PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy.

Abstract

A novel triblock amphiphilic copolymer (PAL-PEG-Birinapant) was designed and synthesized as a dual-functional micellar carrier utilizing birinapant (an inhibitor of inhibitor-of-apoptosis proteins) as a pH-sensitive segment and inhibitor-of-apoptosis proteins-targeting ligand. The mixed micelles comprised of PAL-PEG-Birinapant (PPB) and mPEG2k-PDLLA2k (MPP), named as PPB/MPP (2/1,w/w) micelles were developed for enhanced solubility and antitumor potency of hydrophobic drugs as paclitaxel (PTX). In vitro cell viability and cytotoxicity studies revealed that the PTX-loaded PPB/MPP micelles were more potent than the commercial PTX formulation (Taxol®), as well as the in vitro cell apoptosis study. Clear differences in the intracellular uptake of free coumarin-6 (C6) solution and C6-loaded PPB/MPP micelles were observed and indicated that the PPB/MPP micelles could efficiently deliver chemical compound into tumor cells. PPB copolymer and PTX-loaded PPB/MPP micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of above 1.2 g copolymer/kg and above 100 mg PTX/kg in mice respectively in contrast to 20˜24 mg/kg of Taxol®. The near infrared (NIR) fluorescence imaging showed that PPB/MPP micelles persisted for a relatively long time in the circulation and accumulated preferentially in tumor tissue. Moreover, PTX loaded PPB/MPP micelles significantly inhibited the tumor growth both in MDA-MB-231 and Ramos cancer xenograft mice models without obvious toxicity. Collectively, our study presents a new dual-functional micelles that improve the therapeutic efficacy of PTX in vitro and in vivo.

• Authors: Xiaoming Shu, Zhejiang Zhu, Dan Cao, Li Zheng, Fang Wang, Heying Pei, Jiaolin Wen, Jianhong Yang, Dan Li, Peng Bai, Minghai Tang, Haoyu Ye, Aihua Peng, Weimin Li, Lijuan Chen
• Journal: Colloids and surfaces. B, Biointerfaces (Colloids Surf B Biointerfaces) Vol. 182 Pg. 110356 (Oct 01 2019) ISSN: 1873-4367 [Electronic] Netherlands
• PMID: 31319226 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• Antineoplastic Agents, Phytogenic
• Coumarins
• Dipeptides
• Drug Carriers
• Fluorescent Dyes
• Indoles
• Micelles
• Polyethylene Glycols
• birinapant
• Paclitaxel

Topics

• A549 Cells
• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coumarins (metabolism)
• Dipeptides (chemistry)
• Drug Carriers
• Female
• Fluorescent Dyes (metabolism)
• Humans
• Hydrogen-Ion Concentration
• Indoles (chemistry)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Micelles
• Neoplasms (pathology)
• Paclitaxel (chemistry, pharmacology)
• Polyethylene Glycols (chemistry)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays