Aqueous Self-Assembly of Block Copolymers to Form Manganese Oxide-Based Polymeric Vesicles for Tumor Microenvironment-Ac

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Cite as Nano-Micro Lett. (2020) 12:124 Received: 26 February 2020 Accepted: 21 April 2020 © The Author(s) 2020

https://doi.org/10.1007/s40820-020-00447-9

Aqueous Self‑Assembly of Block Copolymers to Form Manganese Oxide‑Based Polymeric Vesicles for Tumor Microenvironment‑Activated Drug Delivery Yalei Miao1, Yudian Qiu1, Mengna Zhang1, Ke Yan1, Panke Zhang1, Siyu Lu1, Zhongyi Liu1 *, Xiaojing Shi1 *, Xubo Zhao1 * * Zhongyi Liu, [email protected]; Xiaojing Shi, [email protected]; Xubo Zhao, [email protected] 1 Green Catalysis Center, College of Chemistry, and Laboratory Animal Center, Zhengzhou University, Zhengzhou 450001, People’s Republic of China

HIGHLIGHTS 

• The formation of manganese oxide induces self-assembly of block copolymers to form polymeric vesicles. • The polymeric vesicles possessed strong stability and high drug loading capacity. • The drug-loaded polymeric vesicles have been demonstrated, especially in in vivo studies, to exhibit a higher efficacy of tumor suppression without known cardiotoxicity. ABSTRACT  Molecular self-assembly is crucially fundamental to

nature. However, the aqueous self-assembly of polymers is still a challenge. To achieve self-assembly of block copolymers [(poly-

acrylic acid–block–polyethylene glycol–block–polyacrylic acid ­(PAA68–b–PEG86–b–PAA68)] in an aqueous phase, manganese

oxide ­(MnO2) is first generated to drive phase separation of the

PAA block to form the P ­ AA68–b–PEG86–b–PAA68/MnO2 polymeric assembly that exhibits a stable structure in a physiological

medium. The polymeric assembly exhibits vesicular morphology with a diameter of approximately 30 nm and high doxorubicin (DOX) loading capacity of approximately 94%. The transformation from ­MnO2 to ­Mn2+ caused by endogenous glutathione (GSH)

facilitates the disassembly of ­PAA68–b–PEG86–b–PAA68/MnO2 to

enable its drug delivery at the tumor sites. The toxicity of DOXloaded ­PAA68–b–PEG86–b–PAA68/MnO2 to tumor cells has been

verified in vitro and in vivo. Notably, drug-loaded polymeric vesicles have been demonstrated, especially in in vivo studies, to overcome the cardiotoxicity of DOX. We expect this work to encourage the potential application of polymer self-assembly. KEYWORDS  Polymer; Aqueous self-assembly; Vesicles; Tumor microenvironment; Drug delivery system

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1 Introduction In nature, self-assembly is one of the most crucial approaches that enables the building of micro- and nanostructures [1]. In biology, from structures of plant to those of multicellular organisms, it plays an important role in generating sophisticated superstructures through different interactions between a large number of building blocks [2–4]. Inspired by nature, polymer self-assembly has attracted extensive attention since the 1960s and serves as a “bottom-up” strategy for building complexes naturally [5, 6]. The self-assembly of block copolymers in solution developed by Armes, Kataoka, Discher, and Eisenberg has been utilized to design a series of polymeric ar