Camptothecin Research Articles

Camptothecin and Its Derivatives from Traditional Chinese Medicine in Combination with Anticancer Therapy Regimens: A Systematic Review and Meta-Analysis

Background/Objectives: Camptothecin (CPT) and its derivatives, irinotecan and topotecan, are integral components of cancer chemotherapy, often used in combination therapies. This meta-analysis evaluates the efficacy of CPT-based combination treatments in cancer patients. Methods: We systematically searched the literature database using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist for articles published between 2000 and 2022. Published studies were retrieved through an electronic search on the Web of Science, PubMed, and Google Scholar databases. A total of 138 studies were downloaded and examined, and 71 eligible studies were selected for meta-analysis after excluding studies that did not meet the inclusion criteria. Results: Ultimately, a total of 71 studies were included in the analysis, comprising non-small cell lung cancer (NSCLC), colorectal cancer (COLRC), oesophageal/gastric cancer (O/GC), and small cell lung cancer (SCLC). For NSCLC, the objective response rate (RR) was 31.8% (95% CI: 27.3–37.1%, p = 0.025), with irinotecan plus cisplatin showing significantly higher efficacy compared to other irinotecan-based combinations. In COLRC, irinotecan and 5-fluorouracil/leucovorin plus bevacizumab demonstrated superior efficacy with a RR of 44% (95% CI: 34–58, p < 0.001) and minimal haematological toxicity. In O/GC, irinotecan-based combinations showed an average RR of 43% (95% CI: 27–70, p < 0.001) and average overall survival (OS) and progression-free survival (PFS) rates of 10.2 and 5.5 months, respectively. For SCLC, irinotecan-based combinations had a higher control response than topotecan-based ones, while the latter exhibited higher rates of stable and progressive disease. The overall RR for SCLC was 45% (95% CI: 34.3–60.2, p < 0.001). Conclusions: The existing evidence underscored the potential of CPT-based combination therapy in various cancers. Among the various combinations discussed in this analysis, irinotecan plus cisplatin demonstrated the highest objective RR in 12 trials focused on NSCLC. This study provides valuable insights into potential treatment strategies for various types of cancer, emphasising the importance of personalised and tailored approaches to maximise efficacy and minimise adverse effects.

Antitumor Effect of Peptide-Camptothecin Conjugate Targeting CD133 Protein.

The peptide-drug conjugate (PDC) has emerged as one of the new approaches for cancer therapy, which has the advantages of improved drug target ability and reduced adverse effects compared with the traditional chemotherapy. CD133 is a surface antigen specific to cancer stem cells, which are thought to be responsible for the self-renewal, proliferation, metastasis, and chemoresistance of cancer cells. A PDC for CD133 was designed by us, and it consists of CD133 targeting peptide LS-7 (amino acid sequence LQNAPRS), a pH-sensitive linker (succinyl), and a cytotoxic payload, the cytotoxic molecule camptothecin (CPT) with potent toxicity in vivo and in vitro. An antitumor study exhibited that the conjugate LS-7-CPT has not only improved its cytotoxicity in tumor cells but also retained its anticancer effect in vivo. In addition, the acute toxicity in mice of LS-7-CPT has been improved and the maximum tolerated dose has been increased by at least 56.2-fold. Pull-down and in vivo fluorescent imaging results indicated that LS-7-CPT was enriched in mice tumors by targeting CD133 protein. As far as we know, this is the first report for a PDC molecule designed for CD133, which is important for the study of CPT drug development.

