Development of peptide conjugated drugs

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A drug delivery system, the process of getting drugs to their intended target without unleashing toxic side effects on healthy cells, represents an area of great significance in medical research. At its core, this system seeks to achieve a number of objectives, including mitigating toxicity, bolstering stability, improving bioavailability, minimizing degradation, and maintaining a consistent and efficacious blood drug concentration.

There exist two primary approaches to crafting drug delivery systems. One method involves the use of delivery carriers, which serve to augment the stability of drugs. The other tactic, the prodrug strategy, operates by inhibiting drug activity temporarily through covalent modification. Of the two methods, the prodrug strategy may offer the most utility, as it can sidestep safety concerns such as immunogenicity and toxicity brought about by delivery carriers. Additionally, it may alleviate the metabolic burden placed on patients by these carriers, a benefit that may expand its overall applicability in the medical field.

Peptide-drug conjugates (PDCs) are a new emerging prodrug strategy in targeted drug delivery systems, consisting of peptides, linkers, and drugs. The mechanism of action varies depending on the types of peptides and linkers. Firstly, the peptide enters the cell by recognizing specific receptors on the cell surface, then the linker disintegrates under certain stimuli, releasing the drug and exerting its therapeutic effect. This prodrug strategy has the potential to improve the targeting of drugs and reduce the toxic side effects on other cells.

Advantages of peptide-drug conjugates

When comparing drug delivery approaches, one finds that the use of antibody-drug conjugates (ADCs) and peptide-drug conjugates (PDCs) share a construction strategy. However, the latter stands out due to its unique advantages.

Firstly, the small molecular size and high drug-loading capacity of peptides render them more adept at penetrating tumor stroma and infiltrating tumor cells. As an added benefit, peptides are highly biodegradable and do not prompt any immunogenic reactions in the body.

Furthermore, certain targeted peptides possess the ability to overcome tumor cell resistance by altering the drug's cellular entry mechanism, thereby achieving effective killing of drug-resistant tumors.

What's more, the structural flexibility of PDCs, attributed to their short peptide characteristics, enables them to undergo easier modification and conjugation with a range of drugs, such as chemical, protein, and peptide drugs. As a result, targeted drug preparation becomes more effective, significantly reducing off-target toxicity.

Lastly, the production process of peptide fragments remains simple and easily scalable, suggesting the vast potential of PDCs in the development of targeted drug delivery systems.

Clinical research progress of PDCs

Types and mechanisms of peptides

Peptides are an important component of PDCs and can be classified into cell-penetrating peptides (CPPs), cell-targeting peptides (CPTs), self-assembling peptides (SAPs), and responsive peptides based on their functions. CPPs are small and short molecular peptides that can enter cells without destroying the integrity of their membranes, usually composed of 5-30 amino acids. CPPs contain abundant basic amino acids such as arginine and lysine, which carry a positive charge in a physiological environment. In recent years, CPPs have been widely used in drug delivery systems. The mechanism by which CPP penetrates the cell membrane can be divided into two categories: endocytosis and direct translocation.

Cell-targeting peptides (CPTs) are defined as peptides that bind specifically to cells or tissues. There are generally two types of targeting delivery systems: passive targeting and active targeting. Passive targeting refers to the passive accumulation of drugs in diseased tissues through the properties of the delivery system itself (such as size, shape, charge) or the characteristics of the target tissue (such as poor blood vessel development or insufficient lymphatic tissue reflux) as they circulate through the bloodstream. Active targeting delivers drugs to diseased tissues by recognizing receptors or proteins that are specifically expressed in the target tissue and delivering drugs to the diseased tissue through receptor-ligand interactions. Most CPTs achieve drug delivery through active targeting.

Self-assembling peptides (SAPs) are peptides that spontaneously and selectively form one or more ordered structures from complex mixtures through non-covalent interactions (including van der Waals forces, electrostatic interactions, hydrogen bonds, and stacking interactions) without external stimuli. The type and arrangement of amino acids, the basic building blocks of peptides, form the basis of the self-assembling ability of peptides. In addition, the key to designing self-assembling peptides is to use a variety of molecular interactions, including hydrogen bonding, electrostatic interactions, π-π stacking, van der Waals forces, metal ligand complexes, and entropy. Peptides with self-assembling ability tend to be amphiphilic, aromatic, charge-dispersive, and have different symmetrical charge alternating arrangements. Compared to ordinary peptides, SAPs have the main advantages of biocompatibility, biodegradability, and multifunctionality.

