 modified lipid-coated mesoporous silica nanoparticles for glioma targeting therapy overcoming BBB
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.
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).
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These authors contributed equally to this paper.