Synthesis of curcumin polyprodrug via click chemistry and construction of dual-drug-loaded nano platform for highly efficient tumor treatment

Micellar nanostructures formed by amphiphilic polymers are prone to dissociation when the in vivo environment changes. Polyprodrug micelles can cross-link with other hydrophobic drugs through non-covalent bonds, which has the advantage of fixed structure and avoids the use of chemical cross-linking agents. In this study, we prepared a polyprodrug with hydrophobic curcumin (CUR) and hydrophilic poly(ethylene glycol) (PEG) in the main chain through a click reaction between CUR derivatives containing azide groups and di-alkynly-capped PEG. Due to the presence of benzene rings in the structure of CUR, the polyprodrug can form non-covalent cross-linked nanoparticles (NCCL-CUR NPs) through hydrophobic and π-π stacking interaction. The structure, molecular weight, and self-assembly properties of the polyprodrug were characterized. The anti-cancer drug camptothecin (CPT) was encapsulated in the polyprodrug nanoparticles, producing dual-drug-loaded nanoparticles (abbreviated as CPT@NCCL-CUR NPs). The test results indicate that the NPs have reductive responsiveness and can release the original drugs CUR and CPT in phosphate buffer (PB) solution containing glutathione (GSH), while remaining stability in physiological environment. Cell and in vivo experiments further demonstrate that the dual-drug-loaded CPT@NCCL-CUR NPs can inhibit the growth of tumor through synergistic effects. This work provides a valuable approach for the preparation of amphiphilic polyprodrug with anti-tumor CUR as the backbone, and the stable dual-drug-loaded NPs containing both CUR and CPT through non-covalent crosslinking for synergistic therapy.

Design, Synthesis, and Biological Evaluation of Some Novel Retinoid Derivatives

Background: As cancer stands as a significant global health concern, many heterocyclic compounds that are more effective in cancer cells than healthy cells are being investigated for their selective anticancer potentials. One such compound is fenretinide, a synthetic derivative of retinoic acid that has a broad spectrum of cytotoxic activity against primary tumor cells, cell lines, and/or xenografts of various cancers. In this context, bexarotene and its derivatives, synthesized from hybridization of the fenretinide, are expected to possess a potential anticancer activity. Objective: The objective of the present study was to investigate the synthesis of novel amid-derived and bexarotene-based compounds, as well as to assess their cytotoxic effects in different cancer cell lines. Methods: This study involved the synthesis of twelve novel retinoid derivatives (6-17) in a six-step process. The cytotoxic activities of these compounds were assessed against various cancer cell lines, such as A549 (human lung carcinoma), HeLa (human cervical cancer), MCF7 (human breast adenocarcinoma), and WiDr (human colon adenocarcinoma). The chemical structures of these compounds were elucidated through their elemental analysis, mass spectrometry (ESI+, ESI-), as well as 1H-NMR and 13C-NMR spectroscopic data. Results: The obtained cell toxicity results indicated that compounds 6, 8, 11, 12, 13, 14, and 17 were found to exhibit the strongest cytotoxic activity in above mentioned cancer cell lines. The IC50 values for active compounds, 11 and 12, were determined as 2.38μM and 2.29μM, respectively. Remarkably, these compounds displayed higher cytotoxic activity in the WiDr cell line related to positive control, camptothecin (CPT). Moreover, compounds 14 and 17 demonstrated very similar level of cytotoxic activity to CPT, indicating their potential for antitumoral applications upon further studies. Conclusion: While compounds 11, 12, 14, and 17 indicated a very comparable anticancer activity to CPT, compounds 6, 8, 11 and 12 showed more selective anticancer effect against cancer cells than noncancerous cells. In accordance with the findings of the present study, they can be evaluated as primary candidates for further studies, specifically as RXRα-targeted anticancer agents.

