History of drug delivery evolution

Drug delivery strategies have greatly aided drug therapy and administration. Small molecule drugs were the most common therapeutic agents decades ago, but their delivery was largely dependent on the physicochemical nature of their structure, which had a significant impact on their bioavailability. As a result, the first delivery issues to be addressed were improving their solubility, controlling their release, optimizing their activity, and improving their pharmacokinetics. Proteins, peptides, monoclonal antibodies, nucleic acids, and living cells have all developed as new therapeutic techniques over time, offering new therapeutic capabilities.

In a review published in the internationally recognized journal Nature Biomedical Engineering, Samir Mitragotri's team systematically summarizes the drug delivery challenges associated with five classes of therapeutics—small molecules, nucleic acids, peptides, proteins and cells, and three different strategies to address these challenges.

• Modification from the drug itself
• Optimization of the drug according to the surrounding environment in which it is placed
• Create delivery systems by controlling the interaction between the drug and its microenvironment

Challenges

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. The toxicity of off-target drugs is also an issue of concern.

For proteins, peptides, antibodies and nucleic acids, in addition to the key challenge of controlling PK parameters like small molecules, it is also worth considering how to improve structural stability and how to achieve non-invasive drug delivery. It is well known that the immunogenicity of protein as well as nucleic acid drugs is high and reducing the immunogenicity is a problem that cannot be ignored. Protein drugs also need to solve the problem of bypassing the biological barrier, and similarly, how to enter the cells more easily for nucleic acid drugs is also a big headache. For the emerging live-cell drugs in recent years, there are issues of persistence and viability in vivo, immunogenicity, fixation at the focal site, maintenance of the therapeutic cell phenotype, and manufacturing and scale-up issues that have to be considered.

Modification from the drug itself

• Small molecule drugs can be modified by changing some functional groups, or by hiding some active groups.
• For protein and peptide drugs, their stability can be enhanced by optimizing the sequence of amino acids and inserting unnatural amino acids.
• For nucleic acid drugs, their stability can be improved by codon optimization as well as chemical nucleotide modifications.
• For live cell therapy, either by immobilizing the cells at the site of the lesion or by delivering the cells using particles and particulate implants.

Optimization of the drug according to the surrounding environment in which it is placed

Adding solubilizing excipients to small molecule drugs can improve their solubility. Alternatively, by limiting the clearance pathway, the drug concentration can be enhanced. Protease inhibitors can prevent protein and peptide drugs from succumbing to fast degradation. It's also possible to implement pH modifiers.

Create delivery systems by controlling the interaction between the drug and its microenvironment

Many delivery systems for small molecule drugs have been developed, including controlled release capsules, implants, inhalable devices, transdermal patches, stimulus-responsive drug release, and nanomaterials. For protein and peptide drugs, delivery systems such as controlled-release particle reservoirs, targeted transport systems, and non-invasive delivery systems such as Afrezza, an inhaled insulin nebulizer, have been developed, while for nucleic acid drugs, there are lipid-based nanoparticle carrier systems for mRNA vaccines and viral vectors for the Johnson & Johnson's COVID-19 vaccine have been developed. Polymer-coupled vector delivery systems, for example, are available.

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