Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents

JOURNAL OF CONTROLLED RELEASE

卷:288

Article

Xu, Jieni^1,2,3  Zhao, Whenchen²  Sun, Jingjing^1,2,3  Huang, Yixian^1,2,3  Wang, Pengcheng^1,2  Venkataramanan, Raman²  Yang, Da^1,2  Ma, Xiaochao^1,2  Rana, Ajay⁴  Li, Song^1,2,3 

[1] Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA

[2] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, 718 Salk Hall, Pittsburgh, PA 15261 USA

[3] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15261 USA

[4] Univ Illinois, Coll Med, Dept Surg Surg Oncol, Chicago, IL 60612 USA

关键词: PPMP;    Ceramide;    Doxorubicin;    Co-delivery;    Prodrug micelles;   

DOI  :  10.1016/j.jconrel.2018.09.011

来源: Elsevier

【 摘 要 】

In order to improve the efficacy of chemotherapy for cancers, we have developed a novel prodrug micellar formulation to co-deliver ceramide-generating anticancer agents and ceramide degradation inhibitor (PPMP). The prodrug nanocarrier is based on a well-defined POEG-b-PPPMP diblock copolymer. The hydrophilic block of POEG-b-PPPMP is POEG, and the hydrophobic block is composed of a number of PPMP units, which could work synergistically with loaded anticancer drugs. POEG-b-PPPMP was readily synthesized via a one-step reversible addition-fragment transfer (RAFT) polymerization from a PPMP monomer. The newly synthesized polymers were self-assembled into micelles and served as a carrier for several hydrophobic anticancer drugs including DOX, PTX and C6-ceramide. POEG-b-PPPMP prodrug polymer exhibited intrinsic antitumor activity in vitro and in vivo. In addition, POEG-b-PPPMP prodrug polymer was comparable to free PPMP in selectively enhancing the production of pro-apoptotic ceramide species as well as down-regulating the mRNA expression of GCS. DOX-loaded POEG-b-PPPMP micelles exhibited an excellent stability of 42 days at 4 degrees C. Moreover, DOX loaded in POEG-b-PPPMP micelles showed higher levels of cytotoxicity than DOX loaded in a pharmacologically inert polymer (POEG-b-POM) and Doxil formulation in several tumor cell lines. Consistently, in a 4T1.2 murine breast cancer model, the tumor inhibition followed the order of DOX/POEG-b-PPPMP > DOX/POEG-b-POM= Doxil > POEG-b-PPPMP > POEG-b-POM. Our data suggest that POEG-b-PPPMP micelles are a promising dual-functional carrier that warrants more studies in the future.

【 授权许可】

Free