Biophysical Analysis of EGCG’s Protective Effects on Camptothecin-Induced Oxidative Stress in Bone-like Cancer Cells Using Electric Cell-Substrate Impedance Sensing (ECIS)

Various medical treatments aim to counteract the impact of oxidants on mammalian cells. One such antioxidant is Epigallocatechin-3-gallate (EGCG), an active ingredient in green tea, which has demonstrated protective effects against cellular oxidants like camptothecin (CAMPT). This study examines how EGCG mitigates CAMPT’s effects on UMR cells, focusing on cell proliferation and biophysical parameters. UMR cells were treated with different CAMPT concentrations and incubated for 72 h. Subsequently, cell proliferation and viability were assessed. In a separate experiment, UMR cells were co-treated with CAMPT and varying EGCG concentrations to evaluate EGCG’s ability to mitigate CAMPT’s oxidative effect. Electric Cell–Substrate Impedance Sensing (ECIS) technology was also used to assess the biophysical parameters of CAMPT-treated UMR cells, including cell monolayer resistance, cell spreading, and cell attachment. The results showed a concentration-dependent decrease in cell proliferation for CAMPT-treated UMR cells. However, co-treatment with EGCG reversed CAMPT’s oxidative effects in a concentration-dependent manner. ECIS technology revealed a decrease in biophysical parameters when UMR cells were treated with CAMPT alone. Statistical analysis indicated significant differences with p-values < 0.05. This study suggests that EGCG effectively protects UMR cells from oxidative stress and highlights its potential role in mitigating oxidative stress in mammalian cells. Additionally, the use of ECIS technology validates its application in corroborating the biological effects of CAMPT and EGCG on UMR cells.

Glycosylated AIE‐active Red Light‐triggered Photocage with Precisely Tumor Targeting Capability for Synergistic Type I Photodynamic Therapy and CPT Chemotherapy

AbstractPhotocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near‐infrared light‐triggered photolysis process of current photocage is largely singlet oxygen (1O2)‐dependent and lack of compatibility with other reactive oxygen species (ROS)‐activated techniques, which has proven to be the major bottleneck in achieving efficient and precise treatment. Herein, we reported a lactosylated photocage BT‐LRC by covalently incorporating camptothecin (CPT) into hybrid BODIPY‐TPE fluorophore via the superoxide anion radical (O2−⋅)‐cleavable thioketal bond for type I photodynamic therapy (PDT) and anticancer drug release. Amphiphilic BT‐LRC could be self‐assembled into aggregation‐induced emission (AIE)‐active nanoparticles (BT‐LRCs) owing to the regulation of carbohydrate‐carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates. BT‐LRCs could simultaneously generate abundant O2−⋅ through the aggregation modulated by lactose interactions, and DNA‐damaging agent CPT was subsequently and effectively released. Notably, the type I PDT and CPT chemotherapy collaboratively amplified the therapeutic efficacy in HepG2 cells and tumor‐bearing mice. Furthermore, the inherent AIE property of BT‐LRCs endowed the photocaged prodrug with superior bioimaging capability, which provided a powerful tool for real‐time tracking and finely tuning the PDT and photoactivated drug release behavior in tumor therapy.

Development of Chitosan-Coated Graphene Oxide and Iron Oxide Nanocomposites for Targeted Delivery of Camptothecin to Liver Cancer Cells.

Innovative drug delivery platforms for selective, regulated, and sustained release of anticancer drugs are crucial in cancer treatment. This study presents nanoparticles developed from chitosan (CS), graphene oxide (GO), and magnetite (Fe3O4), and their nanocomposites, to enhance the loading and release efficiency of camptothecin (CPT). Nanostructures were characterized using imaging microscopy, FT-IR, and X-ray diffraction, with an average crystallite size of 5.5 nm. Camptothecin binding proportions were 70% for CS, 81% for CS@Fe3O4, 58% for CS@GO, and 74% for CS@GO/Fe3O4. At pH 5.0, CPT release ratios were 87%, 80%, 88%, and 90%, respectively, and at pH 7.4, 84%, 72%, 89%, and 87%. Cytotoxicity was assessed using the MTT assay against HepG2 and SMMC-7721 cancer cells. CPT-CS@GO/Fe3O4 exhibited the highest survival at 5 µM and 12.5 µM concentrations, indicating it as the most effective nanocarrier for camptothecin delivery. The study demonstrates CS@GO/Fe3O4's potential as a superior drug delivery system.

