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Cell-Penetrating Peptides and Their Role in Cancer Research

The global market size for cell-penetrating peptides has been on the rise over the last few years, and it is anticipated that the growth will continue in the coming years. The use of peptides has offered a great opportunity for the creation of a variety of drugs. Their size – which lies somewhere between the size of a small molecule and the size of normal biological compounds, has been a great asset in drug formulation since it makes it possible for effective targeting.

For instance, peptides known to bind with high affinity to their receptors come with low immunogenicity and they portray well-tolerated metabolic building blocks following their proteolytic degradation. Though peptides come with high compatibility, their ease of synthesis, as well as ease for various modifications, makes them stand out from most of the other molecules.

Additionally, due to their smaller size, they are able to bypass off-target molecules and, as such, they become ideal in facilitating the administration of short doses. Some of the drawbacks that are currently being associated with peptides therapeutics include their relatively short plasma life as well as their low oral bioavailability. Due to these deficiencies, the development process of a variety of peptide therapeutics has been slowed down significantly.

However, as the synthesis techniques continue to evolve, the demand for peptides continues to increase, and this comes with a positive influence on the drug development market. Presently, there are three main centers of focus for peptide therapeutics, with cancer treatment being one of them. Cancer is experienced whenever there is an uncontrollable cell division which is normally attributed to mutations or certain abnormal changes taking place in the genes responsible for regulating the growth of the cells, and cancer still remains one of the top causes of deaths worldwide.

Though the market currently has a high number of chemotherapeutics with high potential, most of the available options come with adverse effects and they still don’t have sufficient pharmacological profiles. Therefore, one of the major efforts in cancer research is to find therapeutic strategies with the ability to limit or completely avoid most if not all the drawbacks associated with the current cancer chemotherapy strategies.

Considering this approach, one of the ways to move in the right direction is to enhance the bioavailability of small medical molecules so that they can become efficient peptide drug carriers. There is great potential for achieving this with the help of cell-penetrating peptides.

A Short Overview of Cell-Penetrating Peptides

Cell-penetrating peptides feature a class of peptides with the ability to move across the cell membrane and also with the potential of being used as a carrier for covalently or non-covalently attached cargos of different sizes that range from nucleic acids to peptides, to small molecules, to proteins and even to particles.

Most of the time, the cell-penetrating peptides have short sequences that range between 5 and 30 amino acids. This short sequence negates the need for a specific transport system or special receptors in order for them to achieve translocation. Since cell-penetrating peptides were first described way back in the 1980s, there is an unknown number of these peptides that have been presented to have varying sequence lengths and varying compositions of amino acids. There are various ways through which cell-penetrating peptides can be classified. For instance, the classification can be done based on whether they are naturally or synthetically derived, whether they are made of cyclic or linear compounds, or they can be classified based on their physicochemical properties where we have amphipathic, hydrophilic, and hydrophobic sequences.

It should be noted that it is also possible to predict certain features of the cell-penetrating peptides with the help of certain suitable databases. The presence of basic amino acid residues is one of the commonly observed structural features. On translocation, whenever the cell penetration peptides approach the plasma membrane, they will primarily interact with the negatively charged substituents of the bi-lipid layers, giving way for the structuring and accumulation of the peptides at the lipid phase.

This process of clustering then produces certain unique events within the cell membrane that ultimately leads to the final uptake of the cell-penetrating peptides. As a matter of fact, this mode of cellular uptake may model after a variety of routes and is sometimes dependent on a variety of factors, including the temperature, the concentration, the pH, the particular cell-penetrating peptides and the cell-lines used, and the cargo attached, among others factors. Because of this, the uptake of cell-penetrating peptides – with or without cargo, is a process whose details are still not clear, and it is a matter that has always been subjected to a lot of intense debates.

Despite that, there are two major pathways that have so far been predicted for the cellular uptake of the cell-penetrating peptides. Firstly, it is believed that the cell-penetrating peptides have the ability to directly permeate the plasma membrane following methods that have been extensively explored in the past. The second mechanism for the translocation of the cell-penetrating peptides across the plasma membrane is believed to occur when the cell-penetrating peptides fuse with a cargo of a large size and through use of energy, as well as throughprocesses like endocytosis, it becomes possible for them to access the interior of the cells.

cell penetrating peptides

Cell-Penetrating Peptides in Clinical Trials to Treat Different Kinds of Cancer

Despite the fact that there are a plethora of cell-penetrating peptides to be discovered and studied, the number of cells penetrating peptides that have been subjected to pre-clinical or clinical trials still remains low. The reason for this may be due to the fact that researchers have gained a more comprehensive picture of the actions of the peptides, and as such, they have improved the fine-tuning process of pharmacological profiles to ensure that only the cell-penetrating peptides with the highest potential get to the trials. Below is a brief overview of some of the current research on cell-penetrating peptides therapeutics on certain forms of cancer-:

