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TNYL peptide functional chitosan-g-stearate conjugate micelles for tumor specific targeting
Feng-Ying Chen1, Jing-Jing Yan1, Han-Xi Yi2
1Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Abstract:
Nowadays, a real challenge in cancer therapy is to design drug delivery systems that can achieve high concentrations of drugs at the target site for improved therapeutic effect with reduced side effects. In this research, we designed and synthesized a homing peptide-(TNYLFSPNGPIA, TNYL) modified chitosan-g-stearate (CS) polymer micelle (named T-CS) for targeting delivery. The peptide displayed specific binding affinity to EphB4 which is a member of the Eph family of receptor tyrosine protein kinases. The amphiphilic polymer T-CS can gather into micelles by themselves in an aqueous environment with a low critical micelle concentration value (91.2 μg/L) and nano-scaled size (82.1 ± 2.8 nm). The drug encapsulation efficiency reached 86.43% after loading the hydrophobic drug doxorubicin (DOX). The cytotoxicity of T-CS/DOX against SKOV3 cells was enhanced by approximately 2.3-fold when compared with CS/DOX. The quantitative and qualitative analysis for cellular uptake indicated that TNYL modification can markedly increase cellular internalization in the EphB4-overexpressing SKOV3 cell line, especially with a short incubation time. It is interesting that relatively higher uptake of the T-CS/DOX micelles by SKOV3 cells (positive-EphB4) than A549 cells (negative-EphB4) was observed when the two cells were co-incubated. Furthermore, in vivo distribution experiment using a bilateral-tumor model showed that there was more fluorescence accumulation in the SKOV3 tumor than in the A549 tumor over the whole experiment. These results suggest that TNYL-modified CS micelles may be promising drug carriers as targeting therapy for the EphB4-overexpressing tumor.
Insights
Researchers developed TNYL-modified chitosan-g-stearate (CS) polymer micelles for targeted cancer drug delivery. These micelles effectively deliver doxorubicin (DOX) to EphB4-overexpressing tumors, enhancing efficacy and reducing side effects.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cancer Therapy
Background:
- Designing effective cancer drug delivery systems remains a challenge.
- Targeted delivery aims to increase drug concentration at the tumor site and minimize systemic toxicity.
- EphB4 receptor tyrosine kinase is implicated in various cancers, presenting a potential therapeutic target.
Purpose of the Study:
- To design and synthesize a novel homing peptide-modified chitosan-g-stearate (CS) polymer micelle for targeted drug delivery.
- To evaluate the drug loading capacity, micelle characteristics, and in vitro/in vivo targeting efficiency of the developed system.
Main Methods:
- Synthesis of TNYL-peptide modified CS-g-stearate (T-CS) polymer micelles.
- Characterization of micelle size, critical micelle concentration, and doxorubicin (DOX) encapsulation efficiency.
- In vitro cytotoxicity assays and cellular uptake studies using EphB4-positive (SKOV3) and negative (A549) cancer cell lines.
- In vivo biodistribution studies in a bilateral tumor model.
Main Results:
- T-CS micelles formed stable nanoparticles (82.1 ± 2.8 nm) with high DOX encapsulation efficiency (86.43%).
- T-CS/DOX demonstrated significantly enhanced cytotoxicity (2.3-fold) against SKOV3 cells compared to non-targeted micelles.
- TNYL modification markedly increased cellular internalization in EphB4-overexpressing cells and showed preferential uptake in vivo in EphB4-positive tumors.
Conclusions:
- TNYL-modified CS micelles represent a promising targeted drug delivery platform for EphB4-overexpressing tumors.
- This system enhances drug efficacy and offers potential for reduced side effects in cancer therapy.
- Further investigation into this targeted nanocarrier system is warranted for clinical translation.
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