Camptothecin and its derivatives: Advancements, mechanisms and clinical potential in cancer therapy.

Camptothecin (CPT), an alkaloid isolated from the Camptotheca tree, has demonstrated significant anticancer properties in a range of malignancies. However, its therapeutic efficacy is limited by its hydrophobicity, poor bioavailability, and systemic toxicity. Derivatives, analogues, and nanoformulations of CPT have been synthesized to overcome these limitations. The aim of this review is to comprehensively analyze existing studies to evaluate the therapeutic efficacy, mechanistic aspects, and clinical potential of CPT and its modified forms, including derivatives, analogues, and nanoformulations, in cancer treatment. A comprehensive literature review was performed using PubMed/Medline, Scopus, and Web of Science databases; articles were selected based on specific inclusion criteria, and data were extracted on the pharmacological profile, clinical studies, and therapeutic efficacy of CPT and its different forms. Current evidence suggests that derivatives and analogues of CPT have improved water solubility, bioavailability, and reduced systemic toxicity compared to CPT. Nanoformulations further enhance targeted delivery and reduce off-target effects. Clinical trials indicate promising outcomes with enhanced survival rates and lower side effects. CPT and its modified forms hold significant promise as potent anticancer agents. Ongoing research and clinical trials are essential for establishing their long-term efficacy and safety; the evidence overwhelmingly supports further development and clinical testing of these compounds.

FL118 Enhances Therapeutic Efficacy in Colorectal Cancer by Inhibiting the Homologous Recombination Repair Pathway through Survivin-RAD51 Downregulation.

Background/Objectives: Irinotecan, a camptothecin (CPT) derivative, is commonly used as a first-line therapy for colorectal cancer (CRC), but resistance remains a significant challenge. This study aims to explore the therapeutic potential of FL118, another CPT derivative, with a focus on overcoming resistance to irinotecan. Methods: The effects of FL118 on CRC cells were evaluated, and bioinformatics analysis was performed on RNA-seq data. Transfection was conducted to observe the knockdown effect of survivin, and the in vivo efficacy of FL118 was assessed using a xenograft model. Results: FL118 induces apoptosis, G2/M arrest, and DNA damage. A notable mechanism of action of FL118 is a reduction in survivin levels, which downregulates the expression of RAD51, a key marker of homologous recombination, and attenuates DNA repair processes. Given that SN38 is the active metabolite of irinotecan, FL118 reduces cell viability and RAD51 in SN38-resistant LOVO cells. Conclusions: Our findings provide effective insights into the antitumor activity of FL118 and its potential as a therapeutic agent for overcoming irinotecan resistance in CRC.

Camptothecin and its Analogs: High-Yielding Ophiorrhiza Species from Sri Lanka for Sustainable Anticancer Compound Production

Introduction: Camptothecin (CPT) is pivotal in cancer treatment, derived from various CPT-producing plant species, and is a fundamental component in synthesizing valuable cancer drugs like Irnotican and Topotecan. Sourcing from nature poses conservation issues, fostering interest in the herbaceous Ophiorrhiza plant as a more sustainable alternative. Ophiorrhiza species in Sri Lanka lack comprehensive study, warranting exploration for echo-friendly anticancer compound production. Objectives: This study examines CPT and analog content in Ophiorrhiza mungos, O. pectinata, and O. rugosa across diverse Sri Lankan regions. Methods: The study employs Thin Layer Chromatography (TLC), High-Performance Liquid Chromatography-DAD (HPLC-DAD), and Liquid Chromatography-Mass Spectrometry (LC-MS) to quantify and confirm CPT and its analogs. Results: Significant variations in the content of CPT and its analogs were observed among plant parts and regions. O. mungos from Deraniyagala and Bibile regions notably exhibited elevated CPT levels in fruits and roots. O. rugosa var. Angustifolia and O. pectinata also exhibited a considerable content of CPT in their roots, though it was significantly lower (p < 0.005) than O. mungos. Conclusion: The study validates analytical methods for specificity, linearity, precision, accuracy, and sensitivity per ICH guidelines. The results indicate that Ophiorrhiza species, especially O. mungos and O. rugosa var. Angustifolia holds the potential to be a sustainable source of CPT. Optimizing cultivation practices offers an eco-friendly solution for anticancer compound production, alleviating species threats and conserving biodiversity.

