State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, PR China; Materials, Physics, and Molecular, Cellular & Developmental Biology Departments, University of California at Santa Barbara, Santa Barbara, CA, 93106, USA.
Materials, Physics, and Molecular, Cellular & Developmental Biology Departments, University of California at Santa Barbara, Santa Barbara, CA, 93106, USA.
Biomaterials. 2019 Nov;221:119412. doi: 10.1016/j.biomaterials.2019.119412. Epub 2019 Aug 6.
Monitoring of nanoparticle-based therapy in vivo and controlled drug release are urgently needed for the precise treatment of disease. We have synthesized a multifunctional Gd-DTPA-ONB (GDO) lipid by introducing the Gd-DTPA contrast agent moiety into an o-nitro-benzyl ester lipid. By design, liposomes formed from the GDO lipid combine MRI tracking ability and dual-trigger release capabilities with maximum sensitivity (because all lipids bear the cleavable moiety) without reducing the drug encapsulation rate. We first confirmed that both photo-treatment and pH-triggered hydrolysis are able to cleave the GDO lipid and lyse GDO liposomes. We then investigated the efficiency of drug release via the combined release processes for GDO liposomes loaded with doxorubicin (DOX). Relative to neutral pH, the release efficiency in acidic environment increased by 10.4% (at pH = 6.5) and 13.3% (at pH = 4.2). This pH-dependent release response is conducive to distinguishing pathological tissue such as tumors and endolysosomal compartments. The photo-induced release efficiency increases with illumination time as well as with distance of the pH from neutral. Photolysis increased the release efficiency by 13.8% at pH = 4.2, which is remarkable considering the already increased amount of drug release in the acidic environment. In addition, the relaxation time of GDO liposomes was 4.1 times that of clinical Gd-DTPA, with brighter T-weighted imaging in vitro and in vivo. Real-time MRI imaging and in vivo fluorescence experiments demonstrated tumor targeting and MRI guided release. Furthermore, significant tumor growth inhibition in a treatment experiment using DOX-loaded GDO liposomes clearly demonstrated the benefit of photo-treatment for efficacy: the tumor size in the photo-treatment group was 3.7 times smaller than in the control group. The present study thus highlights the benefit of the design idea of combining efficient imaging/guiding, targeting, and triggerable release functions in one lipid molecule for drug delivery applications.
体内纳米颗粒治疗监测和控制药物释放对于疾病的精确治疗非常必要。我们通过将 Gd-DTPA 造影剂部分引入邻硝基苄基酯脂质，合成了多功能 Gd-DTPA-ONB (GDO) 脂质。设计中，由 GDO 脂质形成的脂质体结合了 MRI 跟踪能力和双重触发释放能力，具有最大的灵敏度（因为所有脂质都带有可切割的部分），而不会降低药物包封率。我们首先证实光处理和 pH 触发水解都能够切割 GDO 脂质并裂解 GDO 脂质体。然后，我们通过加载阿霉素 (DOX) 的 GDO 脂质体的联合释放过程研究了药物释放的效率。与中性 pH 相比，在酸性环境下的释放效率增加了 10.4%（在 pH=6.5 时）和 13.3%（在 pH=4.2 时）。这种 pH 依赖性释放响应有利于区分肿瘤等病理性组织和内溶酶体隔室。光诱导释放效率随光照时间以及 pH 与中性的距离增加而增加。在 pH=4.2 时，光解增加了 13.8%的释放效率，考虑到在酸性环境中已经增加了药物释放量，这是非常显著的。此外，GDO 脂质体的弛豫时间是临床 Gd-DTPA 的 4.1 倍，体外和体内 T 加权成像更亮。实时 MRI 成像和体内荧光实验证明了肿瘤靶向和 MRI 引导的释放。此外，使用 DOX 负载的 GDO 脂质体进行治疗实验显著抑制了肿瘤生长，清楚地证明了光处理对疗效的益处：光处理组的肿瘤大小比对照组小 3.7 倍。因此，本研究强调了将高效成像/引导、靶向和触发释放功能结合在一个脂质分子中用于药物输送应用的设计理念的益处。
