Abstract: Camptothecin (CPT) and its derivatives, such as 10-hydroxycamptothecin (HCPT) and SN-38, are potent natural alkaloids that exhibit significant anticancer activity by targeting intracellular topoisomerase I. Despite their high efficacy and broad anticancer spectrum, the clinical application of these compounds has been historically limited by poor water solubility, lactone ring instability, and systemic toxicity. Recent advances in biomedical nanotechnology and combination therapies have provided innovative strategies to overcome these challenges. This review explores the pharmacological activity, molecular mechanisms, and structure-activity relationships of CPT and its derivatives. It highlights the development of various nano-drug delivery systems—including organic, inorganic, and carrier-free nanoparticles—and their integration into combination therapies such as chemo-photodynamic, chemo-photothermal, and targeted antibody-drug conjugates (e.g., sacituzumab govitecan). Furthermore, current limitations, including chemotherapy-induced intestinal mucositis and nanomedicine translational barriers, are discussed alongside future perspectives for optimizing CPT-based anticancer therapies.
1. Introduction
Cancer treatment involves multiple modalities, including conventional radiotherapy and chemotherapy, but these approaches often suffer from limited efficacy and severe side effects [1]. Natural compounds serve as a valuable resource for discovering novel, safe alternatives to synthetic drugs. Among these, alkaloids have shown potent apoptotic and antitumor abilities [1]. Camptothecin (CPT), a natural plant alkaloid isolated from Camptotheca, and its derivatives like 10-hydroxycamptothecin (HCPT) and SN-38 (the active metabolite of irinotecan), are highly potent anticancer agents [1][5]. HCPT, for instance, exhibits an anticancer activity equivalent to 30 times that of CPT and is clinically used to treat colorectal, liver, gastric, ovarian, and head and neck tumors [1].
Despite their high efficiency and broad anticancer spectrum, the clinical application of CPT and its analogs is severely restricted by their extreme hydrophobicity, poor bioavailability, and the instability of the pharmacologically active lactone ring [1]. To overcome these hurdles, researchers have increasingly turned to nanotechnology and combination therapies. Nano-drug delivery systems (NDDS) can significantly improve the stability and water solubility of CPT/HCPT, enhance tumor-targeted delivery via the enhanced permeability and retention (EPR) effect, and integrate multiple therapeutic modalities (e.g., photodynamic therapy, photothermal therapy, and gene therapy) into a single platform [1]. Additionally, antibody-drug conjugates (ADCs) like sacituzumab govitecan have successfully utilized CPT derivatives (SN-38) for targeted therapy in triple-negative breast cancer (TNBC) and other solid tumors [5][6].
2. Pharmacological Activity
CPT and its derivatives exhibit potent antiproliferative and apoptotic activities against a wide range of malignancies. HCPT has demonstrated significant efficacy against colorectal cancer, liver cancer, gastric cancer, ovarian cancer, leukemia, and head and neck tumors [1]. In vitro and in vivo studies have shown that HCPT inhibits tumor growth by decreasing topoisomerase I enzyme activity and mediating antiproliferative effects through apoptosis and autophagy [1].
In combination therapies, CPT derivatives show synergistic effects. For example, the combination of HCPT with other agents like triptolide, methotrexate (MTX), or doxorubicin (DOX) significantly enhances cytotoxicity and overcomes multidrug resistance (MDR) [1]. Furthermore, targeted delivery systems, such as aptamer-modified PEG-PAMAM-CPT dendrimers, have shown higher antiproliferation activity towards nucleolin-positive colorectal cancer cells (HT29 and C26) compared to free CPT, improving cellular uptake and mouse survival rates [2]. Sacituzumab govitecan, an ADC linking an anti-Trop-2 antibody with SN-38, has demonstrated potent in vitro and in vivo activity against TNBC, cervical, endometrial, ovarian, and urothelial carcinomas by delivering high concentrations of the active drug directly to Trop-2-expressing tumors [5][6].
3. Molecular Mechanism of Action
The primary molecular target of CPT and its derivatives is intracellular topoisomerase I. By binding to the topoisomerase I-DNA complex, CPT stabilizes the cleavable complex, preventing DNA re-ligation. This leads to DNA double-strand breaks during DNA replication, ultimately triggering cell cycle arrest and apoptosis [1]. In the context of targeted therapies, high levels of SN-38 delivered via sacituzumab govitecan may overcome Rad51-mediated homologous recombination repair of DNA breaks in Trop-2-expressing solid tumors [6].
