TNYL peptide functional chitosan-g-stearate conjugate micelles for tumor specific targeting

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.

Targeting the Eph System with Peptides and Peptide Conjugates

“…The TNYL peptide has also been conjugated through a C-terminal PEG linker to chitosan-g-stearate, generating an amphiphilic polymer that spontaneously forms nanosized micelles in aqueous solutions, which can be efficiently loaded with drugs or imaging agents and can be readily internalized into cells [119]. Despite the low EphB4 binding affinity of monomeric TNYL [23], the peptide could preferentially target doxorubicin-loaded nanoparticles to EphB4-positive SKOV3 ovarian cancer cells compared to non-targeted nanoparticles, leading to enhanced toxicity towards the cancer cells [119].…”

“…Despite the low EphB4 binding affinity of monomeric TNYL [23], the peptide could preferentially target doxorubicin-loaded nanoparticles to EphB4-positive SKOV3 ovarian cancer cells compared to non-targeted nanoparticles, leading to enhanced toxicity towards the cancer cells [119]. In addition, in vivo imaging showed that the TNYL-targeted nanoparticles could preferentially deliver the encapsulated near-infrared dye DiR to SKOV3 mouse tumor xenografts compared to EphB4-negative A549 lung cancer xenografts.…”

Fabrication of oxygen‐carrying microparticles functionalized with liver ECM‐proteins to improve phenotypic three‐dimensional in vitro liver assembly, function, and responses

“…In this study, biofunctionalization with the ECM proteins plasma fibronectin, laminin‐111, 511, and 521 to the surface of PFC–MPs was accomplished by a coupling reaction between the carboxyl residues of proteins to the free amine residues of chitosan using EDC as a crosslinker and NHS ester as an enhancer of coupling (Figure 4a). The EDC/NHS coupling reaction is a selective method for preservation of biological activity of the protein and has previously been applied in the production of protein‐functionalized chitosan derivatives (Chen et al, 2014; Ho et al, 2005; Taylor et al, 2015). Since the pH of the reaction solution is critical for maximizing the amination reaction, we tested different pH levels keeping all other conditions the same, to determine the favored pH to maximize attachment.…”

Enhancing the antibacterial activity of PMAP‐37 by increasing its hydrophobicity

“…New drugs are needed to replace antibiotics. Therefore, AMPs have become an important research topic due to their strong antibacterial activity (Dawgul, Maciejewska, Jaskiewicz, Karafova, & Kamysz, 2014). PMAP-37 is an AMP that was first isolated from pig myeloid cells (Tossi et al, 1995).…”