Quality by design enabled development & in-vitro assessment of a Nanoemulgel formulation for Nose-to-Brain delivery of Nintedanib for glioblastoma multiforme treatment

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics Pub Date : 2025-04-21 DOI:10.1016/j.ijpharm.2025.125632

Dnyandev Gadhave , Mural Quadros , Sravani Ravula , Akanksha R Ugale , Mayssam Alkyam , Jeanette C Perron , Vivek Gupta

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Abstract

Glioblastoma multiforme (GBM) is a deadly malignant brain tumor that spreads uncontrollably and invades the surrounding brain parenchyma. GBM treatment remains challenging due to the rigid blood–brain barrier, limiting therapeutic entry into the brain. Therefore, the current study focused on formulating a Nintedanib (Nint) loaded in-situ Nanoemulgel (Nint-Nanoemulgel) and exploring its permeation and therapeutic potential under in-vitro models to address these limitations. Nint-Nanoemulgel was optimized through the QbD-enabled Box-Behnken design. Optimized Nint-Nanoemulgel revealed significant globule size (27.4 ± 0.8 nm), PDI (0.17 ± 0.01), % encapsulation efficiency (93.5 ± 3.5 %), zeta potential (−4.7 ± 0.6 mV), %T (98.2 ± 0.2 %), pH (6.0 ± 0.2), and viscosity (2.59 ± 0.24 cP) at 25 °C. A cumulative in-vitro release study revealed 87.4 ± 1.9 % Nint release through Nanoemulgel after 12 h while 90.1 ± 2.1 % release after 24 h. The cytotoxicity potential of developed Nint-Nanoemulgel was screened in GBM cell lines, demonstrating a > 2-fold reduction in IC₅₀ than plain Nint. However, after treatment with 100 µM of Nint-Nanoemulgel, % growth inhibition was found to be 91.0 ± 1.0 %, 92.1 ± 1.3 %, and 82.7 ± 1.0 % in LN229, U87, and U138 cell lines, respectively. Further, in-vitro cellular uptake exhibited significant coumarin cellular internalization through nanoformulations against coumarin solution. Moreover, clonogenic and scratch assay studies demonstrated the ability of Nint-NE to inhibit cell proliferation and colony formation. However, the outcomes of the live-dead assay demonstrated more cell death in Nint-nanoformulation-treated spheroids than in Nint-treated spheroids. Nint-Nanoemulgel improved intracellular permeation and demonstrated a 2-fold increase in Nint transport across the RPMI-2650 epithelial monolayer. Finally, favorable outcomes of intranasal Nint-Nanoemulgel could provide a novel avenue for the safe and effective delivery of Nint in GBM patients.

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设计的质量使尼达尼布用于多形性胶质母细胞瘤治疗的鼻到脑输送纳米凝胶配方的开发和体外评估成为可能

多形性胶质母细胞瘤（GBM）是一种致命的恶性脑肿瘤，其扩散不受控制并侵犯周围的脑实质。由于僵硬的血脑屏障限制了治疗进入大脑，GBM的治疗仍然具有挑战性。因此，目前的研究重点是制备一种负载尼达尼布（Nint）的原位纳米凝胶（Nint-Nanoemulgel），并在体外模型下探索其渗透和治疗潜力，以解决这些局限性。通过启用qbd的Box-Behnken设计对nint - nano凝胶进行了优化。优化后的nint - nanogel在25°C下的粒径（27.4±0.8 nm）、PDI（0.17±0.01）、包封率（93.5±3.5%）、zeta电位（- 4.7±0.6 mV）、%T（98.2±0.2%）、pH（6.0±0.2）和粘度（2.59±0.24 cP）显著提高。体外累积释放研究显示，纳米乳凝胶在12 h后释放量为87.4±1.9%，24 h后释放量为90.1±2.1%。IC50比普通尼古丁降低2倍。然而，经100µM的Nint-Nanoemulgel处理后，LN229、U87和U138细胞株的生长抑制率分别为91.0±1.0%、92.1±1.3%和82.7±1.0%。此外，通过纳米配方对抗香豆素溶液，体外细胞摄取表现出显著的香豆素细胞内化。此外，克隆和划痕实验研究表明，Nint-NE能够抑制细胞增殖和集落形成。然而，活死实验的结果表明，纳米纳米制剂处理的球体比纳米纳米处理的球体更多的细胞死亡。纳米乳状液改善了细胞内渗透，并证明纳米乳状液通过RPMI-2650上皮单层的转运增加了2倍。最后，鼻内纳米乳凝胶的良好效果为GBM患者安全有效地给药提供了新的途径。

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来源期刊

International Journal of Pharmaceutics 医学-药学

CiteScore

10.70

自引率

8.60%

发文量

951

审稿时长

72 days

期刊介绍： The International Journal of Pharmaceutics is the third most cited journal in the "Pharmacy & Pharmacology" category out of 366 journals, being the true home for pharmaceutical scientists concerned with the physical, chemical and biological properties of devices and delivery systems for drugs, vaccines and biologicals, including their design, manufacture and evaluation. This includes evaluation of the properties of drugs, excipients such as surfactants and polymers and novel materials. The journal has special sections on pharmaceutical nanotechnology and personalized medicines, and publishes research papers, reviews, commentaries and letters to the editor as well as special issues.