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

Abstract

Highlights:

1. The formation of manganese oxide induces self-assembly of block copolymers to form polymeric vesicles.

2. The polymeric vesicles possessed strong stability and high drug loading capacity.

3. 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 [(polyacrylic 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 PAA₆₈–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 DOX-loaded 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.

Electronic supplementary material: The online version of this article (10.1007/s40820-020-00447-9) contains supplementary material, which is available to authorized users.

Keywords: Aqueous self-assembly; Drug delivery system; Polymer; Tumor microenvironment; Vesicles.

Scheme 1

Schematic illustration of aqueous self-assembly of polymer and its tumor microenvironment-activated release

Fig. 1

a ¹H NMR spectra of HO–PEG₈₆–OH (I), Br–PEG₈₆–Br (II), PtBA₆₈–b–PEG₈₆–b–PtBA₆₈ (III), and PAA₆₈–b–PEG₈₆–b–PAA₆₈ (IV). b GPC spectra of HO–PEG₈₆–OH and PtBA₆₈–b–PEG₈₆–b–PtBA₆₈. c FT-IR spectra of HO–PEG₈₆–OH, Br–PEG₈₆–Br, PtBA₆₈–b–PEG₈₆–b–PtBA₆₈, and PAA₆₈–b–PEG₈₆–b–PAA₆₈

Fig. 2

a TEM, b and f HADDF-STEM, c high-magnification TEM, d and e AFM height images of PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂. g EDS, h XPS, and high-resolution (HR) XPS spectra of i C 1s, j O 1s, and k Mn 2p of PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ are presented

Fig. 3

a D_h distributions, b hydrodynamic particle size and Tyndall effect of dispersed stability of PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ in PBS at different times. TEM images c before and d after dissociation of PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂. e D_h distributions, f hydrodynamic particle size and Tyndall effect of dispersed stability of DOX-loaded PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ in PBS at different times. TEM images g before and h after dissociation of DOX-loaded PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂. Schematic illustrations of i disintegration of PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ and j DOX-loaded PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ at pH 5.0 with 10 mM GSH

Fig. 4

a Cumulative release of DOX from DOX-loaded PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ in simulated body fluids. b Intracellular DOX release from DOX-loaded PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ in MCF-7 cells over a range of different times. c Free DOX used as control group. d CLSM visualization of cellular DOX release from DOX-loaded PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ after incubation for 9 h. e Free DOX used as control group, scale bar: 50 μm. For CLSM and flow cytometric analyses, equivalent DOX dose was 2.5 μg mL⁻¹

Fig. 5

Cancer chemotherapy in vivo using PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ (I), free DOX (II), and DOX-loaded PAA₆₈–b–PEG₈₆–b–PAA₆₈/MnO₂ (III) in MCF-7 tumor-bearing mice. a Digital images of tumors from MCF-7 tumor-bearing mice after 31 days in vivo cancer chemotherapy, scale bar: 1 cm. b Weight of tumor excised from MCF-7 tumor-bearing mice after treatment. c Body weight changes of MCF-7 tumor-bearing mice during therapy. d Tumor size change of MCF-7 tumor-bearing mice during therapy. e Histological analyses of major tissues from MCF-7 tumor-bearing mice after 31 days in vivo cancer chemotherapy, scale bar: 200 μm