Basics and modern developments in the transport of peptide and protein drugs

in StemSocial7 months ago



A class of biologic called peptide and protein therapies is playing a larger role in the treatment of conditions like cancer, autoimmune, neurodegenerative, and hormonal problems. Because they only work in very specific places, they are usually a better and safer way to treat diseases than small-molecule drugs. Currently, there are more than 100 peptides and more than 200 medicinal proteins that have been authorized for use. These together account for 10% of the $40 billion annual prescription industry. This industry is anticipated to continue expanding over the next 5 to 10 years, with hundreds of protein and peptide medicines currently undergoing clinical trials and many more in preclinical research.

The biopharmaceutical business still struggles to deliver protein and peptide medicines to the proper location within the therapeutic range, although their marketplaces are expanding. Protein and peptide medications have much greater molecular weights (MWs) than small-molecule drugs, which makes it more difficult for them to be absorbed through epithelial cells. They must be properly coiled and receptive to changes in their physical and molecular states for them to perform therapeutically. To overcome their inherent structural instability, get past physical obstacles, and achieve the desired degree of bioavailability, proteins, and peptides need an effective transport mechanism. The majority of research into the best protein delivery methods is concentrated on increasing absorption and figuring out how to deliver protein without harming the body.
Now, let's see the mechanisms employed so far in transporting protein and peptide.

Direct fundamental alterations

Direct structural modification is a typical method for increasing the bioavailability of protein and peptide medicines. Cyclization (as in cyclosporine), amino acid replacement, coupling to polyethylene glycol (PEG) polymer chains (referred to as "pegylation"), oligosaccharide conjugation (referred to as "glycosylation"), and fatty acids can all be used to achieve this (called "lipidization"). It has been demonstrated that pegylation and glycosylation are two techniques that aid in the stability, bioavailability, and passage of proteins and peptides through cellular membranes. Improved solubility, reduced dosage requirements due to the drug's increased stability in the body, increased efficacy, a better safety profile, and a suppressed immune reaction are additional advantages of these technologies. Peginterferon alfa-2a (Pegasys, Genetech), alfa-2b (PEG-Intron, Merck), both used to treat hepatitis C, and peginterferon beta-1a (Plegridy, Biogen Idec), used to treat multiple sclerosis, are examples of authorized pegylated interferon drugs that have done well in the market.

Pegylation can be used to create prodrugs as well. Prodrugs are pharmacologically inert, but when they are processed by the body, they can become active medications. Prodrugs are an additional method for increasing the solubility, bioavailability, and toxicity of protein- and peptide-based medications. Modern pegylation techniques make it simple to create PEG polymers with high site-specificity and purity in a variety of forms and configurations. In addition, this further lessens inflammation and the inactivation of proteins during conjugation. Additionally, it has been demonstrated that stapling peptides with numerous synthesized hydrocarbon backbones increases a peptide's stability, capacity to enter cells, and propensity for binding.

Drug delivery devices

Another method to make proteins and peptides more bioavailable is to incorporate them into medication delivery devices. The digestive enzymes and environmental changes are prevented from destroying the proteins and peptides by the transport. Additionally, it transports the peptides and proteins across cellular barriers. A variety of materials, including microparticles, nanoparticles (NPs), liposomes, solid lipid NPs, and various polymers, can be used to create carriers (e.g., hydrophilic mucoadhesive polymers, thiolated polymers, and hydrogels).

NPs have been heavily involved in creating novel, more effective means of drug delivery over the past few decades. The dimension of NPs, which are solid colloidal particles, ranges from 10 nm to 1000 nanometer. Natural polymers like chitin and gelatin, semi-natural polymers like cellulose compounds, and synthetic polymers like polylactic acid can all be used to create them (PLA). These plastics are secure, biodegradable, and don't inflame the body or trigger the production of antibodies. Polymeric NPs are also very durable in bodily systems when compared to other transporters.

NPs can be applied in numerous contexts. Their physical and chemical characteristics can be changed to suit your needs by adjusting their diameters, surface charges, and hydrophobicity. Through direct encapsulation, absorption, or chemical coupling, NPs can also be engineered to contain a variety of compounds, from tiny molecular components to substantial macromolecules. NPs can also be altered externally to perform various tasks, such as transporting medications to particular locations or releasing them gradually over time. Attaching NPs to substances like PEG polymers, using absorption boosters (like lectin and chitosan), and focusing on compounds are a few of these modifications (e.g., antibodies and cell-penetrating ligands).

