Facile synthesis of lactoferrin conjugated ultra small large pore silica nanoparticles for the treatment of glioblastoma,Nanoscale

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Facile synthesis of lactoferrin conjugated ultra small large pore silica nanoparticles for the treatment of glioblastoma
Nanoscale ( IF 5.8 ) Pub Date : 2021-09-06 , DOI: 10.1039/d1nr03553c
Taskeen Iqbal Janjua ₁ , Aria Ahmed-Cox _{2,

3,

4} , Anand Kumar Meka ₁ , Friederike M Mansfeld _{2,

3,

4,

5} , Helen Forgham _{2,

3,

4} , Rosa Mistica C Ignacio _{2,

3,

4} , Yuxue Cao ₁ , Joshua A McCarroll _{2,

3,

4} , Roberta Mazzieri _{6,

7,

8} , Maria Kavallaris _{2,

3,

4} , Amirali Popat _{1,

9}

Affiliation

School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia.
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, 2031, Australia.
School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, 2052, Australia.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW 2052, Australia.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
Diamantina Institute, Translational Research Institute, The University of Queensland Brisbane QLD, 4102, Australia.
Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia.
Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba QLD 4102, Australia.

The blood brain barrier (BBB) and blood tumour barrier (BTB) remain a major roadblock for delivering therapies to treat brain cancer. Amongst brain cancers, glioblastoma (GBM) is notoriously difficult to treat due to the challenge of delivering chemotherapeutic drugs across the BBB and into the tumour microenvironment. Consequently, GBM has high rates of tumour recurrence. Currently, limited numbers of chemotherapies are available that can cross the BBB to treat GBM. Nanomedicine is an attractive solution for treating GBM as it can augment drug penetration across the BBB and into the heterogeneous tumour site. However, very few nanomedicines exist that can easily overcome both the BBB and BTB owing to difficulty in synthesizing nanoparticles that meet the small size and surface functionality restrictions. In this study, we have developed for the first-time, a room temperature protocol to synthesise ultra-small size with large pore silica nanoparticles (USLP, size ∼30 nm, pore size >7 nm) with the ability to load high concentrations of chemotherapeutic drugs and conjugate a targeting moiety to their surface. The nanoparticles were conjugated with lactoferrin (>80 kDa), whose receptors are overexpressed by both the BBB and GBM, to achieve additional active targeting. Lactoferrin conjugated USLP (USLP-Lf) were loaded with doxorubicin – a chemotherapy agent that is known to be highly effective against GBM in vitro but cannot permeate the BBB. USLP-Lf were able to selectively permeate the BBB in vitro, and were effectively taken up by glioblastoma U87 cells. When compared to the uncoated USLP-NPs, the coating with lactoferrin significantly improved penetration of USLP into U87 tumour spheroids (after 12 hours at 100 μm distance, RFU value 19.58 vs. 49.16 respectively). Moreover, this USLP-Lf based delivery platform improved the efficacy of doxorubicin-mediated apoptosis of GBM cells in both 2D and 3D models. Collectively, our new nano-platform has the potential to overcome both the BBB and BTB to treat GBM more effectively.

中文翻译：

用于治疗胶质母细胞瘤的乳铁蛋白偶联超小大孔二氧化硅纳米粒子的简便合成

血脑屏障 (BBB) 和血肿瘤屏障 (BTB) 仍然是提供治疗脑癌的主要障碍。在脑癌中，众所周知，胶质母细胞瘤 (GBM) 难以治疗，因为要通过 BBB 递送化疗药物并进入肿瘤微环境。因此，GBM 具有很高的肿瘤复发率。目前，可以通过 BBB 治疗 GBM 的化学疗法数量有限。纳米医学是治疗 GBM 的一种有吸引力的解决方案，因为它可以增强药物穿过 BBB 并进入异质肿瘤部位。然而，由于难以合成满足小尺寸和表面功能限制的纳米颗粒，很少有纳米药物可以轻松克服 BBB 和 BTB。在这项研究中，我们首次开发了一种室温方案，用于合成超小尺寸的大孔二氧化硅纳米粒子（USLP，尺寸 ∼30 nm，孔径 >7 nm），能够加载高浓度的化疗药物和偶联物其表面的靶向部分。纳米粒子与乳铁蛋白 (>80 kDa) 结合，其受体被 BBB 和 GBM 过表达，以实现额外的主动靶向。乳铁蛋白缀合的 USLP (USLP-Lf) 含有多柔比星——一种已知对 GBM 非常有效的化疗药物 7 nm) 能够加载高浓度的化疗药物并将靶向部分结合到其表面。纳米粒子与乳铁蛋白 (>80 kDa) 结合，其受体被 BBB 和 GBM 过表达，以实现额外的主动靶向。乳铁蛋白缀合的 USLP (USLP-Lf) 含有多柔比星——一种已知对 GBM 非常有效的化疗药物 7 nm) 能够加载高浓度的化疗药物并将靶向部分结合到其表面。纳米粒子与乳铁蛋白 (>80 kDa) 结合，其受体被 BBB 和 GBM 过表达，以实现额外的主动靶向。乳铁蛋白缀合的 USLP (USLP-Lf) 含有多柔比星——一种已知对 GBM 非常有效的化疗药物在体外但不能渗透 BBB。USLP-Lf 能够在体外选择性渗透血脑屏障，并被胶质母细胞瘤 U87 细胞有效吸收。与未涂覆的 USLP-NP 相比，乳铁蛋白涂层显着提高了 USLP 对 U87 肿瘤球体的渗透（在 100 μm 距离处 12 小时后，RFU 值分别为19.58和49.16）。此外，这种基于 USLP-Lf 的递送平台在 2D 和 3D 模型中提高了多柔比星介导的 GBM 细胞凋亡的功效。总的来说，我们的新纳米平台有可能克服 BBB 和 BTB，从而更有效地治疗 GBM。

更新日期：2021-09-17

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