Tumor Homing Peptides: Advanced Application in Cancer Therapies
This entry was posted on December 14, 2021.
Currently, there is an increase in the focus on “precision medicine” in oncology, a term used to refer to advanced modes of treatments or therapies. Most of the time, the term is used to indicate very particular tumor therapies that utilize antitumor agents with the capability of working in a gene-specific manner, to deliver an antitumor payload to a specific cell or tissue with the help of a compound delivery system technology.
There are various types of recently developed small molecule inhibitors which have been proven to have the ability to inactivate kinase-involved signaling pathways and which represent a group of very specific antibody medications and antibody-compound conjugates (ADC). These ADCs are suggested to possess certain therapeutic effects by having the ability to precisely regulate the dynamics of the compound in vivo, making the efficient accumulation of the payload at target cells by binding the conjugated antibody to very specific cell surface antigens.
One good example of bio-carriers for tumor antitumor cell targeting agents, is tumor cell-permeable oligopeptides. Such oligopeptides may feature several amino acids, and they have the ability to work as full bio-tools, which can be used in the regulation of dynamic antitumor payloads in vivo. It is also possible to link them to certain anticancer moieties, so as to create a compound-delivery system – DDS-based antitumor compound conjugates. In this piece, we explore the tumor-homing peptides system, as well as its potential application, in advanced cancer therapies.
About Tumor-homing Peptides
There are several peptides with tumor cell penetration properties that have been recently classified as tumor-homing peptides. These peptides included oligopeptides, which were isolated through biopanning phage display libraries. The libraries ranged in size, between five to approximately 30 amino acids in length.
Also, these peptides are not anchored to the surfaces, but they are incorporated intracellularly, with affinity binding to specific cell surface molecules, like receptor-associated proteins, identified using their expression characteristics on the target tumor or the tumor microenvironment cells. Consequently, unlike the conventional cell-penetrating peptides, whose mode of intracellular uptake is through comprehensive permeation to diverse lineages of cells, it has been shown that these cells can incorporate into specific target cells, through the processes of endocytosis, with the help of certain specific receptors.
It has also been observed that most of the tumor-homing cells possess the ability to penetrate through the cell membranes, without causing any interference to the normal functioning of the cell, as well as the normal functioning of the cell-penetrating peptides, such as TAT. However, some of the tumor-homing peptides may exert both penetrations, as well as antitumor effects on certain tumor cells. For instance, iRGD is a stereotyping tumor-homing peptide that has been observed to penetrate tumor cells of various types, including endothelial cells, while at the same time, stopping the process of cancer metastasis in vivo.
Normally, the complex mode of every tumor-homing peptide incorporation, is molecularly different from each other, however, their uptake is normally mediated by endocytosis, which involves binding to the cell surface receptors.
Tumor-homing peptide isolated from mRNA display-based random peptide library
There are various methods that have been applied in the isolation of tumor-homing peptides. One of these methods, and which happens to be one of the most basic forms, involves trimming the amino acid sequence from the protein, which acts as the specific ligands for the interactive receptors. This is then followed by screening the resulting subsequences with the goal of recognizing an appropriate binding site on the cognate receptor.
The other approach involves screening random peptide libraries, which have been constructed with the help of established techniques, like ribosomal display, phage display, and mRNA display. In order to come up with peptides that have desired selective permeability for specific tumors, mRNA display is used in the preparation of a random peptide library, as a source for the isolation of the tumor-homing peptide.
This primary reason for this is because mRNA is believed to be more suitable for this application since the technique comes with a myriad of benefits when compared with other approaches, such as ribosomal display, and phage display, especially when considering recovering peptides with very good performance.
To begin with, mRNA display uses peptide/mRNA chimeras of small molecule size, unlike both ribosomal display and phage display, which uses relatively large molecular components. This difference in the sizes of molecules used, has a direct impact on the efficiency of isolating the encoded peptide. Secondly, mRNA display makes it easy to get high quality libraries compared to the other two methods.
The third benefit that comes with using mRNA display, is that it allows flexible changes to be made in the size of the resulting peptide during the process of preparing the library. For example, you can easily change the number of amino acids present in the sequence during the process of preparing the library.
The unique biological characteristics of tumor-homing peptides
To get a clearer picture of the extremely unique biological characteristics of tumor-homing peptides, it is vital to first examine them alongside antibodies. One of the major differences between tumor-homing peptides and antibodies, is the time they need to bind or get incorporated into the target tumor cells.
With the homing peptides, it has been observed that they can quickly bind and incorporate into a variety of target cells, through processes that will take more than 120 minutes. Antibodies, on the other hand, will require more time to bind and incorporate into the target cells. For instance, the signal responsible for indicating that binding, as well as the internalization of anti-human epidermal growth factor receptor – EGFR, by a human pancreatic ductal adenocarcinoma cell – PDAC, was still missing after the first 120 minutes, yet, it was possible to incorporate PDAC-homing peptides into the cells within the same time frame.
