camptothecin

Overview

Camptothecin (CPT) is a naturally occurring cytotoxic monoterpene indole alkaloid first isolated from the bark and wood of Camptotheca acuminata (the "happy tree"), a deciduous tree native to southern China. Its core mechanism of action centers on the inhibition of topoisomerase I (Top1), an enzyme essential for relieving torsional stress in DNA during replication and transcription. Camptothecin stabilizes the transient Top1–DNA cleavage complex, preventing DNA re-ligation and causing irreversible strand breaks that ultimately trigger apoptosis in rapidly dividing cancer cells. Due to its potent antiproliferative activity, CPT has served as the chemical scaffold for several clinically approved derivatives, including irinotecan, topotecan, and the more recent exatecan, which retain the core lactone pharmacophore while addressing the pharmacokinetic limitations of the parent compound.

Beyond its direct clinical use, camptothecin occupies a central role in contemporary oncology drug development as a payload in antibody-drug conjugates (ADCs). Its high cytotoxic potency at picomolar concentrations makes it an attractive warhead when precision tumor targeting is required. The compound's reactivity, limited aqueous solubility, and narrow therapeutic window have driven sustained innovation in prodrug design, linker chemistry, and nanoparticle-based delivery systems, establishing CPT as one of the most intensively engineered small molecules in translational cancer research.

Focus of Latest Publications

Recent publications have focused on camptothecin as a cytotoxic payload in stimulus-responsive delivery systems designed to improve selectivity, reduce systemic toxicity, and enable imaging-guided therapy. Several studies coupled camptothecin to nanostructures or prodrug platforms that respond to tumor- or disease-associated microenvironmental cues, including acidic pH, γ-glutamyl transpeptidase, glutathione, hypochlorous acid, and reactive oxygen species. Across these reports, camptothecin was used to test whether controlled release could preserve antitumor activity while improving solubility, stability, and tissue specificity.

In one study, camptothecin was incorporated into an HOCl-activated acyl hydrazide prodrug platform, where the camptothecin conjugate DHU-OH-6 showed improved aqueous solubility and reduced intrinsic cytotoxicity relative to free camptothecin, while retaining efficient HOCl-triggered release of the active drug. The same platform enabled fluorescence imaging of exogenous and endogenous HOCl and supported fluorescence-guided therapy in an imiquimod-induced psoriasis mouse model, where it alleviated skin lesions and reduced systemic toxicity compared with free camptothecin. Another report described a tandem-responsive dendritic dot in which camptothecin was covalently conjugated to a Cy5-containing polylysine dendrimer; sequential activation by acidic pH and γ-glutamyl transpeptidase exposed amines that promoted camptothecin release and turned on fluorescence, resulting in enhanced cellular transcytosis and potent antitumor activity in vitro and in vivo against hepatocellular carcinoma.

Additional work developed a γ-glutamyl transferase/glutathione cascade-responsive unimolecular nanoprodrug in which camptothecin was linked through glutathione-cleavable moieties and decorated with a γ-glutamyl transferase-responsive surface group to improve uptake and tumor selectivity. This system was reported to show satisfactory cancer/normal cell selectivity, safety, and anticancer efficacy in vitro and in vivo. A separate ROS/pH dual-responsive nanosystem, CPT@EZ@HP, encapsulated camptothecin within Zn2+-epigallocatechin gallate metal-phenolic coordination structures and used phenylboronic acid-conjugated hyaluronic acid for CD44-targeting and ROS responsiveness; in liver fibrosis models, it targeted activated hepatic stellate cells, scavenged ROS, promoted macrophage polarization toward the M2 phenotype, and released camptothecin under acidic conditions to inhibit HIF-1α-mediated glycolysis and suppress fibrotic progression.

