Drug Modification
Drug modification involves altering the chemical structure of the drug itself (such as functional groups, amino acids or nucleic acid skeletons) and coupling the drug with known partial or targeted ligands. The aim is to regulate the interactions between drugs and molecules, cells, tissues and drugs and targets in vivo, allowing some degree of control over the distribution and handling of drugs in vivo, from initial administration to their intended function. Drug modifications can be used to improve delivery of all classes of therapy. (Table 1)
The physicochemical properties of small molecules can be controlled by introducing molecular bodies or direct chemical structure change, such as lidocaine has improved efficacy, toxicity and function (a duration of alkaloid isogramine derivatives) and fentanyl (a kind of high efficient opioids, and its therapeutic index is better than that of morphine and its parent compound pethidine). These lay the foundation for medicinal chemistry and facilitate high-throughput screening techniques that allow rational design and selection of desirable molecular properties. These methods can also be used for the development of new therapeutics, such as high-throughput screening methods for protein and peptide drugs to obtain molecules with desirable properties.
Peptide and protein drugs also require new modification strategies such as PEG modification to improve circulation time and immunogenicity. Drug modifications are important for insulin delivery, such as long-acting agents of insulin glygine (Lantus, a modified human insulin with PH-dependent solubility that forms microprecipitates in the subcutaneous space), insulin deglutin (Tresiba, an acylated insulin analogue that can form a high molecular weight complex) is achieved by rational modification of the insulin structure. In these formulations, insulin monomers are released slowly from a subcutaneous reservoir to mimic the natural process of hom-mediated insulin secretion, reducing injection frequency and the risk of hypoglycemia and improving glycemic control.
The development of mAb technology has promoted the success of ADCs in addressing the cytotoxicity, off-target toxicity and lack of tissue-specific delivery of many small molecule drugs. ADCs also benefits from advances in small molecule and antibody drug modification technology. Nucleic acid therapies also benefit from conjugation strategies, with the recently launched GalNAc-siRNA conjugate being the best example. The success of conjugation chemistry of nucleic acids is the result of a combination of bioorthogonal reactions and the introduction of conjugate molecules as non-nucleoside monomers during oligonucleotide synthesis. In particular, chemical modifications to the 2′ hydroxyl of ribose, polyadenylation of the 3′ end and displacement of phosphodiester bonds to control the effect of nucleic acid drugs.
In summary, drug modifications provide new functions for various therapies by improving the stability of drugs in physiological and humoral fluids, controlling the interactions between drugs and individual cells, and changing the interactions between drugs and targets. Drug modifications have been able to address the changing structural complexity, specificity, and function of various agents and are now being used in the further development of cell therapies.
Table 1 Drug modifications and selected clinical examples
| Class of Therapeutic | Modification | Example |
| Small Molecules | Modification of functional group | Ritonavir |
| Masking undesirable chemical groups | Benazapril | |
| High-throughput and combinatorial chemistry libraries | Ezetimibe | |
| Conjugation of targeting ligands | Vintafolide | |
| PEGylation | Naloxegol | |
| Peptides and proteins | Alterations to the amino acid sequence | Belatacept |
| Alterations of intramolecular bonding | Cyclosporine A | |
| Addition of non-natural amino acids | Desmopressin | |
| Chemical backbone modifications | Cyclosporine A | |
| PEGylation | Pegademase bovine | |
| Antibodies | Affinity maturation and variable-region engineering | Ramucirumab, Obinutuzumab |
| Antibody humanization | Daclizumab, Panitumumab | |
| Modification of Fc binding to the neonatal Fc receptor | MEDI4893, Ravulizumab | |
| Modification of antigen binding for pH responsiveness | Ravulizumab | |
| Conjugation to PEG | Certolizumab pegol | |
| Conjugation to small molecules | Brentuximab vedotin | |
| Nucleic acids | Codon optimization and chemical nucleotide modification | Patisiran, Givosiran, Nusinersen |
| Chemical backbone modifications | Fomivirsen, Givosiran | |
| Conjugation to targeting ligands | Givosiran |
Microenvironmental Regulation
Microenvironmental modifications include a range of approaches ranging from highly targeted alterations of the site of action to systemic delivery adjuvants that alter the host environment. Microenvironmental modification is a broad drug delivery strategy that facilitates drug penetration through biological barriers. (Table 2)
Small molecules can improve the humoral solubility of drugs by introducing excipients to change local pH. Due to their large size and limitations on crossing epithelial barriers, biologic agents require osmotic promoters, subcutaneous dispersion enhancers, and other environmental regulators to promote systemic absorption. Nucleic acids can enter intracellular loci and limit their interaction with target genes. Therefore, strategies such as modification to accommodate intracellular pH, introduction of cell-penetrating peptides and cationic lipids improve cellular uptake, intracellular escape, and nuclear targeting. Microenvironmental modulators may also be used to alter humoral or mechanical processes that impede drug action.
