Lee Jae-Young, Termsarasab Ubonvan, Lee Mee Yeon, Kim Dong-Hwan, Lee Song Yi, Kim Jung Sun, Cho Hyun-Jong, Kim Dae-Duk
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Acta Biomater. 2017 Jul 15;57:262-273. doi: 10.1016/j.actbio.2017.05.012. Epub 2017 May 5.
A chitosan oligosaccharide (CSO)-indomethacin (IDM) conjugate (CI) was synthesized to fabricate chemosensitizing nanoparticles (NPs) for tumor-targeted drug delivery. IDM was conjugated to a CSO backbone via amide bond formation, of which successful synthesis was confirmed by proton-nuclear magnetic resonance analyses. Doxorubicin (DOX)-loaded CI (CI10/DOX; CI:DOX=10:1 [w/w]) NPs with <75nm of mean diameter, polydispersity index of ∼0.2, and positive zeta potential were prepared. The release of DOX from the NPs was enhanced at acidic pH (pH 5.5 and 6.8) compared to physiological pH (pH 7.4). The release of IDM increased in the presence of A549 cell lysates. In A549 cells (human lung carcinoma cells), more efficient cellular uptake of CI10/DOX NPs than that of free DOX was observed by using confocal laser scanning microscopy and flow cytometry. The in vitro cytotoxicity of CI10/DOX NPs in A549 cells was higher than those of free DOX and CI NPs with free DOX groups. In vivo pharmacokinetic studies after intravenous administration in rats showed significantly lower clearance of DOX from NPs compared with the free DOX group. Tumor targetability of the developed CI NPs was also verified by a real-time optical imaging study. In summary, the chemosensitizing CI/DOX NP with enhanced anticancer activity, prolonged blood circulation, and passive tumor targeting can be a promising anticancer drug delivery system for tumor-targeted therapy.
Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the anti-proliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse model by a real-time optical imaging. Developed CI NPs can be used as a multifunctional nanosystem for the therapy of MRP-expressed cancers.
合成了壳寡糖（CSO）-吲哚美辛（IDM）缀合物（CI），以制备用于肿瘤靶向给药的化学增敏纳米颗粒（NPs）。通过酰胺键形成将IDM缀合到CSO主链上，质子核磁共振分析证实了其成功合成。制备了平均直径<75nm、多分散指数约为0.2且ζ电位为正的负载阿霉素（DOX）的CI（CI10/DOX；CI:DOX = 10:1 [w/w]）纳米颗粒。与生理pH（pH 7.4）相比，纳米颗粒中DOX在酸性pH（pH 5.5和6.8）下的释放增强。在A549细胞裂解物存在下，IDM的释放增加。在A549细胞（人肺癌细胞）中，通过共聚焦激光扫描显微镜和流式细胞术观察到CI10/DOX纳米颗粒比游离DOX更有效地被细胞摄取。CI10/DOX纳米颗粒在A549细胞中的体外细胞毒性高于游离DOX和含游离DOX组的CI纳米颗粒。大鼠静脉给药后的体内药代动力学研究表明，与游离DOX组相比，纳米颗粒中DOX的清除率显著降低。实时光学成像研究也证实了所开发的CI纳米颗粒的肿瘤靶向性。总之，具有增强抗癌活性、延长血液循环和被动肿瘤靶向性的化学增敏CI/DOX纳米颗粒可能是一种有前途的用于肿瘤靶向治疗的抗癌药物递送系统。
开发了基于两亲性壳寡糖-吲哚美辛（CSO-IDM；CI）缀合物的化学增敏纳米颗粒（NPs），用于阿霉素（DOX）的肿瘤靶向递送。将IDM作为疏水残基引入CSO主链，以合成两亲性缀合物和DOX的化学增敏剂，从而提高抗肿瘤疗效。与CSO缀合的IDM可能通过多药耐药相关蛋白（MRP）抑制细胞摄取的DOX的外排，并随后增强DOX在A549细胞（表达MRP的人肺癌细胞）中的抗增殖潜力。在细胞培养模型中评估了所开发的CI纳米颗粒的化学增敏特性，并通过实时光学成像在A549肿瘤异种移植小鼠模型中证明了CI/DOX纳米颗粒的肿瘤靶向性。所开发的CI纳米颗粒可作为一种多功能纳米系统用于治疗表达MRP的癌症。
