Enhanced safety and efficacy profile of CD40 antibody upon encapsulation in pHe-triggered membrane-adhesive nanoliposomes.

Nanomedicine (London, England) Pub Date : 2025-01-01 Epub Date: 2024-12-29 DOI:10.1080/17435889.2024.2446008

Salma Althobaiti, Prahlad Parajuli, Duy Luong, Samaresh Sau, Lisa A Polin, Seongho Kim, Yubin Ge, Arun K Iyer, Navnath S Gavande

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Abstract

Aim: To develop pH (pHe)-triggered membrane adhesive nanoliposome (pHTANL) of CD40a to enhance anti-tumor activity in pancreatic cancer while reducing systemic toxicity.

Materials and methods: A small library of nanoliposomes (NL) with various lipid compositions were synthesized to prepare pH (pHe)-triggered membrane adhesive nanoliposome (pHTANL). Physical and functional characterization of pHTANL-CD40a was performed via dynamic light scattering (DLS), Transmission Electron Microscopy (TEM), confocal microscopy, and flow cytometry. In vivo studies were performed using PDAC (Panc02) transplanted mice. Tumor tissue was analyzed by flow cytometry, and plasma cytokines and liver enzymes were analyzed by ELISA.

Results: pHTANL-CD40a reduced tumor growth, enhanced tumor immune infiltration/activation, and enhanced survival compared to vehicle and free-CD40a. Importantly, pHTANL-CD40a treatment resulted in significantly lower systemic toxicity as indicated by unchanged body weight, minimal organ deformity, and reduced serum levels of liver enzyme alanine transaminase (ALT) and inflammatory cytokine IL-6.

Conclusion: pHTANL-CD40a is more effective than free CD40a in anti-tumor activity, especially in altering the TME immune landscape for a potential therapeutic benefit in combination with immunotherapy.

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在ph触发的膜粘附纳米脂质体中包封CD40抗体增强了安全性和有效性。

目的：开发 pH（pHe）触发的 CD40a 膜粘附纳米脂质体（pHTANL），以增强胰腺癌的抗肿瘤活性，同时降低全身毒性：合成了一小批具有不同脂质组成的纳米脂质体（NL），以制备pH（pHe）触发的膜粘附纳米脂质体（pHTANL）。通过动态光散射（DLS）、透射电子显微镜（TEM）、共聚焦显微镜和流式细胞术对 pHTANL-CD40a 进行了物理和功能表征。使用 PDAC（Panc02）移植小鼠进行了体内研究。结果：与药物和游离 CD40a 相比，pHTANL-CD40a 能降低肿瘤生长，增强肿瘤免疫浸润/激活，提高存活率。结论：pHTANL-CD40a的抗肿瘤活性比游离CD40a更有效，尤其是在改变TME免疫格局方面，与免疫疗法联合使用可产生潜在的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Nanomedicine (London, England)

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