School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
Department for Nanostructured Materials, Jožef Stefan Institute, Ljubljana, Slovenia.
J Control Release. 2021 Apr 10;332:419-433. doi: 10.1016/j.jconrel.2021.03.002. Epub 2021 Mar 4.
This study investigates the effect of PD1 blockade on the therapeutic efficacy of novel doxorubicin-loaded temperature-sensitive liposomes. Herein, we report photothermally-activated, low temperature-sensitive magnetoliposomes (mLTSL) for efficient drug delivery and magnetic resonance imaging (MRI). The mLTSL were prepared by embedding small nitrodopamine palmitate (NDPM)-coated iron oxide nanoparticles (IO NPs) in the lipid bilayer of low temperature-sensitive liposomes (LTSL), using lipid film hydration and extrusion. Doxorubicin (DOX)-loaded mLTSL were characterized using dynamic light scattering, differential scanning calorimetry, electron microscopy, spectrofluorimetry, and atomic absorption spectroscopy. Photothermal experiments using 808 nm laser irradiation were conducted. In vitro photothermal DOX release studies and cytotoxicity was assessed using flow cytometry and resazurin viability assay, respectively. In vivo DOX release and tumor accumulation of mLTSL(DOX) were assessed using fluorescence and MR imaging, respectively. Finally, the therapeutic efficacy of PD1 blockade in combination with photothermally-activated mLTSL(DOX) in CT26-tumor model was evaluated by monitoring tumor growth, cytokine release and immune cell infiltration in the tumor tissue. Interestingly, efficient photothermal heating was obtained by varying the IO NPs content and the laser power, where on-demand burst DOX release was achievable in vitro and in vivo. Moreover, our mLTSL exhibited promising MR imaging properties with high transverse r relaxivity (333 mM s), resulting in superior MR imaging in vivo. Furthermore, mLTSL(DOX) therapeutic efficacy was potentiated in combination with anti-PD1 mAb, resulting in a significant reduction in CT26 tumor growth via immune cell activation. Our study highlights the potential of combining PD1 blockade with mLTSL(DOX), where the latter could facilitate chemo/photothermal therapy and MRI-guided drug delivery.
本研究考察了 PD1 阻断对新型阿霉素负载温敏脂质体治疗效果的影响。在此，我们报告了光热激活的低温热敏磁脂质体(mLTSL)，用于高效药物输送和磁共振成像(MRI)。mLTSL 通过将小的硝丁多巴胺棕榈酸酯(NDPM)包覆的氧化铁纳米粒子(IO NPs)嵌入低温热敏脂质体(LTSL)的脂质双层中，使用脂质薄膜水合和挤出来制备。使用动态光散射、差示扫描量热法、电子显微镜、荧光光谱法和原子吸收光谱法对载阿霉素(DOX)的 mLTSL 进行了表征。进行了使用 808nm 激光辐照的光热实验。通过流式细胞术和 Resazurin 活力测定分别评估了体外光热 DOX 释放研究和细胞毒性。分别使用荧光和磁共振成像评估了 mLTSL(DOX)在体内的 DOX 释放和肿瘤蓄积。最后，通过监测肿瘤生长、细胞因子释放和肿瘤组织中免疫细胞浸润，评估了 PD1 阻断联合光热激活 mLTSL(DOX)在 CT26 肿瘤模型中的治疗效果。有趣的是，通过改变 IO NPs 的含量和激光功率，可以获得有效的光热加热，从而实现体外和体内按需爆发 DOX 释放。此外，我们的 mLTSL 表现出有前途的磁共振成像特性，具有高横向 r 弛豫率(333mM s)，从而在体内实现了优越的磁共振成像。此外，mLTSL(DOX)的治疗效果与抗 PD1 mAb 联合增强，通过免疫细胞激活导致 CT26 肿瘤生长显著减少。我们的研究强调了将 PD1 阻断与 mLTSL(DOX)联合使用的潜力，后者可以促进化疗/光热治疗和 MRI 引导的药物输送。