Brain Cancer

Glioblastoma (GBM), is one of the most aggressive tumor types with a median survival period of about 15 months. One of the challenges encountered when dealing with GBM therapy is having to deal with blood-brain-barrier (BBB). This is the barrier responsible for protecting the brain from the circulation of toxins and pathogens while preferentially allowing the passage of nutrients to access the brain. Recent studies have, however, provided very promising results in using cell-penetrating peptides drug- conjugate in safely going past the BBB so as to target tumor cells within the brain. In a study carried out by Josh et al. whose focus was to investigate the effects of Tat when administered intravenously or intra-arterially in vivo brain tumor cells of a mouse, it was observed that there was a four-fold increase in fluorescently labeled CPP following intravenous application. In conclusion, Tat demonstrated that it had the ability to cross the BBB efficiently while at the same time remaining localized in the brain relative to admission intravenously. This was a vital finding that could be used in designing and formulating a variety of anticancer drug delivery systems in the future.

Breast Cancer

This is one of the most common cancer types among women, and millions are affected. Its risk factors include family history, age, and lifestyle factors. The more common type of this cancer is invasive breast cancer while the less common type is triple-negative breast cancer. Though the survival rate for breast cancer is relatively promising compared to other forms of cancer, it requires early detection and proper intervention if the patient is to have a better chance of surviving.

Chemotherapy is one of the top treatments for breast cancer, but there are still a variety of active and selective drugs specifically designed to deal with this kind of cancer. In this regard, Mitra and colleagues formulated an all hydrocarbon helical peptide that was to be bounded to a protein known as RAB25. This protein is normally involved in the pathogenesis of various types of cancers, with breast cancer included. It has been shown that the complexation of RAB25 and RAB-family interaction proteins (FIP) can lead to dysregulated signaling.

With this knowledge, the constructed peptide by Mitra and his colleagues is generated to bind RAB25 so as to functionally block any instances of the formation of RAB25:FIP complex, in addition to inhibiting the phenotypes associated with RAB25. During studies, it was observed that there was the inhibition of cell migration and a low rate of proliferation of MCF-7 breast cancer cells. This was a clear indication that RAB25 binding was effectively disrupted, signaling a potential new point of intervention when it comes to the migration of breast cancer cells.

Lung Cancer

Lung cancer is another type of cancer affecting millions of people across the globe. The two main types of lung cancer are small-cell lung cancer – SCLC and non-small cell lung cancer – NSCLC. The treatments for these two types of lung cancers are different, though they mainly revolve around radiation therapy, chemotherapy, immune therapy, and surgery. In a study conducted by Lostale-Seijo et al. to establish the CRRISPR/Cas9 methods of applications for cancer therapies, a strategy for transporting the Cas9 ribonucleoprotein – RNP into cancer cells was studied in detail.

A cell-permeable peptide named PT24 containing an amphiphilic peptide joined to a hydrophobic aldehyde tail through a hydrazine bond was designed. When this peptide was incubated with the Cas9 RNP, it was observed that there was the formation of supramolecular nanoparticles when Cas9 RNP and PT24 were bound non-covalently, and it was also observed that it was possible to successfully deliver the cargo into the cell. During the study, the efficacy for the delivery into the lung cancer cell line was observed to be fine, and a result, this approach was considered for conceptualizing a new system instead of the direct delivery of endonucleases.

Colorectal Cancer

Colorectal Cancer (CR), is considered the second most deadly type of cancer in the world. It is a type of cancer that affects both the colon and the rectum. The common therapy for this kind of cancer usually includes a combination of surgery, radiation therapy, and chemotherapy. Because the bulk of the therapeutics used usually come with unwanted side effects, there is still a great need for novel strategies and diagnostic approaches in dealing with this form of cancer.

Accordingly, the research world is currently focusing on plant-derived peptides that have anti-tumor activities for formulating potential therapies for dealing with colorectal cancer. Regarding cell-penetrating peptide-based approaches, in the past few years Zeng and Co managed to design an imaging probe that would help in the early detection of colorectal cancer. During the process, they came up with an activatable cell-penetrating peptide (ACPP) that would be activated by MMP-2 or MMP-9 which are normally overexpressed in the case of colorectal cancer.

Additionally, when a fluorescent dye was attached to the ACPP, and the uptake of this constructed in colorectal cancer cells was investigated, it was observed that there were higher fluorescence activities in the colorectal tumor cells compared to the activities in the cells of the normal organs. This provided a glimmer of hope as such a construct could be immensely useful in the early detection of colorectal tumor localization.


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