Entropically driven binding of Camptothecin in the minor groove of salmon testes DNA

The present study focuses on binding association of Camptothecin (CMT) towards natural deoxy-ribonucleic acid (salmon testes, ST) under physiological conditions of pH 7.4. Extensive spectroscopic and computational techniques have been employed to elucidate thermodynamics of the said interaction. UV and fluorescence analyses portrays significant intensity changes (hyper-chromic and hypsochromic) in the spectra, which confirms effective CMT binding to ST DNA. The McGhee-von Hipple method and Scatchard plot analyses estimated the binding affinities in 105 M−1 range. Associated thermodynamic data revealed spontaneous and exothermic nature of binding. Temperature-dependent fluorescence showed negative change in enthalpy and positive change in entropy, leading to the formation of a 1:1 adduct. Non-polyelectrolytic forces appeared to be the driving force of the ligand-DNA interaction, according to salt-dependent fluorescence. Dye displacement assay, viscosity study, DNA melting, iodide quenching, urea denaturation assay examined the minor groove nature of CMT. In silico docking study examined precise molecular representations of the minor groove binding mechanism that formed between the complex, and the study's findings were consistent with the experimental results. Simulation studies also validated the experimental analysis and docking data. These findings could expedite the process of creating new and improved CMT molecular derivatives and help in the creation of DNA-targeted medicines, which may be beneficial from a pharmaceutical point of view.

Extraction of camptothecin and 10-hydroxycamptothecin from Camptotheca acuminata fruits by natural deep eutectic solvent

A natural deep eutectic solvent-based ultrasound-assisted simultaneous extraction (NADES-UAE) of camptothecin (CPT) and 10-hydroxycamptothecin (10-HCPT) was established. The 1.31 mg of CPT and 1.66 mg of 10-HCPT were obtained from each gram of the fruit powder of Camptotheca acuminata under the optimum conditions with a water content of 20%, a liquid-solid ratio of 12 mL/g and an ultrasound time of 20 min. The recovery efficiencies of CPT and 10-HCPT after AB-8 resin enrichment were 70.5% and 74.8%, respectively. The stronger interaction between NADES3 which was screened from 12 kinds of NADES and target components compared with methanol or water was demonstrated using molecular dynamics simulation. Moreover, the recovered NADES3 could be reused at least 4 times. The present research provided an efficient, environment-friendly, and sustainable method for extracting and recovering CPT and 10-HCPT from the fruits of C. acuminata.

Efficient ultrasonic extraction of alkaloids and glycosides from Camptotheca acuminata Decne via deep eutectic solvents: Kinetics and mechanisms

The study investigated the extraction of alkaloids and glycosides from the Camptotheca acuminata Decne using deep eutectic solvent (DES). 18 types of deep eutectic solvents (DESs) were prepared, and it was found that the extraction performance of choline chloride (ChCl)-formic acid (FA) was optimal, surpassing traditional solvents such as methanol/70 % methanol. In comparison to methanol, the extracted amount of compounds by DES was 2–3 times higher. The extraction processes involving the molar ratio of ChCl-FA, pH, DES/H2O mass ratio, solid/liquid ratio, as well as ultrasonic power were optimized. A mathematical model for solid/liquid extraction kinetics from Camptotheca acuminata Decne was developed. The extraction mechanism was investigated using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and 1H nuclear magnetic resonance(1H NMR). The results revealed that the DES caused dissociation in Camptotheca acuminata Decne and formed hydrogen bonds with Camptothecin (CPT). Meanwhile, density functional theory (DFT) calculations verified that FA-based exhibited the highest extracted amount for CPT. In addition, this study investigated the recovery rate of DES, and the results showed that after 10 cycles, the DES system remained effective for the extraction of alkaloids and glycosides.