Responsive peptides refer to peptides that undergo structural changes in response to external stimuli. These changes occur at the structural level, and are different from the self-assembling behavior of peptides. Responsive peptides require external environmental stimuli to undergo structural changes. Typically, external environmental stimuli include temperature, pH, enzymes, and so on. Generally, when tissues or organs undergo pathological changes, the physiological environment involved also changes. For example, in the case of tumors, due to excessive proliferation of tumor cells and incomplete development of blood vessels, tumor tissues are usually in a hypoxic environment, causing changes in their metabolic processes. Compared to aerobic metabolism in normal tissues, the metabolism of tumor tissues relies more on glycolysis, and the metabolic products lactate and CO2 produced by respiration together cause the acidification of the tumor microenvironment. The weakly acidic nature of the tumor microenvironment has also become a new method for targeting tumors. In recent years, the construction of PDCs based on responsive peptides has attracted the interest of many researchers.

Classification of linkers

As the connecting bridge between drugs and peptides, linkers determine the circulation time and stability of PDCs in the body. The ideal linker should remain stable in circulation to avoid premature drug release, while quickly and effectively releasing the drug when it reaches diseased tissue. The linker should not affect the affinity of the peptide for its receptor and drug activity.

The hydrophobicity of the linker should not be too strong to prevent PDCs from aggregating due to hydrophobicity, which would lead to poor stability and reduced efficacy in the body, as well as strong systemic toxicity and immune side effects. According to the drug release mechanism of the linker, the linker is mainly divided into non-cleavable linkers and cleavable linkers. Cleavable linkers include acid-labile linkers, enzyme-labile linkers, and disulfide linkers.

Drug for building PDCs

The payload of PDCs consists of drugs that have cell toxicity or therapeutic effects. Most of these drugs have disadvantages such as low solubility, poor selectivity, short half-life, and poor stability, which limit their clinical application. Drugs delivered through PDCs strategy need feasible attachment sites, no pharmacological activity upon binding, clear mechanism of action, strong pharmacological activity, and exert therapeutic effects after release in lesion tissue. When coupled with peptides, the solubility of the drug can be improved, drug selectivity can be promoted, in vivo circulation time can be prolonged, bioavailability can be optimized, and adverse effects and toxicity on other tissues can be prevented. Drugs used for PDC construction can be classified as chemical drugs, protein drugs, and peptide drugs. Chemical drugs include mitomycin, paclitaxel, camptothecin, methotrexate, cisplatin, etc., and protein drugs include interferon, tumor necrosis factor, which can achieve effective anti-tumor therapy by inducing apoptosis and inhibiting protein synthesis in cells. However, protein drugs have disadvantages such as poor in vivo stability, lack of targeting, and low bioavailability. Therefore, PDCs composed of the combination of peptides and protein drugs have become a new approach to solve this problem. Peptide drugs are a hot spot in new drug development in recent years.

Compared with traditional chemical and protein drugs, peptide drugs have obvious advantages:

1. Peptide drugs generally have higher activity;
2. Compared with protein drugs, peptide drugs have smaller molecular weight, are easy to synthesize artificially, and are easy to modify structurally;
3. The synthesis efficiency of peptide drugs is high. With the advancement of technology in recent years, solid-phase peptide synthesis is simple, highly automated, and easy to control;
4. Peptide drugs have fewer side effects.

Most peptide drugs have high homology with the human sequence, small molecular weight, no immunogenicity, and do not cause immune reactions. However, the disadvantages of peptide drugs are also obvious. Unlike chemical and protein drugs, the physicochemical properties of peptide drugs are unstable, easily oxidized and hydrolyzed, and prone to aggregation. In addition, the half-life of peptide drugs is short, and the clearance rate is fast, making it difficult to penetrate cell membranes.