Peptide Knowledge Center

4 long-acting studies on peptide drugs: nanotechnology has the most potential

The biomedical industry is developing rapidly. As of 2019, more than 90 peptide drugs have been marketed globally, and a large number of peptide drugs have entered the clinical research stage. Polypeptide drugs have good biological activity, high specificity and low toxicity. Compared with ordinary small molecule drugs, they are safer and more effective, so they are widely used in disease treatment.


The biggest drawback of peptide drugs is that they have large molecular weight and are easily degraded by most enzymes in the body, so they have a short half-life and low membrane permeability. The appropriate route of administration can make up for this deficiency, but care must be taken to avoid the resulting immune side effects and loss of drug biological activity. Nowadays, more and more scientific research teams are improving drug treatment by slowing down the effect of drugs. The main methods include chemical modification, micro-nanoparticle embedding and protein fusion. Among them, nanotechnology has great potential for drug encapsulation, especially lipid carrier nanoparticles, polymer carrier nanoparticles and inorganic carrier nanoparticles.


The following are commonly used long-acting strategies for peptide drugs:


1. Chemical modification

The chemical modification of peptide drugs mainly involves the combination of peptide drugs and modifiers through chemical methods to extend the half-life of the drug, including polyethylene glycol (PEG) modification, peptide main chain end modification, side chain modification, cyclization, amino acid substitution, and glycosylation modification


After PEG is combined with peptide drugs, the molecular weight increases and cannot be filtered by the glomerulus, thereby improving the stability of the drug and prolonging the half-life of the drug. At present, some PEG-modified peptide drugs have been approved and listed on the market, such as omontys, pegasys, pegintron and plegridy.


Peptide chain modification and amino acid substitution are also common methods to extend the half-life of drugs. For example, Novo Nordisk’s liraglutide palmitoylates the 26th amino acid of natural glucagon-like peptide 1 (GLP-1), and then The 34-position amino acid substitution enhances its binding force to albumin with a longer half-life to achieving the effect of prolonging the half-life of the drug.


Glycosylation modification can improve the biological activity of drugs and change the physicochemical and pharmacological properties of peptide drugs, but it also often leads to changes in the solubility and conformation of peptide drugs. Peptide cyclization method can prevent the enzymatic hydrolysis of amino acids and prolong the half-life of polypeptides. It is currently widely used in the preparation of oral intestinal peptide drugs.Our company has a series of mature and stable peptide cyclization products for anti-cancer research.


2. Microsphere embedding method

At present, peptide drug formulations on the market mainly include implants and microsphere injections. Due to its good slow-release performance and mature preparation technology, the microsphere drug delivery system is widely used in the production of long-acting peptide drugs. Among them, the copolymer polylactide-glycolide (PLGA) is one of the few biodegradable materials approved by the FDA. It has the advantages of good biodegradability, biocompatibility, and simple preparation process been widely used in the packaging of peptide drugs.


Peptide drug microspheres are mainly prepared by double emulsion , single emulsion , phase separation, spray drying, ultrasonic atomization and microfluid technology method. The embedding effect of microspheres is mainly affected by the production method, loading amount, particle size, polymer molecular weight and solvent type. At present, there are a large number of peptide drug microsphere injections on the market, such as Novartis's octreotide, Amylin's long-acting exenatide PLGA microsphere injection Bydureon, and Debiao's triptorelin, but most of the peptide microsphere injections there are also problems of obvious burst effect and easy aggregation of particles.


Recently, Gasmi et al. pointed out that the swelling kinetics of PLGA microparticles may be a key factor in controlling drug release, because a large amount of water penetrates into the microparticles, which will increase the drug release rate. In addition, the degree of polymer crosslinking will affect the swelling rate and restrict the drug. This may be a breakthrough to solve the burst release effect of peptide microspheres. In addition, the microsphere embedding method also needs to avoid the degradation of biodegradable materials, which will change the pH of the environment and cause the peptides to aggregate and reduced efficacy.


3. Protein fusion technology

Serum protein fusion technology makes the molecular weight of peptide drugs greater than the glomerular filtration value, so that it can be endowed and recirculated, and the half-life of the drug is prolonged. Currently commonly used fusion proteins are albumin and immunoglobulin (IgG). GSK’s Albiglutide is the first diabetes peptide drug fused with albumin approved by the FDA.


In addition, the use of immunoglobulin Fc fusion strategy is also an effective way to increase the half-life of peptide drugs. Dulaglutide developed by Lilly is an effective hypoglycemic drug that combines GLP-1 with Fc. It has passed phase III clinical trials.


These technique, like the PEG method, to prolongs the half-life of the drug by reducing the renal clearance of peptide drugs. Although protein recombinant technology can improve the efficacy of peptide drugs, there is a potential risk of endogenous gene cross-reaction, which affects the safety of long-term drug applications.


4. Nano delivery technology

Polymer nanoparticles can control the properties of nanoparticles by changing the monomer composition and molecular weight ratio, thus becoming one of the most promising drug carriers in recent years.


PLGA is a common nanocarrier for peptide drugs, but because PLGA peptide drugs can interact with nucleophiles, such as the N-terminal of the peptide and the primary amine group of the lysine residue, it triggers the acylation between PLGA and the peptide reaction. The acylation of peptides may lead to the loss of drug activity or the change of affinity with the receptor, or even immunogenicity.


Since liposome delivery effect is not affected by the solubility of the drug, it is often used as a large molecule drug carrier, but its stability and release efficiency are not well controlled. Wang et al. recently designed a cationic lipid nanoparticle to carry protein or peptide drugs. The experimental results show that the fat-like molecular carriers all show low toxicity and more than 90% cell viability, which indicates that the development of cationic fat-like molecular nanoparticles to deliver peptide drugs still has great potential.


Nanoparticle drug delivery systems are widely used in drug slow-release technology due to their unique physical and chemical properties. Their further development mainly faces the following challenges: ① The loading volume of peptide drugs is often low. ② Improper carriers may interact with peptide drugs and affect their activity. ③ The preparation methods of peptide nanoparticles are often complicated and organic solvents are often used. How to use simple, green and easy-to-scale processes has become one of the research directions. ④ Nanoparticles are easy to be swallowed by endosomes, so appropriate methods should be used to prevent endocytosis. In short, the safety and stability of peptide nanoparticles should be considered when designing peptide nanoparticles, and it is best to use biodegradable carriers approved by the FDA (such as PLGA). The use of new drug delivery methods (microneedle array technology, quantum dot technology) may become another research direction for peptide sustained-release drugs.


At present, nanoparticle drug delivery systems are mainly used in some small molecule drugs (doxorubicin, paclitaxel, etc.), but macromolecular drugs cannot meet the current clinical needs, so adopting appropriate nano drug delivery strategies may become large molecules new directions for drug development.

For more informations about peptide synthesis,please get in touch with Omizzur Biotech :

  1. Peptide Synthesis Service

  2. Mail: [email protected]