Recently, Samir Mitragotri's team published a review in Nature Biomedical Engineering, systematically summarizing five types of therapeutic drugs, which are small molecules, nucleic acids, peptides, proteins, and cells, as well as related drug delivery challenges and three measures taken to face these challenges.
Modify the drug itself.
Optimize the drug according to the surrounding environment where the drug is located.
Create a delivery system (
) by controlling the interaction between the drug and its microenvironment.

The biggest problem facing small molecule drugs is to control 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 controlling PK parameters like small molecules is a key challenge, how to improve structural stability and how to achieve non-invasive drug use are also worth considering. Protein and nucleic acid drugs are highly immunogenic, and reducing immunogenicity is a problem that cannot be ignored. The problem of bypassing biological barriers of protein drugs also needs to be solved. Similarly, how nucleic acid drugs can enter cells more easily is also a big headache. In recent years, emerging live-cell drugs are facing problems of persistence and viability in the body, immunogenicity problems, fixation problems in the focus of the disease, maintenance and treatment of cell phenotype problems, and the problems of manufacturing and scale-up production that have to be resolved.

Optimize the drug according to the surrounding environment where the drug is located.
Some functional groups of small molecule drugs can be modified. For example, Ritonavir is a protease inhibitor for HIV treatment, metabolic stability and water solubility can be improved after modification with thiazole. Or it can be modified to mask some active groups. For example, Lotensin, an alkyl ester prodrug, can mask ionizable groups and increase the overall lipophilicity.

For protein and peptide drugs, the sequence of amino acids and insert unnatural amino acids can be optimized to improve their stability.

For nucleic acid drugs, codon optimization and chemical nucleotide modification can be used to improve drug stability.

Small molecule drugs can increase solubility by adding solubilizing excipients.

Development of drug delivery systems
For small molecules, many delivery systems have been developed, such as controlled-release capsules, controlled-release grafts, inhalable devices, transdermal patches, stimulus-responsive drug release, and nanomaterials. For protein and peptide drug delivery systems, there are controlled release microparticle reservoirs, targeted delivery systems, and non-invasive delivery systems such as inhaled insulin powder Afrezza. For nucleic acid drugs, currently the lipid-based nanoparticle carrier system for mRNA vaccines and the viral vector are commonly seen. There are also polymer-coupled carrier delivery systems and so on.

Delivery strategies have greatly promoted the treatment and application of drugs. The rapid development of drug therapy is inseparable from the continuous pursuit of progressive delivery technologies and strategies. Decades ago, small molecule drugs were the most important therapeutic drugs, but their delivery largely depends on the physicochemical properties of their structure, which seriously affects the bioavailability of drugs, so improving the solubility of drugs, controlling their release, optimizing their activity, and improving their pharmacokinetics are the first delivery problems to be solved. As time lapses, a new generation of therapeutics continues to emerge, including proteins, peptides, monoclonal antibodies (mAbs), nucleic acids, and living cells, which provide 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 expansion of living cells. To meet these challenges, drug delivery strategies must continue to innovate.

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