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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+Show Affiliations

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, PR China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China. Electronic address: chenlijuan125@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31319226

Citation

Shu, Xiaoming, et al. "PEG-derivatized Birinapant as a Nanomicellar Carrier of Paclitaxel Delivery for Cancer Therapy." Colloids and Surfaces. B, Biointerfaces, vol. 182, 2019, p. 110356.
Shu X, Zhu Z, Cao D, et al. PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy. Colloids Surf B Biointerfaces. 2019;182:110356.
Shu, X., Zhu, Z., Cao, D., Zheng, L., Wang, F., Pei, H., ... Chen, L. (2019). PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy. Colloids and Surfaces. B, Biointerfaces, 182, p. 110356. doi:10.1016/j.colsurfb.2019.110356.
Shu X, et al. PEG-derivatized Birinapant as a Nanomicellar Carrier of Paclitaxel Delivery for Cancer Therapy. Colloids Surf B Biointerfaces. 2019 Jul 13;182:110356. PubMed PMID: 31319226.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy. AU - Shu,Xiaoming, AU - Zhu,Zhejiang, AU - Cao,Dan, AU - Zheng,Li, AU - Wang,Fang, AU - Pei,Heying, AU - Wen,Jiaolin, AU - Yang,Jianhong, AU - Li,Dan, AU - Bai,Peng, AU - Tang,Minghai, AU - Ye,Haoyu, AU - Peng,Aihua, AU - Li,Weimin, AU - Chen,Lijuan, Y1 - 2019/07/13/ PY - 2019/04/14/received PY - 2019/07/05/revised PY - 2019/07/08/accepted PY - 2019/7/19/pubmed PY - 2019/7/19/medline PY - 2019/7/19/entrez KW - Birinapant KW - Drug delivery KW - Micelles KW - Paclitaxel KW - pH-sensitive SP - 110356 EP - 110356 JF - Colloids and surfaces. B, Biointerfaces JO - Colloids Surf B Biointerfaces VL - 182 N2 - 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. SN - 1873-4367 UR - https://www.unboundmedicine.com/medline/citation/31319226/PEG-derivatized_birinapant_as_a_nanomicellar_carrier_of_paclitaxel_delivery_for_cancer_therapy L2 - https://linkinghub.elsevier.com/retrieve/pii/S0927-7765(19)30490-4 DB - PRIME DP - Unbound Medicine ER -