Small molecule drugs improve drug absorption in the small intestine by adding excipients to prolong intestinal transport time or by actively inhibiting specific metabolic mechanisms to increase drug circulation time. PH regulators, such as citric acid, inhibit proteolysis and improve the stability of proteins and peptides in body fluids. In addition, whole-administered steroids have been used to modulate the immune environment and prevent harmful reactions to protein and nucleic acid therapies. In summary, microenvironmental modification can guide therapeutic agents through biological barriers and improve their efficacy in diseased tissues, and this approach is also used in living cell therapy.
Table 2 Environmental modification and selected clinically relevant examples
| Class of Therapeutic | Modification | Example |
| Small Molecules | Addition of solubilizing excipients | Ciprofloxacin |
| Inhibition of clearance pathways | Co-administration of penicillin and probenecid | |
| Inhibition of drug metabolism | Not yet in clinical trials | |
| Peptides and proteins | Use of protease inhibitors | Calcitonin-salmon |
| Use of pH modifiers | Semaglutide, Calcitonin-salmon | |
| Use of permeation enhancers | Semaglutide, Octreotide | |
| Use of Immunomondulators | Enzyme replacement therapy co-administered with methotrexate in Pompe disease | |
| Use of hyaluronidases | Hylenex administration with insulin | |
| Antibodies | Use of enzyme inhibitor | Not yet in clinical trials |
| Use of pH modifiers | Adalimumab | |
| Use of permeation enhancers | Not yet in clinical trials | |
| Use of Immunomondulators | Infliximab co-administration with methotrexate | |
| Use of dispersion enhancers | Trastuzumab and hyaluronidase-oysk | |
| Nucleic acids | Use of Immunomondulators | Patisiran, Givosiran |
| Use of endosomal-pH modifiers | Not yet in clinical trials | |
| Use of endosomal-release agents | Patisiran |
Drug Delivery System
Modifications to drugs and their microenvironments can adjust and optimize drug activity. Drug delivery system can combine the advantages of the above two strategies by establishing the interaction between drugs and their microenvironment. (Table 3)
PK parameters, biodistribution, half-life, drug exposure within a certain period of time and maximum plasma concentration can be changed by changing the in vivo release rate of a drug. Although these parameters can also be affected by changing the dose, frequency and infusion speed, the controlled release system can achieve a higher level of regulation. Controlled drug release systems include hydrogels and polymer implants based on four controlled release mechanisms of dissolution, diffusion, infiltration and ion exchange, particles and nanoparticles (which can be modified by particle surface to improve drug half-life and achieve specific tissue targeting through specific interactions with the microenvironment). In addition, controlled drug release systems can reformulate small molecule preparations to achieve controlled drug release, such as the formulation of the calcium channel blocker nifedipine, which can prolong drug efficacy and reduce side effects. Polymers with controlled degradation, erosion, and in situ formation are the basis of many controlled drug release systems, such as pH-responsive enteric-coated capsules that release loaded drugs at specific sites in the gastrointestinal tract, demonstrating the core advantage of drug delivery systems: physical protection from adverse environmental effects. Controlled release systems have been used for many small molecule agents, such as the fentanyl transdermal patch Duragesic for noninvasive systemic delivery of the opioid fentanyl, in which ethanol acts as an osmotic promoter.
Table 3 Drug delivery system and selected clinical examples
| Class of Therapeutic | System | Examples |
| Small Molecules | Controlled-release capsules | Methylphenidate HCl, Fexofenadine and pseudoephedrine |
| Controlled-release implants | Etonogestrel implant, Fluocinolone | |
| Inhalable devices | Albuterol inhalation, Budesonide/formoterol | |
| Transdermal patches | Fentanyl transdermal system, transdermal nicotine | |
| Stimuli-responsive drug release | Verteporfin for injection | |
| Microparticles | Risperidone | |
| Nanoparticles | Doxorubicin, Protein-bound paclitaxel | |
| Targeted delivery | Ado-trastuzumab emtansine | |
| Peptides and proteins | Controlled-release microparticle depots | Leuprolide acetate, Somatropin |
| Targeted delivery systems | No clinical products yet | |
| In-situ-forming polymer matrix | Leuprolide acetate | |
| Implants | Leuprolide acetate implant | |
| Non-invasive delivery systems | Inhalation powder of human insulin, Semaglutide | |
| Antibodies | ADCs | Brentuximab vedotin, ado-trastuzumab emtansine |
| Minimally invasive subcutaneous injections combining humanized antibodies with dispersion enhancers | Trastuzumab and hyaluronidase-oysk | |
| Non-invasive delivery systems | Inhalation power of anti-IL-13 antigen-binding fragment | |
| Nucleic acids | Lipid-based nanparticles | Patisiran, mRNA COVID-19 vaccines |
| Viral vectors | Recombinant human p53 adenovirus, Janssen COVID-19 vaccine | |
| Polymer conjugates | Pegaptanib | |
| Targeting-ligand conjugates | Givosiran |
With the development of drugs from small molecules to peptides and proteins, to nucleic acid drugs, and finally to live cell therapy, drug delivery technology has made new progress. Various therapeutic challenges can be addressed by drug modification and microenvironmental regulation. In fact, multifunctional delivery systems improve the delivery efficiency of many drug types by combining drug modification and microenvironmental regulation to achieve better regulation of drug action.