Camptothecin also appeared in broader oncology prodrug and ADC design efforts. A Tyrosinase-responsive prodrug strategy introduced a Tyrosinase-specific recognition unit into camptothecin and doxorubicin constructs, but only the doxorubicin prodrug showed efficient Tyrosinase activation and improved melanoma selectivity, indicating that the camptothecin version did not exhibit similar activity under the reported conditions. In parallel, discovery chemistry efforts on camptothecin-based linker-payloads for antibody-drug conjugates identified novel N-linked camptothecin derivatives with favorable biophysical properties, in vitro potency, and strong target-mediated in vivo efficacy. Collectively, these publications emphasize camptothecin’s continued role as a benchmark topoisomerase I-targeting payload and as a scaffold for engineering responsive prodrugs and conjugates with improved therapeutic performance.

Key Publications

• Jun An HOCl-Activated Acyl Hydrazide Platform for Fluorescence-Guided Release of Hydroxyl-Containing Drugs. (Analytical chemistry, 2026, PMID 42224648): "As a representative therapeutic application, we designed a camptothecin (CPT) conjugate, DHU-OH-6, which exhibits markedly improved aqueous solubility and reduced intrinsic cytotoxicity compared to CPT, while retaining efficient HOCl-triggered release of the active drug."
• May A Tandem-Responsive and Multifunctional Dendritic Dot for Acid and γ-Glutamyl Transpeptidase-Activated Cancer Theranostics. (Small (Weinheim an der Bergstrasse, Germany), 2026, PMID 42143689): "Utilizing a polylysine dendrimer with a Cy5 core and covalently conjugated camptothecin (CPT), Cy5 fluorescence is initially quenched by CPT via photoinduced electron transfer (PET) ("off" state)."
• May Enhancing camptothecin biosynthesis in Camptotheca acuminata through CrLAMT transfer from Catharanthus roseus. (Biotechnology letters, 2026, PMID 42138768): "Camptothecin (CPT), a monoterpene indole alkaloid with significant anticancer properties, is primarily sourced from Camptotheca acuminata."
• Jun γ-Glutamyl Transferase/Glutathione Cascade-Responsive Unimolecular Nanoprodrug for Precise Cancer Chemotherapy. (Biomacromolecules, 2026, PMID 42068279): "The toxic drug camptothecin was covalently conjugated to the nanostructures through glutathione cleavable linkers to allow for potent release in tumors."
• May Discovery of Novel N-Linked Camptothecin Linker-Payloads to Access Antibody-Drug Conjugates with High Target-Mediated In Vivo Efficacy. (Journal of medicinal chemistry, 2026, PMID 42059187): "We describe a discovery chemistry campaign for novel camptothecin-based linker-payloads enabling high drug-to-antibody ratio (DAR) ADCs with good biophysical properties, good in vitro potency, and strong in vivo efficacy."
• Apr A general tyrosinase-responsive prodrug strategy: design and synthesis of melanoma-selective anticancer agents. (Bioorganic & medicinal chemistry, 2026, PMID 41955916): "By introducing a TYR-specific recognition unit into the molecular structures of doxorubicin (DOX) and camptothecin (CPT) and coupling them via a self-immolative linker, two potential prodrugs, TYR-DOX and TYR-CPT, were successfully designed and synthesized."
• Mar Rational design and synthesis of flavonolactam derivatives as potent topo I inhibitors with antitumor activity. (European journal of medicinal chemistry, 2026, PMID 41934689): "Notably, NL-26 displayed the most potent Topo I inhibitory activity, which was comparable to that of the reference inhibitor camptothecin (CPT)."
• Apr Learnings from Approved Antibody-Drug Conjugates: Clinical Pharmacology Perspectives. (Journal of clinical pharmacology, 2026, PMID 41906492): "DDI potential has been reported for payloads associated with auristatins, maytansinoids, and camptothecin: SN38."
• Mar Metal-phenolic nanoparticles with ROS/pH dual-responsiveness for liver fibrosis therapy via synergistic microenvironment remodeling and metabolic reprogramming. (Colloids and surfaces. B, Biointerfaces, 2026, PMID 41819037): "The nanosystem utilized Zn2+ -epigallocatechin gallate (EGCG) metal-phenolic coordination to encapsulate camptothecin (CPT), followed by surface modification with phenylboronic acid-conjugated hyaluronic acid to impart CD44-targeting and ROS-responsive properties."