Genotoxic and Anti-Migratory Effects of Camptothecin Combined with Celastrol or Resveratrol in Metastatic and Stem-like Cells of Colon Cancer.

Background: Colorectal cancer is one of the leading and most lethal neoplasms. Standard chemotherapy is ineffective, especially in metastatic cancer, and does not target cancer stem cells. A promising approach to improve cancer treatment is the combination therapy of standard cytostatic drugs with natural compounds. Several plant-derived compounds have been proven to possess anticancer properties, including the induction of apoptosis and inhibition of cancer invasion. This study was focused on investigating in vitro the combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic (LOVO) and stem-like (LOVO/DX) colon cancer cells. Methods: The genotoxic effects that drive cancer cells into death-inducing pathways and the ability to inhibit the migratory properties of cancer cells were evaluated. The γH2AX+ assay and Fast-Halo Assay (FHA) were used to evaluate genotoxic effects, the annexin-V apoptosis assay to rate the level of apoptosis, and the scratch test to assess antimigratory capacity. Results: The results showed that both combinations CPT-CEL and CPT-RSV improve general genotoxicity of CPT alone on metastatic cells and CSCs. However, the assessment of specific double-stranded breaks (DSBs) indicated a better efficacy of the CPT-CEL combination on LOVO cells and CPT-RSV in LOVO/DX cells. Interestingly, the combinations CPT-CEL and CPT-RSV did not improve the pro-apoptotic effect of CPT alone, with both LOVO and LOVO/DX cells suggesting activation of different cell death mechanisms. Furthermore, it was found that the combinations of CPT-CEL and CPT-RSV improve the inhibitory effect of camptothecin on cell migration. Conclusions: These findings suggest the potential utility of combining camptothecin with celastrol or resveratrol in the treatment of colon cancer, including more aggressive forms of the disease. So far, no studies evaluating the effects of combinations of these compounds have been published in the available medical databases.

Impact of camptothecin exposures on the development and larval midgut metabolomic profiles of Spodoptera frugiperda

Spodoptera frugiperda is an economic agricultural pest that has invaded many countries around the world and caused huge losses in grain production. Camptothecin (CPT) is one of the botanical compounds with insecticidal activity and has the potential for pest control. However, the effects of CPT on development and metabolism of S. frugiperda remain unknown. In this study, we have investigated the adverse effects of 1.0 and 5.0 mg/kg CPT exposures on the growth and development of S. frugiperda. Our results found that 1.0 and 5.0 mg/kg CPT treatments altered the parameters of the life cycle, including inducing larval mortality, altering the weight of larvae, pupae, and adults, the larval duration, and decreasing the pupation rate and emergence rate. In addition, comparative metabolomics analysis was performed in the larval midgut of S. frugiperda to explore the toxicity mechanism of CPT. A total of 261 and 348 differential metabolites were identified in the groups with 1.0 and 5.0 mg/kg CPT treatments, respectively. Further analysis found that pantothenate and CoA biosynthesis, sulfur relay system, selenocompound metabolism, and fatty acid biosynthesis pathways were significantly altered by 5.0 mg/kg CPT exposure. Our results provided new insight into the toxicological mechanisms of CPT against S. frugiperda and laid the foundation for the field application of CPT in pest control.

Glycosylated AIE-active Red Light-triggered Photocage with Precisely Tumor Targeting Capability for Synergistic Type I Photodynamic Therapy and CPT Chemotherapy.

Photocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near-infrared light-triggeredphotolysis process of current photocage is largely singlet oxygen (1O2)-dependent and lack of compatibility with other reactive oxygen species (ROS)-activated techniques, which has proven to be the major bottleneck in achieving efficient and precise treatment. Herein, we reported a lactosylated photocage BT-LRC by covalently incorporating camptothecin (CPT) into hybrid BODIPY-TPE fluorophore via the superoxide anion radical (O2-•)-cleavable thioketal bond for type I photodynamic therapy (PDT) and anticancer drug release. Amphiphilic BT-LRC could be self-assembled into aggregation-induced emission (AIE)-active nanoparticles (BT-LRCs) owing to the regulation of carbohydrate-carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates. BT-LRCs could simultaneouslygenerate abundant O2-• through the aggregation modulated by lactose interactions, and DNA-damaging agent CPT was subsequently and effectively released. Notably, the type I PDT and CPT chemotherapy collaboratively amplified the therapeutic efficacy in HepG2 cells and tumor-bearing mice. Furthermore, the inherent AIE property of BT-LRCs endowed the photocaged prodrug with superior bioimaging capability, which provided a powerful tool for real-time tracking and finely tuning the PDT and photoactivated drug release behavior in tumor therapy.

Carcinomembrane-Camouflaged Perfluorochemical Dual-Layer Nanopolymersomes Bearing Indocyanine Green and Camptothecin Effectuate Targeting Photochemotherapy of Cancer.

Photochemotherapy has been recognized as a promising combinational modality for cancer treatment. However, difficulties such as off-target drug delivery, systemic toxicity, and the hypoxic nature of the tumor microenvironment remain hindrances to its application. To overcome these challenges, cancer cell membrane camouflaged perfluorooctyl bromide (PFOB) dual-layer nanopolymersomes bearing indocyanine green (ICG) and camptothecin (CPT), named MICFNS, were developed in this study, and melanoma was exploited as the model for MICFNS manufacture and therapeutic application. Our data showed that MICFNS were able to stabilize both ICG and CPT in the nanocarriers and can be quickly internalized by B16F10 cells due to melanoma membrane-mediated homology. Upon NIR irradiation, MICFNS can trigger hyperthermia and offer enhanced singlet oxygen production due to the incorporation of PFOB. With ≥10/2.5 μM ICG/CPT, MICFNS + NIR can provide comparable in vitro cancericidal effects to those caused by using an 8-fold higher dose of encapsulated CPT alone. Through the animal study, we further demonstrated that MICFNS can be quickly brought to tumors and have a longer retention time than those of free agents in vivo. Moreover, the MICFNS with 40/10 μM ICG/CPT in combination with 30 s NIR irradiation can successfully inhibit tumor growth without systemic toxicity in mice within the 14 day treatment. We speculate that such an antitumoral effect was achieved by phototherapy followed by chemotherapy, a two-stage tumoricidal process performed by MICFNS. Taken together, we anticipate that MICFNS, a photochemotherapeutic nanoplatform, has high potential for use in clinical anticancer treatment.

Modulating the Self-Assembly of a Camptothecin Prodrug with Paclitaxel for Anticancer Combination Therapy: A Molecular Dynamics Approach.

Camptothecin (CPT) and paclitaxel (PTX), derived from natural products, are recognized for their significant efficacy in clinical cancer treatments. Despite its therapeutic advantages, CPT is challenged by issues of toxicity and solubility, necessitating its use in conjugation with other compounds for enhanced compatibility. This study delves into the coassembly mechanism of Evans blue-conjugated camptothecin (EB-CPT) with PTX, aiming to elucidate their synergistic potential in combination therapy applications, employing all-atom molecular dynamics simulations. The EB-CPT prodrug is reported to form a self-aggregated cluster. Our findings suggest that increasing the PTX concentration induces a dispersion of EB-CPT clusters, thereby disrupting their inherent self-assembly. This disruption is explained to be facilitated by the coassembly of EB-CPT and PTX. With increasing concentration of PTX, a lengthening of the coassembled structures is observed, supporting the experimental findings of tube-like coassembled structures at higher weight ratios of PTX. Hydrophobic interactions and π-π stacking are the primary forces responsible for the formation of both self- and coassembled structures. Interestingly, the structural analysis reveals that the CPT moiety of EB-CPT is less involved in assemblies due to steric hindrances. Instead, the interaction and coassembly processes are predominantly mediated by the EB derivative component of the prodrug. This research underscores the critical role of the solubilizing agent, EB derivative, in mediating the flexibility and interaction of CPT in combination therapy strategies, particularly with PTX, thus emphasizing the importance of conjugates for therapeutic developments. Furthermore, the molecular insights into the interaction sites and mechanisms facilitating coassembly between EB-CPT and PTX contribute valuable knowledge to the field, highlighting the potential of these nanomedicine combinations in advancing cancer treatment modalities.

