Small molecule-drug conjugates (SMDCs) have become a new strategy for cancer targeted therapy. In general, SMDC is composed of a targeted molecule, a linker and an effective molecule such as cytotoxic molecule or E3 ligase, this composition is similar to antibody drug conjugates (ADC). While the most direct difference between SMDC and ADC is the targeting molecule, with ADC using biological antibodies for drug targeting, SMDC takes small molecule targeting. SMDCs provide a novel approach to deliver drug for cancer.

SMDCs have their own advantages. Firstly, SMDCs are composed of small molecules, which is easy to control the synthesis process and cost, and the industrial operation is simple compared with antibody drugs. Secondly, SMDCs are not immunogenic in theoretical with easier safety control. Moreover, the molecular weight of SMDC is much lower than that of ADC, which can provide better cell permeability and in vitro and in vivo stability in solid tumors. However, SMDCs face the intractable problem of oral formulation. Similar to ADCs, almost all SMDCs will likely be administered by injection, which can be a very inconvenient drawback for clinical applications, especially in the absence of significant therapeutic advantages over oral small molecules in the same indications.

Although SMDCs are not well established in the field of targeted drugs, it still attracts increasing interest, and SMDCs might be served as a promising alternative approach to antibodies for drug delivery and tumor therapy.

Targeting ligand

Targeted ligands of SMDCs play a role similar to that of the antibody of ADCs. SMDC ligand design requires consideration of target selectivity, binding affinity and compound size. The selectivity and specificity are important in the design of drug couples, since the original purpose of both SMDC and ADC is to reduce the toxicity of the payload to normal cells. The increased binding affinity of the targeting ligand reasonably reduces the drug dose required to achieve efficient therapy. The ligand size of SMDC should not be neglected either, the size of SMDC molecules can affect drug delivery to solid tumors through different mechanisms, including permeability. Low molecular weight therapeutic drugs are more likely to be released and allow independent diffusion into the tumor. Also, low molecular weight SMDCs are easily metabolized, as off-target drugs are usually excreted from the body in a timely manner, thereby reducing adverse toxicity in normal cells.

SMDC drug target diversity is not very rich. At present, SMDCs targeting folate receptor are well studied. Other targets related to SMDCs, including prostate specific membrane antigen (PSMA), somatostatin receptor (SSTR), glucose transporter 1 (GLUT1), aminopeptidase N (APN), and low-density lipoprotein receptor-related protein 1 (LRP1), etc., have also been reported in clinical or preclinical trials.

Linker

The targeting ligand and the therapeutic payload of SMDC are connected by a linker which usually contains a spacer and a cleavage group. In order to preserve the activity of the targeting ligand and payload efficacy, the linker should be designed to optimize functions such as drug release and pharmacokinetics. Spacer is used to linked the targeting ligand to the cleavable group, and it is importance for SMDC binding to receptor. In addition, another function of the spacer is to improve the hydrophilicity of SMDCs. Targeted ligands and therapeutic payloads are usually hydrophobic to maximize membrane permeability and receptor affinity. The use of water-soluble spacer groups, such as polysaccharides, PEGs and peptidoglycans, confers improved hydrophilicity to SMDCs.

Efficiency of SMDC depends on the ability of the cleavable group to release cytotoxic drugs from the SMDC at predicted cleavage sites and rates after penetration of the target cell. There are two methods for drug releasing in SMDC, the one uses the disulfide bond as release linker, the other one designs cleavers which are sensitive to target cell pH based on differences in pH environment in vivo, such as acetal can be hydrolyzed in an acidic environment in vivo.

Payload

The small molecule payload or active drug is a core part of SMDC, and for the selection of the payload, several aspects need to be considered, such as the release rate of the payload from the SMDC molecule, the cellular activity of the payload and intracellular stability, and the high binding power.

Mechanism of action

In terms of mechanism of action, SMDCs are also highly consistent with ADCs. Take SMDCs targeting folate receptors as an example, SMDCs do not enter cells through reduced folate carrier channels like normal cells absorb folate, but enter cells through endocytosis by binding to high affinity folate receptors, and then cleave and release cytotoxic molecules to killing tumor cells, while folate receptors are recycled to the cell surface again.