Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 May 3:11:1190596.
doi: 10.3389/fchem.2023.1190596. eCollection 2023.

pH-sensitive charge-conversion cinnamaldehyde polymeric prodrug micelles for effective targeted chemotherapy of osteosarcoma in vitro

Jiapeng Deng  1   2 , Su Liu  1   2 , Guoqing Li  1   2 , Yien Zheng  1   2 , Weifei Zhang  1   2 , Jianjing Lin  3 , Fei Yu  1   2 , Jian Weng  1   2 , Peng Liu  1   2 , Hui Zeng  1   2
Affiliations

pH-sensitive charge-conversion cinnamaldehyde polymeric prodrug micelles for effective targeted chemotherapy of osteosarcoma in vitro

Jiapeng Deng et al. Front Chem. .

Abstract

Introduction: Chemotherapy is a common strategy for the treatment of osteosarcoma. However, its therapeutic efficacy is not ideal due to the low targeting, lowbioavailability, and high toxicity of chemotherapy drugs. Nanoparticles can improve the residence time of drugs at tumor sites through targeted delivery. This new technology can reduce the risk to patients and improve survival rates. To achieve this goal, we developed a pHsensitive charge-conversion polymeric micelle [mPEG-b-P(C7-co-CA) micelles] for osteosarcoma-targeted delivery of cinnamaldehyde (CA). Methods: First, an amphiphilic cinnamaldehyde polymeric prodrug [mPEG-b-P(C7-co-CA)] was synthesized through Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization and post-modification, and self-assembled into mPEG-b-P(C7-co-CA) micelles in an aqueous solution. The physical properties of mPEG-b-P(C7-co-CA) micelles, such as critical micelle concentration (CMC), size, appearance, and Zeta potential were characterized. The CA release curve of mPEG-b-P(C7-co-CA) micelles at pH 7.4, 6.5 and 4.0 was studied by dialysis method, then the targeting ability of mPEG-b-P(C7-co-CA) micelles to osteosarcoma 143B cells in acidic environment (pH 6.5) was explored by cellular uptakeassay. The antitumor effect of mPEG-b-P(C7-co-CA) micelles on 143B cells in vitro was studied by MTT method, and the level of reactive oxygen species (ROS) in 143B cells after mPEG-b-P(C7-co-CA) micelles treatment was detected. Finally, the effects of mPEG-b-P(C7-co-CA) micelles on the apoptosis of 143B cells were detected by flow cytometry and TUNEL assay. Results: An amphiphilic cinnamaldehyde polymeric prodrug [mPEG-b-P(C7-co-CA)] was successfully synthesized and self-assembled into spheric micelles with a diameter of 227 nm. The CMC value of mPEG-b-P(C7-co-CA) micelles was 25.2 mg/L, and it showed a pH dependent release behavior of CA. mPEG-b-P(C7-co-CA) micelles can achieve chargeconversion from a neutral to a positive charge with decreasing pHs. This charge-conversion property allows mPEG-b-P(C7-co-CA) micelles to achieve 143B cell targeting at pH 6.5. In addition, mPEG-b-P(C7-co-CA) micelles present high antitumor efficacy and intracellular ROS generation at pH 6.5 which can induce 143B cell apoptosis. Discussion: mPEG-b-P(C7-co-CA) micelles can achieve osteosarcoma targeting effectively and enhance the anti-osteosarcoma effect of cinnamaldehyde in vitro. This research provides a promising drug delivery system for clinical application and tumor treatment.

Keywords: charge-conversion; cinnamaldehyde prodrug; micelles; osteosarcoma targeting; pH-sensitive.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

SCHEME 1
SCHEME 1
Schematic illustration of mPEG-b-P(C7-co-CA) micelles for effective chemotherapy of osteosarcoma through targeted delivery of cinnamaldehyde.
FIGURE 1
FIGURE 1
Synthetic procedure of mPEG-b-P(C7-co-CA).
FIGURE 2
FIGURE 2
1H NMR spectrum of mPEG-b-P(C7-co-CA) in CDCl3.
FIGURE 3
FIGURE 3
Size distribution of mPEG-b-P(C7-co-CA) micelles measured using DLS (A) and TEM (B) (scale bar 200 nm).
FIGURE 4
FIGURE 4
Zeta potential (A) and size (B) of mPEG-b-P(C7-co-CA) micelles at different pH levels.
FIGURE 5
FIGURE 5
CA release profile from mPEG-b-P(C7-co-CA) micelles at different pHs.
FIGURE 6
FIGURE 6
Fluorescence images of 143B cells treated with coumarin 6-loaded mPEG-b-P(C7-co-CA) micelles at pH 7.4 and 6.5 for 3 h (scale bar 100 µm).
FIGURE 7
FIGURE 7
Cell viability of 143B cells treated with mPEG-b-P(C7-co-CA) micelles (A) and cinnamaldehyde (B) for 24 h at pH 7.4 and 6.5 (***p < 0.001, *p < 0.05, vs. the pH 7.4 group, n = 3).
FIGURE 8
FIGURE 8
Intracellular ROS of 143B cells treated with mPEG-b-P(C7-co-CA) micelles (A, C) and cinnamaldehyde (B, D) at pH 7.4 and 6.5. DCFH-DA was used as the ROS probe (scale bar 200 μm, *p < 0.05, vs. the pH 7.4 group, n = 3).
FIGURE 9
FIGURE 9
Effect of mPEG-b-P(C7-co-CA) micelles on the apoptosis of 143B cells was detected by flow cytometry (A,B) and TUNEL assays (C, D) (scale bar 100 μm, ***p < 0.001, vs. the control group, n = 3).
See this image and copyright information in PMC

References

    1. Al Tbakhi B., Nsairat H., Alshaer W., Al-Kadash A., Helal W., Alrawashdeh L., et al. (2022). Cinnamaldehyde–cucurbituril complex: Investigation of loading efficiency and its role in enhancing cinnamaldehyde in vitro anti-tumor activity. RSC Adv. 12 (12), 7540–7549. 10.1039/d2ra00044j - DOI - PMC - PubMed
    1. Bernkop-Schnürch A. (2018). Strategies to overcome the polycation dilemma in drug delivery. Adv. Drug Deliv. Rev. 136-137, 62–72. 10.1016/j.addr.2018.07.017 - DOI - PubMed
    1. Camuzard O., Santucci-Darmanin S., Carle G. F., Pierrefite-Carle V. (2019). Role of autophagy in osteosarcoma. J. bone Oncol. 16, 100235. 10.1016/j.jbo.2019.100235 - DOI - PMC - PubMed
    1. Chu S-C., Hsieh Y-S., Hsu L-S., Lin C. Y., Lai Y. A., Chen P. N., et al. (2022). "Cinnamaldehyde decreases the invasion and u-PA expression of osteosarcoma by down-regulating the FAK signalling pathway." Food & Funct. 13 (12):6574–6582. 10.1039/d2fo00634k - DOI - PubMed
    1. Dong K., Lei Q., Guo R., Wu X., Zhang Y., Cui N., et al. (2019). <p&gt;Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis&lt;/p&gt;. Int. J. Nanomedicine 14, 5713–5728. 10.2147/ijn.S208089 - DOI - PMC - PubMed