Drug delivery strategies (https://www.creative-biolabs.com/targeted-delivery/) have greatly facilitated the treatment and application of drugs. The rapid development of therapeutics is dependent on the continuous pursuit of advances in delivery technologies and strategies. Decades ago, small molecule drugs were the predominant therapeutic agents, but their delivery was largely dependent on the physicochemical nature of their structure, which severely affected their bioavailability, so improving their solubility, controlling their release, optimizing their activity, and improving their pharmacokinetics were the first delivery issues to be addressed. Over time, a new generation of therapeutic approaches has emerged, including proteins, peptides, monoclonal antibodies, nucleic acids, and living cells, which offer new therapeutic capabilities. However, new challenges emerge, such as protein and peptide stability issues, nucleic acid delivery efficiency into cells, and live cell viability and expansion issues.

Recently, Samir Mitragotri's team published a review in the Nature Biomedical Engineering, systematically summarizing the drug delivery challenges associated with five classes of therapeutics—small molecules, nucleic acids, peptides, proteins, and cells, and three different strategies to face them.
First, modification from the drug itself.
Second, optimize the drug according to the environment in which it resides.
Third, creating delivery systems by controlling the interaction between the drug and its microenvironment.

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 need to be considered.

1: Self-modification of drugs
The use of self-modification is a relatively common strategy to enhance the efficiency of drug delivery. Small molecule drugs can be modified with functional groups, such as Ritonavir, a protease inhibitor for HIV treatment, has improved metabolic stability and water solubility with thiazole modification. Alternatively, active groups can be masked by modification, such as Lotensin, an alkyl ester prodrug that masks ionizable groups and increases overall lipophilicity.

For protein and peptide drugs, their stability can be improved by optimizing the sequence of amino acids and inserting unnatural amino acids. For example, desmopressin (DDAVP), an antidiuretic hormone analog, by replacing some natural amino acids with unnatural ones, the stability can be improved. Modification of PEG is a common way to increase the half-life and thus avoid rapid metabolism. For antibody-based drugs, immunogenicity can be reduced by humanizing the antibody sequence. Also, small molecules of toxins can be coupled to play a role in their delivery, such as the common ADC drugs.

For nucleic acid drugs, their drug stability can be improved by codon optimization as well as chemical nucleotide modifications. It is also possible to couple small molecules to improve the efficiency of nucleic acid drugs into cells, such as Givosiran, which is a GalNAc-siRNA coupling that promotes uptake by liver hepatocytes.

For cell therapy, cells can be immobilized at the site of the lesion, as in the case of autologous chondrocyte implantation (MACI), or delivered using particles and particulate implants, such as SIG-001 for hemophilia A, a new type of engineered human cell therapy that is protected with a biomaterial matrix that prevents rejection of the cells by the immune system and avoids foreign body reactions or fibrosis. It is also possible to genetically engineer bacteria to secrete drugs to treat disease.

2: Development of drug delivery devices

For small molecules, many delivery device systems have been developed, such as controlled release capsules, controlled release implants, inhalable devices, transdermal patches, stimulus-responsive drug release, and nanomaterials. For protein and peptide drugs, delivery systems have been developed such as controlled-release particle reservoirs, targeted transport systems, and non-invasive delivery systems such as Afrezza, an inhaled insulin nebulizer, and for nucleic acid drugs, lipid-based nanoparticle carrier systems (https://www.creative-biolabs.com/targeted-delivery/delivery-system-based...) for mRNA vaccines and viral vectors are commonly seen. There are also polymer-coupled vector delivery systems.

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

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