Finding protein transporters that are unique to a target is frequently accomplished by combining the aforementioned techniques. For instance, a team of researchers from Brigham and Women's Hospital and the Massachusetts Institute of Technology (MIT) has created tailored NPs that can be swallowed to transport biologics like insulin. Standard PLA-PEG is used to encapsulate these NPs, and the immunoglobulin G Fc portion is attached to it (IgG). The neonatal Fc segment of the IgG receptor transporter (FCGRT; FCRN), which is present in adult intestines, is the target of the Fc portion. As a result, the intestinal mucosa can be readily traversed by FCRN-targeting nanoparticles. This makes it possible to create tailored delivery thanks to receptors that are particular to a tissue, organ, or illness.

Delivery without intervention

Parenteral administration methods, such as intravenous, subcutaneous, and intramuscular shots, are typically used to administer therapeutic proteins and peptides. This intrusive procedure can result in pain, discomfort, or other responses at the injection site, which can make patients less likely to persist with the therapy, particularly when used for a prolonged time. Better parenteral formulas (such as prefilled syringes and autoinjectors) and needleless administration techniques are preferred by both physicians and patients. Additionally, the market for protein therapies is becoming more competitive because many of the most popular biologics, particularly monoclonal antibodies, will lose their licenses in 2020. The secret to extending copyright protection and creating distinctive goods could be an efficient delivery method that is simpler for patients to use than the existing therapies.

Transdermal administration

In terms of benign techniques, transdermal administration has advanced significantly in recent years. This method enables the delivery of both small and large molecules, permits medicines to start acting rapidly, avoids first-pass metabolism, and can be administered without the use of a needle. Because it is simple to use and causes no discomfort, sublingual administration is also better for patient obedience. Long-lasting, steady, and regulated discharge is also simple to achieve using this technique.

Transdermal delivery aims to pass proteins and peptides through the stratum corneum, the upper layer of the epidermis. Proteins and peptide treatments typically require chemical or physical modifications to briefly increase the skin's permeability due to the size of their molecules. For instance, the stratum corneum may require the creation of tiny openings to allow these big molecules to pass. Among the many technologies being developed to assist in achieving this objective, the microneedle device is the most promising. Microneedles are designed to only puncture the stratum corneum, keeping them away from the blood vessels and nerve receptors in the living epidermis (the skin layer beneath the stratum corneum). Proteins and peptides can be administered in a variety of ways, such as by applying them to the skin following microneedle therapy, injecting them through hollow microneedles, or placing medications in containers inside biodegradable microneedles and allowing them to gently seep out. Injecting or applying microneedles to a covering can also apply to the epidermis.

The lungs and nostrils are two additional non-invasive delivery routes for proteins and peptides that are frequently investigated. Both pulmonary and nasal administration gives a large surface area for absorption, less enzyme activity than the GI system, straight transport to the entire body, and no first-pass metabolism. Proteins can get past physical obstacles and reach their intended locations with the development of delivery methods like dry powder inhalation (DPI) and pressurized metered dosage inhalation (pMDI).

Additionally, nasal formulations give the means to penetrate the blood-brain barrier and enter the central nervous system (CNS). This function seems like a useful method to access the brain directly. Making systems that specifically target CNS receptors, such as the lactoferrin receptor, which is widely expressed in neurodegenerative disorders like Alzheimer's and Parkinson's, is another way to enhance brain delivery.

A comprehensive, combination of technologies, including chemical alterations, tailored drug carrier systems, and possibly novel delivery devices, is needed to make peptide and protein therapies effective through noninvasive pathways.


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  • Patra, Jayanta Kumar, et al. “Nano Based Drug Delivery Systems: Recent Developments and Future Prospects - Journal of Nanobiotechnology.” BioMed Central, 19 Sept. 2018,

  • Xie, Jing, et al. “Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application.” Frontiers, 28 Apr. 2020,

  • Lee, Andy Chi-Lung, et al. “A Comprehensive Review on Current Advances in Peptide Drug Development and Design.” MDPI, 14 May 2019,

  • Wang, Lei, et al. “Therapeutic Peptides: Current Applications and Future Directions - Signal Transduction and Targeted Therapy.” Nature, 14 Feb. 2022,

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