PO.CH01.04 · 化学
包封CXCR7激动剂的脂质纳米颗粒鼻内递送改善胶质母细胞瘤中PD-L1阻断的疗效
Intranasal delivery of lipid-based nanoparticle encapsulating CXCR7 agonist improves PD-L1 blockade efficacy in glioblastoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
[背景] 胶质母细胞瘤(GBM)的特点是治疗选择有限且生存结局差。胶质母细胞瘤相关巨噬细胞(GAMs)是塑造免疫抑制性肿瘤微环境(TME)的关键因素。我们既往的研究揭示,VUF11207(VUF,一种CXCR7激动剂)通过抑制肿瘤向GAMs传递信号的CXCL12释放,有效重获了抗PD-L1抗体(alphaPD-L1)在荷GBM小鼠中的疗效。然而,由于血脑屏障(BBB),VUF的疗效可能因脑内递送不佳而受阻。
[方法] 为优化药物递送,我们开发了脂质纳米颗粒(LNP)制剂,采用喷雾式非侵入性鼻-脑递送方式。我们应用了一个体内脑穿透评价平台来评估其绕过BBB的能力。随后通过观察其分子效应以及在动物模型中对alphaPD-L1治疗的应答,评估了LNP包封的VUF(VUF@LNP)的效果。
[结果] 脂质纳米颗粒的粒径、表面电荷和形状结构通过混合脂质来控制。对包封Evans blue(EB)的LNP制剂的研究表明,当以1,2-二油酰基-3-三甲铵-丙烷(DOTAP)与1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)的比例为1:4合成时,带正电荷的LNPs可实现最高的脑穿透效率。接下来,体内生物发光和荧光成像证实,经鼻内递送的DiL标记VUF@LNP能够在脑肿瘤部位蓄积。与VUF的全身和鼻内给药相比,VUF@LNP的鼻内递送显著改善了荷GBM小鼠的生存结局。与游离VUF联合alphaPD-L1治疗的鼻内递送相比,VUF@LNP联合alphaPD-L1治疗的鼻内递送显著延长了生存。未观察到显著的体重变化,支持VUF@LNP的生物安全性。在生物学方面,与全身给药VUF和鼻内给药LNP对照相比,鼻内给药VUF@LNP显著降低了TME中的CXCL12和pERK1/2水平,导致GAMs中PD-L1下调以及CD8⁺ T细胞浸润增加。
[结论] 总之,这些发现表明鼻内VUF@LNP提供了一种绕过BBB的非侵入性策略,用于递送CXCR7激动剂以重编程免疫TME。该方法可能成为一种针对GBM的联合免疫调节的潜在纳米治疗平台。
查看英文原文 English abstract
[Background] Glioblastoma (GBM) is characterized by limited treatment options and poor survival outcomes. Glioblastoma-associated macrophages (GAMs) are crucial factors that tailor the immunosuppressive tumor microenvironment (TME). Our previous study revealed that VUF11207 (VUF), a CXCR7 agonist, effectively recaptured the efficacy of the anti-PD-L1 antibody (alphaPD-L1) in GBM-bearing mice through inhibited CXCL12 release from tumor to transmit signals to GAMs. However, the efficacy of VUF may be hindered by poor brain delivery due to the blood-brain barrier (BBB).
[Methods] To optimize the drug delivery, we developed lipid-based nanoparticle (LNP) formulations with a non-invasive naso-to-brain delivery manner by spray. We applied an in vivo brain-penetration evaluation platform to assess their ability to bypass BBB. The effect of LNP-encapsulated VUF (VUF@LNP) was then assessed by observing its molecular effect and the response to alphaPD-L1 treatment in the animal model.
[Results] The particle size, surface charge, and shape structure of the lipid nanoparticles was controlled by mixing lipids. Studies of LNP formulations encapsulated with Evans blue (EB) have shown that the highest brain penetration efficiency is achieved with LNPs exhibiting a positive charge when synthesized at a 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) to 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) ratio of 1:4. Next, the in vivo bioluminescent and fluorescent imaging confirmed that DiL-labelled VUF@LNP with intranasal delivery was able to accumulate in brain tumor sites. Comparing with systemic and intranasal administration of VUF, intranasal delivery of VUF@LNP significantly improved the survival outcome of GBM-bearing mice. Intranasal delivery of VUF@LNP combined with alphaPD-L1 treatment markedly prolonged survival in comparison with intranasal delivery of free VUF with alphaPD-L1 treatment. No significant body weight changes were observed, supporting the biosafety of VUF@LNP. In terms of biological aspects, intranasal-administrating VUF@LNP significantly reduced CXCL12 and pERK1/2 levels in TME, leading to PD-L1 downregulation in GAMs and increased CD8⁺ T-cell infiltration in comparison with systemic-administrating VUF and intranasal-administrating LNP control.
[Conclusion] Together, these findings indicated that intranasal VUF@LNP provides a BBB-bypassing, non-invasive strategy for delivering CXCR7 agonists to reprogram the immune TME. This approach may be a potential nanotherapeutic platform for combinatorial immunomodulation against GBM.
利益披露 Disclosure
Y. Yeh, None..
K. Chang, None.