Release date:2022/6/30 17:28:01

Drug delivery strategies have greatly promoted the treatment and application of drugs. The rapid development of drug therapy is inseparable from the continuous pursuit of improved delivery technologies and strategies. A few decades ago, small-molecule drugs were the most important therapeutic drugs, but their delivery largely depends on the physicochemical properties of their structures, which severely affects the bioavailability of drugs, thus improving the solubility of drugs and controlling their release, optimizing their activity and improving their pharmacokinetics are the first delivery issues to be addressed.

As time goes on, a new generation of therapies has emerged, including proteins, peptides, monoclonal antibodies, nucleic acids and living cells, which offer new therapeutic functions. However, new functions inevitably bring new challenges, such as the stability of proteins and peptides, the efficiency of nucleic acid delivery into cells, and the viability and amplification of living cells.  To meet these challenges, drug delivery strategies must continue to innovate.

In April 2021, Samir Mitragotri's team published a review entitled The evolution of commercial drug delivery technologies in the internationally renowned journal "Nature Biomedical Engineering", which systematically summarized five classes of therapeutic drugs - small molecules, nucleic acids, proteins and peptides, antibodies and live cells - related drug delivery challenges and three different strategies for confronting them. First: Modify the drug itself. Second: Optimize the drug based on the surrounding environment in which the drug is located. Third: Create a delivery system by controlling the interaction between the drug and its microenvironment.

 five classes of therapeutic drugs

Five classes of therapeutic drugs

Challenges to face

The biggest problem for small molecule drugs is the control of PK parameters (especially half-life, biodistribution and maximum drug concentration), followed by solubility and permeability. At the same time, the toxicity problem caused by off-target is also a problem that needs attention. For proteins, peptides, antibodies and nucleic acid drugs, in addition to the key challenge of controlling PK parameters like small molecules, how to improve structural stability and how to achieve non-invasive drug delivery is also worth considering.  

As we all know, protein and nucleic acid drugs have high immunogenicity, and reducing immunogenicity is a problem that cannot be ignored. Protein drugs also need to solve the problem of bypassing biological barriers. Similarly, how nucleic acid drugs can enter cells more easily is also a big headache. In recent years, emerging living cell drugs are confronted with problems of persistence and viability in vivo, immunogenicity, fixation to focal sites, maintenance of therapeutic cell phenotypes, and scale-up of manufacturing.

Coping strategy 1 - Self-modification of drugs

 Drug modifications

Drug modifications

Self-modification is a common strategy to improve the efficiency of drug delivery. Small molecule drugs can modify some functional groups, such as Ritonavir, a protease inhibitor used in HIV treatment, but thiazole modification improves metabolic stability and water solubility. Or it can be modified to mask some of the active groups, such as Lotensin, an alkyl ester precursor, which masks ionizable groups and increases overall lipophilicity.  

For protein and polypeptide drugs, the self-stability can be improved by optimizing the amino acid sequence and inserting unnatural amino acids. For example, desmopressin (DDAVP), an vasopressin analog, replaces some natural amino acids with unnatural amino acids to improve stability. Modification of PEG is a common method to increase half-life and avoid rapid metabolism. For antibody-based drugs, immunogenicity can be reduced by humanizing the antibody sequence. At the same time, toxin small molecule drugs can be coupled to play their role in delivery, such as common ADC drugs.

For nucleic acid drugs, the drug stability can be improved by codon optimization and chemical nucleotide modification. At the same time, it can also be coupled with small molecules to improve the efficiency of nucleic acid drugs into cells, such as Givosiran, which is a GalNAc-siRNA conjugate, which can promote the uptake of liver cells.

For live cell therapy, it can be fixed in cells in focal areas, such as Matrix-induced Autologous Chondrocyte Implantation (MACI), or by delivering cells using microparticles and microparticle implants, such as SIG-001 for hemophilia A. This is a novel therapy of engineered human cells protected by a matrix of biomaterials that prevent the immune system from rejecting cells and avoid foreign body reactions or fibrosis. In addition, bacteria can be genetically engineered to secrete drugs to treat diseases.

Coping Strategy 2 - Optimizing drugs according to the environment in which they are administered

 Environmental modifications

Environmental modifications

The solubility of small molecule drugs can be increased by adding solubilizing excipients. Or increase the drug concentration by inhibiting the clearance pathway, such as the combination strategy of penicillin and probenecid, because probenecid can competitively inhibit the secretion of penicillin from the renal tubule, thereby affecting the excretion of penicillin. When the two drugs are combined, the secretion of penicillin can be inhibited, the blood concentration of penicillin can be increased, thereby enhancing the effect of penicillin.

For proteins and peptides, the fate of rapid degradation can be avoided by using protease inhibitors. PH modulators can also be used, such as the oral hypoglycemic drug semaglutide, which is unique in mixing it with a small molecule absorption enhancer called SNAC (Sodium N-(8-[2-Hydroxybenzoyl]amino)caprylate. The combination of SNAC and sommarutide allows sommarutide to be partially absorbed in the stomach.  The dissolution of SNAC in the stomach can improve the pH of the local environment, not only improve the solubility of somarutide, but also buffer the acidic environment in the stomach to resist the degradation of gastric peptidase. For antibody drugs, immunomodulators can be used to increase their effectiveness, such as Infliximab for rheumatoid arthritis, in combination with methotrexate.

Coping Strategy 3 - Developing Drug Delivery Devices

 drug delivery systems

Drug delivery systems

For small molecules, many delivery device systems have been developed, such as controlled-release capsules, controlled-release implants, inhalable devices, transdermal patches, stimuli-responsive drug release, and nanomaterials. Delivery systems for protein and peptide drug development include controlled-release microparticle depots, targeted delivery systems, and non-invasive delivery systems such as Afrezza, an inhaled insulin powder. For nucleic acid drugs, we are currently more familiar with the lipid-based nanoparticle carrier system of mRNA vaccines and the viral carrier of Johnson & Johnson's COVID-19 vaccine. There are also polymer-coupled carrier delivery systems and so on.

 Drug delivery systems

Drug delivery systems


Drug delivery technologies have enabled the development of many pharmaceutical products that improve patient health by enhancing the delivery of therapeutic drugs to their targets, minimizing off-target accumulation, and promoting patient compliance. As therapeutic modalities expand from small molecules to include nucleic acids, peptides, proteins and antibodies, more innovative drug delivery technologies are being used to address the challenges faced by emerging drugs.

Biopharma PEG provides a variety of PEG products or activated PEG derivatives, that are crucial ingredients in the art of PEGylation. Biopharma PEG 's dedicated and experienced PEGylation group meets your unique PEGylation needs for proteins, peptides, oligonucleotides, and small molecules. We provide PEG linkers from lab to GMP commercial scale for your drug delivery. 


The evolution of commercial drug delivery technologies

Related articles:
[1]. Advantages and Disadvantages of PEGylated Liposomes in Drug Delivery System     
[2]. The Evolution of 5 Therapeutic Drug Delivery Technologies


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