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Self-assembled polymeric micelle as a novel mRNA delivery carrier.

ABSTRACT: mRNA-based therapy has been evaluated in preclinical and clinical studies for the treatment of a wide variety of disease such as cancer immunotherapies and infectious disease vaccines. However, it remains challenging to development safe and efficient delivery system. Here, we have designed a novel self-assembled polymeric micelle based on vitamin E succinate modified polyethyleneimine copolymer (PVES) to delivery mRNA. In vitro, PVES could transfect mRNA into multiple cell lines such as HEK-293T, HeLa and Vero and the transfection efficiencies were much higher than PEI 25 k. In addition, the cytotoxicity of PVES was much lower than PEI 25 k. Furthermore, mice administered intramuscularly with PVES/SARS-CoV-2 mRNA vaccine induced potent antibody response and show no obvious toxicity. These results demonstrated the potential of PVES as a safe and effective delivery carrier for mRNA.

SUBMITTER: Ren J

PROVIDER: S-EPMC8411660 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Self-assembled polymeric micelle as a novel mRNA delivery carrier.

Ren Jin J Cao Yiming Y Li Lei L Wang Xin X Lu Haitao H Yang Jing J Wang Shengqi S

Journal of controlled release : official journal of the Controlled Release Society 20210902

mRNA-based therapy has been evaluated in preclinical and clinical studies for the treatment of a wide variety of disease such as cancer immunotherapies and infectious disease vaccines. However, it remains challenging to development safe and efficient delivery system. Here, we have designed a novel self-assembled polymeric micelle based on vitamin E succinate modified polyethyleneimine copolymer (PVES) to delivery mRNA. In vitro, PVES could transfect mRNA into multiple cell lines such as HEK-293T ...[more]

PMID: 34481924

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Project description:PurposePolymeric micelles are attractive nanocarriers for tumor-targeted delivery of paclitaxel (PTX). High antitumor efficacy and low toxicity require that PTX mainly accumulated in tumors with little drug exposure to normal tissues. However, many PTX-loaded micelle formulations suffer from low stability, fast drug release, and lack of tumor-targeting capability in the circulation. To overcome these challenges, we developed a micellar formulation that consists of sodium cholate (NaC) and monomethoxy poly (ethylene glycol)-block-poly (d,l-lactide) (mPEG-PDLLA).MethodsPTX-loaded NaC-mPEG-PDLLA micelles (PTX-CMs) and PTX-loaded mPEG-PDLLA micelles (PTX-Ms) were formulated, and their characteristics, particle size, surface morphology, release behavior in vitro, pharmacokinetics and in vivo biodistributions were researched. In vitro and in vivo tumor inhibition effects were systematically investigated. Furthermore, the hemolysis and acute toxicity of PTX-CMs were also evaluated.ResultsThe size of PTX-CMs was 53.61±0.75 nm and the ζ-potential was -19.73±0.68 mV. PTX was released much slower from PTX-CMs than PTX-Ms in vitro. Compared with PTX-Ms, the cellular uptake of PTX-CMs was significantly reduced in macrophages and significantly increased in human cancer cells, and therefore, PTX-CMs showed strong growth inhibitory effects on human cancer cells. In vivo, the plasma AUC0-t of PTX-CMs was 1.8-fold higher than that of PTX-Ms, and 5.2-fold higher than that of Taxol. The biodistribution study indicated that more PTX-CMs were accumulated in tumor than PTX-Ms and Taxol. Furthermore, the significant antitumor efficacy of PTX-CMs was observed in mice bearing BEL-7402 hepatocellular carcinoma and A549 lung carcinoma. Results from drug safety assessment studies including acute toxicity and hemolysis test revealed that the PTX-CMs were safe for in vivo applications.ConclusionThese results strongly revealed that NaC-mPEG-PDLLA micelles can tumor-target delivery of PTX and enhance drug penetration in tumor, suggesting that NaC-mPEG-PDLLA micelles are promising nanocarrier systems for anticancer drugs delivery.

Project description:Chemical structures bearing a combination of aggregation-induced emission enhancement (AIEE) and intramolecular charge transfer (ICT) properties attracted the attention of many researchers. Recently, there is an increasing demand to pose tunable AIEE and ICT fluorophores that could present their conformation changes-related emission colors by adjusting the medium polarity. In this study, we designed and synthesized a series of 4-alkoxyphenyl-substituted 1,8-naphthalic anhydride derivatives NAxC using the Suzuki coupling reaction to construct donor-acceptor (D-A)-type fluorophores with alkoxyl substituents of varying carbon chain lengths (x = 1, 2, 4, 6, 12 in NAxC). To explain the observation that molecules with longer carbon chains revealed unusual fluorescence enhancement in water, we study the optical properties and evaluate their locally excited (LE) and ICT states by solvent effects combined with Lippert-Mataga plots. Then, we explored the self-assembly abilities of these molecules in water-organic (W/O) mixed solutions and observed the morphology of its nanostructure using a fluorescence microscope and SEM. The results show that NAxC, x = 4, 6, 12 show different degrees of self-assembly behaviors and corresponding aggregation-induced emission enhancement (AIEE) progresses. At the same time, different nanostructures and corresponding spectral changes can be obtained by adjusting the water ratio in the mixed solution. That is, NAxC compounds present different transitions between LE, ICT and AIEE based on the polarity, water ratio and time changes. We designed NAxC as the structure-activity relationship (SAR) of the surfactant to demonstrate that AIEE comes from the formation of micelle-like nanoaggregates, which causes a restriction of the transfer from the LE state to the ICT state, and micelle formation results in a blue-shift in emission and enhances the intensity in the aggregate state. Among them, NA12C is most likely to form micelles and the most obvious fluorescence enhancement, which will switch over time due to the nano-aggregation transition.

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Self-assembled polymeric micelle as a novel mRNA delivery carrier.

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Self-assembled polymeric micelle as a novel mRNA delivery carrier.

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