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

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.

A Systematic Study of Anti-Osteosarcoma Mechanism of pH-Sensitive Charge-Conversion Cinnamaldehyde Polymeric Prodrug Micelles In Vitro

“…Horseradish peroxidase-labeled goat anti-rabbit and goat anti-mouse IgG (secondary antibody), mouse anti-human β-actin Cloned antibodies, PCNA, Bcl-2 monoclonal antibodies and rabbit anti-human N-cadherin, E-cadherin, MMP-2, Snail, PI3K, AKT, Phosphorylated AKT monoclonal antibodies were purchased from Cell Signaling Technology (CST, Danvers, MA, USA). mPEG- b -P(C7- co -CA) and mPEG- b -PC7A were prepared according to our previous report [ 22 ].…”

“…A cinnamaldehyde polymeric prodrug micelle with pH-sensitive charge-conversion ability (mPEG- b -P(C7- co -CA)) was fabricated previously by our group for the effective chemotherapy of osteosarcoma through the targeted delivery of cinnamaldehyde [ 22 ]. Due to their pH-sensitive charge-conversion capability, mPEG- b -P(C7- co -CA) micelles have been demonstrated to be effective in targeting anti-osteosarcoma.…”

Biological fate, functional properties, and design strategies for oral delivery systems for cinnamaldehyde

“…Deng et al developed a pH-sensitive charge-conversion CA polymeric prodrug micelle using a reversible addition–fragmentation chain transfer polymerization method. 74 The CA-loaded micelles had been proven to have a reduced particle size of 227 nm and enhanced anti-tumor effects on 143B osteosarcoma cells compared with free CA, indicating that micelles had great potential to reduce particle sizes and enhance the bioavailability of CA.…”

Engineered nanomaterials enhance drug delivery strategies for the treatment of osteosarcoma

“…However, the disadvantages of high toxicity and low solubility of CA limit its clinical application. Deng et al (2023) made an amphiphilic CA prodrug from polyethylene glycol (mPEG), ethanol, and CA. Amphiphilic polymers can self-assemble into nano micelles in an aqueous solution with a diameter of 227 ± 16 nm and a zeta potential neutral at pH 7.4.…”