A Transformable Chimeric Peptide for Cell Encapsulation to Overcome Multidrug Resistance

Abstract

Multidrug resistance (MDR) remains one of the biggest obstacles in chemotherapy of tumor mainly due to P-glycoprotein (P-gp)-mediated drug efflux. Here, a transformable chimeric peptide is designed to target and self-assemble on cell membrane for encapsulating cells and overcoming tumor MDR. This chimeric peptide (C -K(TPE)-GGGH-GFLGK-PEG , denoted as CTGP) with cathepsin B-responsive and cell membrane-targeting abilities can self-assemble into nanomicelles and further encapsulate the therapeutic agent doxorubicin (termed as CTGP@DOX). After the cleavage of the Gly-Phe-Leu-Gly (GFLG) sequence by pericellular overexpressed cathepsin B, CTGP@DOX is dissociated and transformed from spherical nanoparticles to nanofibers due to the hydrophilic-hydrophobic conversion and hydrogen bonding interactions. Thus obtained nanofibers with cell membrane-targeting 16-carbon alkyl chains can adhere firmly to the cell membrane for cell encapsulation and restricting DOX efflux. In comparison to free DOX, 45-time higher drug retention and 49-fold greater anti-MDR ability of CTGP@DOX to drug-resistant MCF-7R cells are achieved. This novel strategy to encapsulate cells and reverse tumor MDR via morphology transformation would open a new avenue towards chemotherapy of tumor.

Application of Light Scattering Techniques to Nanoparticle Characterization and Development

“…Regarding DLS, it is mostly used to determine the size distribution of the NPs, but some authors use this technique in different ways (Water et al, 2015 ; Xie et al, 2017 ; Xia et al, 2018 ). Confirm surface functionalization, characterize long term stability in different media or pH values, and identification of the aggregation profile are just examples of other possible applications of this technique (Figure 5 ) (Mohanty et al, 2013 ; Casciaro et al, 2017 ; Shmarakov et al, 2017 ; Zhang et al, 2018 ). As for zeta-potential, optimization of peptide anchoring profile to the nanoparticle, confirmation of surface charge modification, and validation of electrostatic interaction between the NP and the target cells are some of the processes where it could be essential (Kuai et al, 2010 ; Takara et al, 2010 ; Pal et al, 2016 ).…”

“…Using parental systems, these authors developed a new one, with higher antimicrobial activity and pro-angiogenic properties in biological burn-wound bandages, named TNS18 (Siriwardena et al, 2018 ). Finally, other authors recently focused in self-assembling peptide nanoparticles that only act on the target cell after activation, using for that specific characteristics of the target tissue, such as overexpressed membrane proteins or enriched proteases concentration (Yu et al, 2018 ; Zhang et al, 2018 ). This field is now expanding and, therefore, more research is needed to understand how this strategy can benefit current therapies relative to other systems that are easier to manipulate.…”

Polymers, responsiveness and cancer therapy

“…The role of MMP-9 came into the picture for exposing the targeting ligand to the pancreatic cancer cells. The responsiveness of cathepsin B has also been used with the chimeric peptides to provide a solution to multidrug resistance occurrence during chemotherapy [41]. The nanomicellar system encapsulating DOX was able to restrict the efflux of DOX and provide higher drug concentration at the site of action.…”

Boronic acid-rich dendrimer for efficient intracellular peptide delivery

“…Peptides are short amino acid sequences that could maintain the same or partial biological functions of natural proteins, and have drawn great interests as promising tools in molecular cell biology or drug candidates in clinical trials [1][2][3][4]. They were reported to play critical roles in cell adhesive and penetrating, tumor targeting, signal transduction, homeostasis and reproduction, cell apoptosis, nuclear localization, and immunity regulation, i.e., induction of T-cell response against pathogens [5][6][7][8][9][10][11][12][13][14][15][16].…”

“…To address this issue, various peptide delivery carriers such as amphiphilic chemicals, lipid nanoparticles, polymers, nanogels and inorganic nanoparticles were developed [5,17,[24][25][26][27]. For example, a host- [2]rotaxane containing both cationic arginine and aromatic moieties to host cargo peptides with various polarities was developed, and the complex could enter cells via passive translocation [18]. In a separate study, an endosomolytic anionic polymer was complexed with cationic cargo peptides via electrostatic interactions to form nanoparticles for efficient cytosolic delivery [17].…”