Beyond topoisomerase I inhibition, CPT derivatives are involved in complex intracellular signaling and metabolic reprogramming. For instance, combination therapies utilizing CPT and photosensitizers (e.g., Chlorin e6) generate reactive oxygen species (ROS) under near-infrared (NIR) irradiation, inducing immunogenic cell death (ICD) and alleviating tumor hypoxia [1]. Additionally, CPT-11 (irinotecan) has been shown to upregulate NADPH oxidase (NOX) and myeloperoxidase (MPO) while downregulating catalase (CAT), superoxide dismutase (SOD), and heme oxygenase (HO) via the Keap-1/Nrf-2 pathway, leading to increased oxidative stress and lipid peroxidation in intestinal tissues [3].
4. Structure-Activity Relationship (SAR)
The structural integrity of the CPT molecule, particularly its lactone ring, is crucial for its pharmacological activity. The closed lactone ring is the active form required for topoisomerase I inhibition; however, it is highly unstable and rapidly hydrolyzes into an inactive carboxylate form under physiological pH [1]. Modifications to the CPT scaffold have led to derivatives with improved properties. For example, the addition of a hydroxyl group at the 10-position yields 10-hydroxycamptothecin (HCPT), which exhibits 30 times the anticancer activity of CPT [1].
To preserve the active lactone form and improve solubility, researchers have developed various prodrugs and nanocarriers. For instance, conjugating CPT with α-lipoic acid (ALA) and tetra(ethylene glycol) (TEG) creates a ROS-responsive prodrug (CPT-TEG-ALA) that self-assembles into nanoprodrugs, significantly extending survival times in glioblastoma models [7]. In ADCs like sacituzumab govitecan, SN-38 is linked to the antibody in its most active, non-glucuronidated form, which not only enhances targeted delivery (up to 136-fold greater than irinotecan) but also reduces gastrointestinal toxicity [6].
5. Current Limitations
Despite significant advancements, several limitations hinder the clinical translation of CPT-based therapies. First, the extreme hydrophobicity and lactone ring instability of free CPT/HCPT result in poor bioavailability and rapid clearance [1]. While nanomedicines address these issues, they introduce new challenges. The EPR effect, heavily relied upon for passive targeting in animal models, shows high heterogeneity and limited tumor penetration in human clinical trials [1]. Different nanocarriers also have specific drawbacks: PEG-based nanoparticles may limit cellular uptake; PLGA and PLA nanoparticles often suffer from an initial uncontrolled burst release; lipid-based carriers can be unstable and prone to membrane leakage; and inorganic carriers (e.g., gold, silica) face issues with agglomeration, potential biotoxicity, and non-degradability [1].
Furthermore, systemic toxicity remains a major concern. Chemotherapy-induced intestinal mucositis (CIM) is a severe side effect of CPT-11 (irinotecan), characterized by crypt apoptosis, villus atrophy, and severe oxidative stress due to the dysregulation of the intestinal redox system (e.g., downregulation of SOD, GPX, and CAT) [3]. Additionally, functional expression of efflux transporters like ABCG2 is associated with resistance to SN-38 and its conjugates, necessitating the co-administration of ABCG2 inhibitors to overcome multidrug resistance [6].
6. Future Perspectives
Future research on CPT and its derivatives must focus on overcoming translational barriers and enhancing targeted combination therapies. The development of smart, stimuli-responsive nanocarriers (e.g., pH, ROS, or enzyme-triggered release) holds promise for precise spatiotemporal drug delivery, minimizing off-target toxicity and maximizing the concentration of the active lactone form at the tumor site [1][7]. Carrier-free nanoparticles, formed by the self-assembly of pure drug molecules (e.g., HCPT and DOX), offer a high drug-loading capacity and avoid carrier-induced toxicity, though their stability requires further optimization [1].
Combination therapies will continue to evolve, integrating CPT with photodynamic therapy (PDT), photothermal therapy (PTT), and immunotherapy. For instance, utilizing mitochondrial-targeted compounds or metabolic reprogramming agents alongside CPT could disrupt cancer cell bioenergetics and induce apoptosis more effectively [4].
