De Novo Computational Design for Development of a Peptide Ligand Oriented to VEGFR-3 with High Affinity and Long Circulation

Abstract

The overexpression of VEGFR-3 is correlated with a worse prognosis in lung cancer and has been regarded as a rational target for specific drug delivery. Here, VEGFR-3 homing peptide library was efficiently established by computational design. Strong fluorescent signals of selected peptides were observed in A549 cells, but much weaker in other cells. The positive immunostaining overlapped with VEGFR-3 confirmed high affinity and selectivity of one novel peptide (CP-7). In addition, cell uptake of FITC-CP-7 peptide was significantly blocked by coinjection of excess CP-7 peptide. After labeled with I, the profile of pharmacology and biodistribution could be traced in vivo. TheI-radiolabeled CP-7 peptide conjugates were >85% stable in serum over 4 h and exhibited a specific uptake of 18.04 ± 2.04% ID/g at 0.5 h after injection to high VEGFR-3 expressing A549 tumor mice. More importantly, lower uptake concentration in heart (1.06 ± 0.15% ID/g) after 2 h demonstrated the safety of peptide in vivo. The high uptake in the kidneys revealed that renal clearance was the main route of I-CP-7 peptide elimination from the body. Lower accumulation ofI-CP-7 peptide in VEGFR-3 negative HeLa tumor mice further indicated that CP-7 peptide exhibited a higher tumor-homing efficiency. These studies provided a straightforward analytical access to design and screen bioactive peptide based on protein structure and revealed that CP-7 peptide represented a promising homing peptide of VEGFR-3-positive cancer in vitro and in vivo which could be used as a novel target molecule to achieve efficient drug delivery.

Targeting Tumor Markers with Antisense Peptides: An Example of Human Prostate Specific Antigen

“…The antisense peptide AVRDKVG was derived using amino acid pairing theory [5,19,20,21]. Following the selection of the molecular target (hPSA epitope), the potential peptide ligand was designed using antisense peptide translation in the 3′ to 5′ direction, and its binding affinity, measured as a dissociation constant ( K d ) was evaluated [10,11,12,19,20,21].…”

“…Only a small number of molecular markers was exploited for development of targeted therapies, and one of the suggested approaches intended to improve production has been the use of small peptides [4]. Theoretically, small peptides for targeting of tumor markers could be used to develop a new generation of diagnostic and therapeutic substances [4,5]. Synthetic peptides have many advantages in comparison to monoclonal antibodies, i.e., relatively simple and inexpensive synthesis, stability and easy storage and transportation [6].…”

“…They show an absence of immunoreactivity, thus minimizing allergic side-effects [7,8]. Their small size gives them favorable pharmacokinetic properties, with better penetration to cancer tissue [5]. Ethical considerations are also significant, because the production of synthetic peptides does not require the sacrifice of animals or the application of procedures painful to them, in contrast to the production of monoclonal antibodies [9].…”

“…Ethical considerations are also significant, because the production of synthetic peptides does not require the sacrifice of animals or the application of procedures painful to them, in contrast to the production of monoclonal antibodies [9]. Peptides developed in this manner could be used for the development of radiopharmaceuticals for the selective targeting of primary and metastatic tumor markers, particularly useful in the detection of early metastases and staging of the disease [4,5].…”

Phenylboronic ester-modified anionic micelles for ROS-stimuli response in HeLa cell

“…The tumor volume was figured out according to the following equation: volume ¼ tumor width 2 Âtumor length/2. In vivo experiments were conducted when the tumor average volume reached 120-150 mm 3 (Liu et al, 2016;Li et al, 2017;Wang et al, 2019).…”