Clinical Application and Development of 7-Ethyl-10-hydroxycamptothecin

7-Ethyl-10-hydroxycamptothecin (SN 38) is a semi-synthetic camptothecin compound and the active ingredient of irinotecan. It is a clinically approved chemotherapy drug belonging to the topoisomerase I inhibitor class. Its mechanism of action has been extensively studied in various cancer cell types; it stabilizes the topoisomerase I-DNA complex, thereby arresting the cell cycle and promoting apoptosis. Therefore, it is often used to prepare nanodelivery systems and antibody-drug conjugates (ADCs) for the treatment of cancer patients.

Nanodelivery Systems

Although 7-Ethyl-10-hydroxycamptothecin exhibits extremely high antitumor activity, it is highly hydrophobic and readily hydrolyzed to its inactive carboxylate form. This is because its synthesis involves introducing a dipiperidine side chain at the C10 hydroxyl group to improve water solubility, resulting in the well-known chemotherapy drug irinotecan. The carbamate bond of this side chain can be hydrolyzed by carboxylesterases, primarily found in the liver, releasing SN-38, which is 1000 times more potent than irinotecan. However, once hydrolyzed, this site can also be rapidly glucuronidated, mainly catalyzed by uridine diphosphate glucuronide transferase UGT-1A. Therefore, to protect the drug's bioactivity, researchers dissolved SN-38 in an organic solvent and embedded it into human serum albumin (HSA) or its derivatives (such as HSA-PLA) using high-pressure homogenization or self-assembly techniques to form a nanoparticle core. This encapsulation strategy effectively maintained the cytotoxic activity of low concentrations of SN-38 under physiological conditions. HSA-PLA nanoparticles were non-specifically taken up by various cancer cells through macropinocytosis, ensuring the broad applicability of SN-38 encapsulated in these nanoparticles. Moreover, these nanoparticles exhibited superior efficacy both in vitro and in vivo compared to cPt-11. Leveraging the high permeability and retention effect (EPR effect) of tumor tissue, albumin nanoparticles can carry SN-38 and accumulate more at the tumor site rather than distributing it in the digestive tract, thus significantly reducing the severe delayed diarrhea toxicity commonly associated with irinotecan.

Antibody-Drug Conjugates (ADCs)

7-Ethyl-10-hydroxycamptothecin, with IC50 values of approximately 1.0–6.0 nM against various human cancer cell lines, was used as the cytotoxic load for this ADC. By binding SN-38 to a humanized anti-trophoblast surface antigen 2 (TROP-2) antibody, which is involved in cancer signaling pathways and is highly expressed in various cancer cells, the ADC drug Sacituzumab govitecan was developed for the treatment of patients with advanced refractory breast cancer, lung cancer, and bladder cancer. Because SN-38 is membrane permeable, when the ADC is intracellularly endocytosed by the target cell and releases SN-38, the drug can diffuse out of the target cell and kill the surrounding "neighboring" tumor cells that do not express TROP-2, thus solving the problem of drug resistance caused by tumor heterogeneity.

References:

[1] GUOJUN XIONG. Albumin-based nanoparticles encapsulating SN-38 demonstrate superior antitumor efficacy compared to irinotecan.[J]. Drug Delivery, 2025, 32 1: 2545519. DOI:10.1080/10717544.2025.2545519.

[2] DAVID M GOLDENBERG; Robert M S. Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan.[J]. mAbs, 2019, 11 6: 987-995. DOI:10.1080/19420862.2019.1632115.

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