Department of Radiology, Chonnam National University Hwasun Hospital, Hwasun, 58128, South Korea.
Biomolecular Theranostics (BiT) Lab, Gwangju, South Korea.
Mol Imaging Biol. 2018 Aug;20(4):533-543. doi: 10.1007/s11307-018-1169-z.
Paclitaxel (PTX) loaded hydrophobically modified glycol chitosan (HGC) micelle is biocompatible in nature, but it requires cancer targeting ability and stimuli release property for better efficiency. To improve tumor retention and drug release characteristic of HGC-PTX nanomicelles, we conjugated cancer targeting heptamethine dye, MHI-148, which acts as an optical imaging agent, targeting moiety and also trigger on-demand drug release on application of NIR 808 nm laser.
The amine group of glycol chitosan modified with hydrophobic 5β-cholanic acid and the carboxyl group of MHI-148 were bonded by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide chemistry. Paclitaxel was loaded to MHI-HGC nanomicelle by an oil-in-water emulsion method, thereby forming MHI-HGC-PTX.
Comparison of near infrared (NIR) dyes, MHI-148, and Flamma-774 conjugated to HGC showed higher accumulation for MHI-HGC in 4T1 tumor and 4T1 tumor spheroid. In vitro studies showed high accumulation of MHI-HGC-PTX in 4T1 and SCC7 cancer cell lines compared to NIH3T3 cell line. In vivo fluorescence imaging of the 4T1 and SCC7 tumor showed peak accumulation of MHI-HGC-PTX at day 1 and elimination from the body at day 6. MHI-HGC-PTX showed good photothermal heating ability (50.3 °C), even at a low concentration of 33 μg/ml in 1 W/cm 808 nm laser at 1 min time point. Tumor reduction studies in BALB/c nude mice with SCC7 tumor showed marked reduction in MHI-HGC-PTX in the PTT group combined with photothermal therapy compared to MHI-HGC-PTX in the group without PTT.
MHI-HGC-PTX is a cancer theranostic agent with cancer targeting and optical imaging capability. Our studies also showed that it has cancer targeting property independent of tumor type and tumor reduction property by combined photothermal and chemotherapeutic effects.
紫杉醇（PTX）负载的疏水性改性壳聚糖（HGC）胶束在本质上是生物相容的，但为了提高效率，它需要具有癌症靶向能力和刺激释放特性。为了提高 HGC-PTX 纳米胶束的肿瘤保留和药物释放特性，我们将癌症靶向七甲川染料 MHI-148 进行了修饰，MHI-148 既可以作为光学成像剂，又可以作为靶向部分，并且在应用 NIR 808nm 激光时可以按需触发药物释放。
通过 1-乙基-3-（3-二甲基氨基丙基）碳二亚胺/N-羟基琥珀酰亚胺化学将疏水性 5β-胆酸修饰的乙二醇壳聚糖的氨基与 MHI-148 的羧基键合。紫杉醇通过油包水乳液法被负载到 MHI-HGC 纳米胶束中，从而形成 MHI-HGC-PTX。
与 Flamma-774 相比，比较近红外（NIR）染料 MHI-148 和与 HGC 偶联的 MHI-148 在 4T1 肿瘤和 4T1 肿瘤球体中显示出更高的 MHI-HGC 积累。体外研究表明，与 NIH3T3 细胞系相比，MHI-HGC-PTX 在 4T1 和 SCC7 癌细胞系中的积累量更高。4T1 和 SCC7 肿瘤的体内荧光成像显示，MHI-HGC-PTX 在第 1 天达到峰值积累，第 6 天从体内消除。MHI-HGC-PTX 具有良好的光热加热能力（50.3°C），即使在 1 分钟时间点以 1W/cm 808nm 激光的 33μg/ml 的低浓度下也是如此。带有 SCC7 肿瘤的 BALB/c 裸鼠肿瘤减少研究表明，与没有 PTT 的 MHI-HGC-PTX 组相比，联合光热疗法的 MHI-HGC-PTX 在 PTT 组中的肿瘤减少更为明显。
MHI-HGC-PTX 是一种具有癌症靶向和光学成像能力的癌症治疗药物。我们的研究还表明，它具有独立于肿瘤类型的癌症靶向特性，并且通过光热和化学治疗的联合作用具有肿瘤减少特性。
