PO.CH01.04 · 化学
通过LRP1靶向的靶向聚合物纳米偶联物,用于黑色素瘤脑转移中的血脑屏障穿透与PD-L1阻断小肽的时间特异性递送
Targeted polymeric nanoconjugates for BBB penetration and time specific delivery of PDL1 blocking small peptides via LRP1 targeting in melanoma brain metastases
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景:黑色素瘤脑转移(MBM)表现出高度的中枢神经系统(CNS)趋向性,从单药免疫检查点阻断(ICB)中获益有限;与AXL抑制剂联合的方案可能改善应答,但会带来相当大的毒性。脑内肿瘤免疫微环境(TiME)特点是T细胞稀少、TAMs丰富以及胶质细胞PD-L1表达,促进免疫逃逸并导致ICB疗效不佳。基于肽的免疫纳米偶联物(INCs)等血脑屏障(BBB)穿透策略正在开发中,尽管鞘内递送尚未改善生存。LRP-1介导的INCs递送可能实现BBB转运和TAM-TiME重编程。在此,我们报告一种可穿越BBB并将PD-L1阻断肽递送至TiME的靶向纳米平台。
方法:免疫纳米偶联物(INCs)通过将一种生物相容性苹果酸聚合物与(i)P-12(一种PD-L1阻断肽)和(ii)Angiopep-2(AP2,一种LRP-1介导跨细胞转运的配体)偶联而合成。使用体外静态BBB-on-a-chip脑肿瘤模型和已建立的小鼠癌症模型进行体内治疗疗效、安全性、毒性和生物分布研究。通过GDC legacy archive分析转移性黑色素瘤(TCGA-SKCM,n = 471)的临床转录组相关数据,以构建Kaplan-Meier生存曲线。
结果:INCs穿越了BBB,并在BBB-on-a-chip脑肿瘤模型中表现出穿透能力。递送后,INCs被激活的TiME环境选择性内化,从而促进抗肿瘤免疫细胞的激活和增殖。体内疗效、安全性、毒性和生物分布研究显示,相较于ICB药物,INCs在脑内蓄积更佳,并具有显著疗效和更好的安全性特征。临床上,高AXL表达与IV期黑色素瘤对ICB无应答相关,并与免疫抑制性髓系特征一致,表明其与脑转移患者生存降低相关。在皮下黑色素瘤模型中,基于P-12(抗PD-L1)的肽与AXL抑制剂Bemcentinib联合使用,较抗PD-1单药疗法带来更大的肿瘤负荷降低,提示其在MBM情境下规避ICB耐药的潜力。
结论:我们的数据表明,INCs通过LRP-1的BBB跨细胞转运介导了PD-L1阻断肽向TiME的增强递送,支持改善MBM的治疗暴露。AXL成为一个关键治疗靶点,也是与靶向纳米平台联合策略以治疗耐药性MBM的合理靶轴。在更多MBM相关模型中正在进行的研究旨在验证这些发现,并进一步优化第二代双特异性INCs方法。
查看英文原文 English abstract
Background: Melanoma brain metastases (MBM) show high CNS tropism with limited benefit from single-agent ICB; a combination regimen with an AXL inhibitor may improve responses but carry substantial toxicity. The brain TiME features scarce T cells, abundant TAMs, and glial PD-L1, promoting immune evasion and poor ICB efficacy. BBB penetrant strategies via peptide-based Immuno-Nano-Conjugates (INCs) are under development, though intrathecal delivery has not improved survival. LRP-1-mediated INCs delivery may enable BBB transport and TAM-TiME reprogramming. Here, we report a targeted nanoplatform that crosses the BBB and delivers PD-L1-blocking peptides to the TiME.
Methods: Immuno-Nano-Conjugates (INCs) were synthesized by conjugating a biocompatible malic acid polymer conjugated with (i) P-12, a PD-L1 blocking peptide, and (ii) Angiopep-2 (AP2), a ligand for LRP-1 mediated transcytosis. Therapeutic efficacy, safety, toxicity, and biodistribution studies were assessed using an in vitro static BBB-on-a-chip brain tumor model and in vivo in established murine cancer models. Clinical transcriptomic correlation data from metastatic melanoma (TCGA-SKCM, n = 471) were analyzed via the GDC legacy archive to construct Kaplan-Meier survival curves.
Results: The INCs traversed the BBB and demonstrated penetration in a BBB-on-a-chip brain tumor model. Upon delivery, INCs were selectively internalized by the activated TiME environment, thereby promoting antitumor immune cell activation and proliferation. In vivo efficacy, safety, toxicity, and biodistribution revealed superior brain accumulation of INCs relative to ICB agents and significant efficacy and a better safety profile. Clinically, high AXL expression correlated with nonresponse to ICB in Stage IV melanoma and aligned with immunosuppressive myeloid signatures, demonstrating an association with reduced survival in patients with brain metastases. In subcutaneous melanoma models, the combination of P-12 (anti-PD-L1)- based peptides with the AXL inhibitor Bemcentinib yielded greater tumor burden reduction than anti-PD-1 monotherapy, suggesting the potential to circumvent ICB resistance in MBM settings.
Conclusion: Our data indicate that BBB transcytosis of INCs via LRP-1 mediates enhanced delivery of PD-L1 blocking peptides to the TiME, supporting improved therapeutic exposure for MBM. AXL emerges as a critical therapeutic target and a rational axis for combination strategies with targeted nanoplatforms to treat resistant MBM. Ongoing studies across additional MBM-relevant models aim to validate these findings and further optimize second-generation bispecific INCs approaches.
利益披露 Disclosure
S. Sharma, None..
J. Chadokiya, None.