Feng Haitao, Kang Jeong-Hun, Qi Song, Kishimura Akihiro, Mori Takeshi, Katayama Yoshiki
Department of Applied Chemistry, Graduate School of Engineering, Kyushu University 744 Motooka, Nishi-ku Fukuoka 819-0395 Japan.
Division of Biopharmaceutics and Pharmacokinetics, National Cerebral and Cardiovascular Center Research Institute 6-1 Shinmachi, Kishibe Suita Osaka 564-8565 Japan.
RSC Adv. 2021 Oct 21;11(54):34101-34106. doi: 10.1039/d1ra06514a. eCollection 2021 Oct 18.
Strategies that combine chemotherapies with unconventional agents such as nitric oxide (NO) have been shown to enhance cancer therapies. Compared with small molecule chemotherapy drugs, nanosized particles have improved therapeutic efficacies and reduced systemic side effects because of the enhanced permeability and retention effect. In this report, we prepared PEGylated liposomes (LP) that incorporated l-arginine (Arg) and the anticancer drug doxorubicin (Dox) to yield a co-delivery system (Dox-Arg-LP). On the basis of our previous research, we hypothesized that Dox-Arg-LP should achieve a synergistic anticancer effect because Arg conversion to NO by activated M1 macrophages augments the chemotherapeutic activity of Dox. Dox-Arg-LP showed comparable physical properties to those of conventional Dox-only liposomes (Dox-LP). assessment revealed that the cytotoxicity of Dox-Arg-LP toward cancer cells was significantly higher than that of Dox-LP. application of Dox-Arg-LP in mice enhanced the chemotherapeutic effect with a 2 mg kg dose of Dox-Arg-LP achieving the same therapeutic efficacy as a two-fold higher dose of Dox-LP (, 4 mg kg). Therefore, co-encapsulation of dual agents into a liposome formulation is an efficient strategy to enhance chemotherapy while reducing systemic toxicity.
将化疗与一氧化氮（NO）等非常规药物相结合的策略已被证明可增强癌症治疗效果。与小分子化疗药物相比，纳米颗粒由于具有增强的渗透和滞留效应，具有更高的治疗效果和更低的全身副作用。在本报告中，我们制备了负载L-精氨酸（Arg）和抗癌药物阿霉素（Dox）的聚乙二醇化脂质体（LP），以产生一种共递送系统（Dox-Arg-LP）。基于我们之前的研究，我们假设Dox-Arg-LP应该能实现协同抗癌效果，因为活化的M1巨噬细胞将Arg转化为NO可增强Dox的化疗活性。Dox-Arg-LP的物理性质与传统的仅含Dox的脂质体（Dox-LP）相当。评估显示，Dox-Arg-LP对癌细胞的细胞毒性显著高于Dox-LP。在小鼠中应用Dox-Arg-LP增强了化疗效果，2 mg/kg剂量的Dox-Arg-LP达到了两倍剂量（4 mg/kg）的Dox-LP相同的治疗效果。因此，将两种药物共包封到脂质体制剂中是一种在增强化疗效果的同时降低全身毒性的有效策略。