Also, the maximum signal/noise ratio was observed for about 12 hours following the administration of the peptide, and for between four and six days with the antibody. Through this result, it was suggested that with all the other factors constant, a peptide compound conjugate – PDC, has the ability to incorporate tumor-homing peptides, and also has the ability to exert anti-tumor effects more quickly, compared to an ADC. With this in mind, it is normal to expect that the tumor homing peptides can be therapeutically superior when they are used together with compound that have short half-lives. The other distinct property of homing peptides from antibodies, is the fact that homing peptides can be broadly incorporated into targeted tumor cells, and this covers nearly all the tumor nests in vivo.
It has also been observed that PDC may also exert potent antitumor effects, without missing the target cells. Also, antibodies such as anti-EGFR, and anti-HER2, can be used as potential carrier tools in the current ADCs, though they come with limited targeting capabilities, meaning that with their application, it is likely that the negative cells’ internal tumor cells will not be affected, save from the bystander effects from the payload.
Another vital aspect of tumor-homing peptides is that the molecules of these peptides can effortlessly target both primary and metastasis foci. The reason for this, is because the peptide is adsorbed in equal proportions in both lesions.
Potential Applications of Tumor-homing Peptides for Advanced Cancer Therapies
Since it has been shown that tumor-homing peptides have the ability to target tumors with certain characteristics in vivo, it is believed that these molecules will be of immense use in the design of advanced cancer therapies and treatments.
A typical application of tumor-homing peptides could be in the use of in vivo tumor imaging, where peptide probes that have been chemically labeled are used with dyes. With this application, there is a strong potential of it leading to the development of novel photodynamic diagnosis – PDD for cancer patients, especially based on the fact that PDD can be used during surgical operations in determining the extent of the invasion of the cancer cells or finding micro-metastatic foci through visualization with the help of the probes.
As an example, with fluorescein-labeled PDAC-homing peptide, it can be shown that PDAC dissemination can clearly delineate within the abdominal cavity of the tumor-bearing mouse. Following the rapid incorporation of the peptide into the target tumor lesions, certain unique physiological characteristics of the tumor-homing peptides were observed, and this made the molecules highly potent for application of PDD, which might as well give way to an indispensable role in the development of precision medicine. Regarding the use of tumor-homing peptides for live tumor imaging in vivo, it is expected that the peptide probes may be ideal for diagnostics that rely on direct-viewing systems, though they would not be ideal for radiolabeled systematic imaging systems, like single-photon emission computed tomography.
Evidently, the magnitude of peptide incorporation into target tumor lesions in vivo may not be detailed, and sufficient consideration in a PET tracer. PET tracers such as F-fluorodeoxyglucose – FDG, need hundredfold accumulations inside the tumor tissues in vivo, for it to be possible to detect small tumor lesions, while the peptide, even when incorporated into the target tissues, will indicate approximately up to 20-fold accumulation.
References
- Ruan H, Chai Z, Shen Q, et al. A novel peptide ligand RAP12 of LRP1 for glioma targeted compound delivery. J Control Release. 2018; 279: 306- 315.Pitt A, Nims Z. Peptide display technologies. Methods Mol Biol.
- Kamide K, Nakakubu H, Uno S, et al. Isolation of novel cell-penetrating peptides from a random peptide library using in vitro virus and their modifications. Int J Mol Med.
- Kondo E, Saito K, Tashiro Y, et al. Tumor lineage-homing cell-penetrating peptides as anticancer molecular delivery systems. Nat Commun.
- Higa M, Katagiri C, Shimizu-Okabe C, et al. Identification of a novel cell-penetrating peptide targeting human glioblastoma cell lines as a cancer-homing transporter. Biochem Biophys Res Commun.
- Grunwald J, Rejtar T, Sawant R, et al. TAT peptide and its conjugates: proteolytic stability. Bioconjug Chem.
- Liu M, Li C, Pazgier M, et al. D-paptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms. Proc Natl Acad Sci USA.
- Verdine GL, Hilinski G. Stapled peptides for intracellular compound targets. Methods Enzymol.
- Park SE, Sajid MI, Parang K, et al. Cyclic cell-penetrating peptides as efficient intracellular compound delivery tools. Mol Pharm.
- Belnoue E, Di Berardino-Besson W, Gaertner H, et al. Enhancing antitumor immune responses by optimized combinations of cell-penetrating peptide-based vaccines and adjuvants. Mol Ther.
- Vinogradov AA, Yin Y, Suga H. Macrocyclic peptides as compound candidates: recent progress and remaining challenges. J Am Chem Soc.
- Saito K, Iioka H, Kojima C, et al. Peptide-based tumor inhibitor encoding mitochondrial p14(ARF) is highly efficacious to diverse tumors. Cancer Sci. 2016.
