Combination therapy of macromolecules and small molecules: approaches, advantages, and limitations

Abstract Macromolecule therapeutics (proteins, nucleic acids) are oligomeric molecules that have bypassed some limitations of small molecule therapeutics. Small molecules have untargeted actions and require complicated production processes. Macromolecule therapeutics are designed to target a specific ligand or messenger molecule, which leads to reduction of unwanted adverse effects. They have high affinity for their targets, so a small quantity of macromolecule therapeutics is needed for target recognition. Their production skips many complicated chemical processes and they can be designed to target any molecule in the body. However, the stability and delivery of macromolecules may also limit the application of this promising biomolecule. Proteins and nucleic acids are susceptible to protease and nuclease degradation, respectively. They cannot pass through the cell membrane directly, so they need some modifications or appropriate carriers that preserve them from harsh in vivo conditions and pass them through cell membrane. Combination therapy of macromolecules and small molecules has synergistic action on improving the efficiency of therapy. Additionally, targeting nanocarriers based on macromolecules can also be used for delivering small molecules with less adverse effect. This strategy is applicable in cancer treatment in order to reduce the adverse effects of chemotherapy. In this chapter, different groups of macromolecules alone or in combination with small molecule drugs are discussed.