Exposure of Arabidopsis thaliana Mutants to Genotoxic Stress Provides New Insights for the Involvement of TDP1α and TDP1β genes in DNA-Damage Response.

Genotoxic stress activates the DNA-damage response (DDR) signalling cascades responsible for maintaining genome integrity. Downstream DNA repair pathways include the tyrosyl-DNA phosphodiesterase 1 (TDP1) enzyme that hydrolyses the phosphodiester bond between the tyrosine of topoisomerase I (TopI) and 3'-phosphate of DNA. The plant TDP1 subfamily contains the canonical TDP1α gene and the TDP1β gene whose functions are not fully elucidated. The current study proposes to investigate the involvement of TDP1 genes in DDR-related processes by using Arabidopsis thaliana mutants treated with genotoxic agents. The phenotypic and molecular characterization of tdp1α, tdp1β and tdp1α/β mutants treated with cisplatin (CIS), curcumin (CUR), NSC120686 (NSC), zeocin (ZEO), and camptothecin (CPT), evidenced that while tdp1β was highly sensitive to CIS and CPT, tdp1α was more sensitive to NSC. Gene expression analyses showing upregulation of the TDP2 gene in the double mutant indicate the presence of compensatory mechanisms. The downregulation of POL2A gene in the tdp1β mutant along with the upregulation of the TDP1β gene in pol2a mutants, together with its sensitivity to replication inhibitors (CIS, CTP), point towards a function of this gene in the response to replication stress. Therefore, this study brings novel information relative to the activity of TDP1 genes in plants.

ScRNA-seq reveals the spatiotemporal distribution of camptothecin pathway and transposon activity in Camptotheca acuminata shoot apexes and leaves.

Camptotheca acuminata Decne., a significant natural source of the anticancer drug camptothecin (CPT), synthesizes CPT through the monoterpene indole alkaloid (MIA) pathway. In this study, we used single-cell RNA sequencing (scRNA-seq) to generate datasets encompassing over 60,000 cells from C. acuminata shoot apexes and leaves. After cell clustering and annotation, we identified five major cell types in shoot apexes and four in leaves. Analysis of MIA pathway gene expression revealed that most of them exhibited heightened expression in proliferating cells (PCs) and vascular cells (VCs). In contrast to MIA biosynthesis in Catharanthus roseus, CPT biosynthesis in C. acuminata did not exhibit multicellular compartmentalization. Some putative genes encoding enzymes and transcription factors (TFs) related to the biosynthesis of CPT and its derivatives were identified through co-expression analysis. These include 19 cytochrome P450 genes, 8 O-methyltransferase (OMT) genes, and 62 TFs. Additionally, these pathway genes exhibited dynamic expression patterns during VC and EC development. Furthermore, by integrating gene and transposable element (TE) expression data, we constructed novel single-cell transcriptome atlases for C. acuminata. This approach significantly facilitated the identification of rare cell types, including peripheral zone cells (PZs). Some TE families displayed cell type specific, tissue specific, or developmental stage-specific expression patterns, suggesting crucial roles for these TEs in cell differentiation and development. Overall, this study not only provides novel insights into CPT biosynthesis and spatial-temporal TE expression characteristics in C. acuminata, but also serves as a valuable resource for further comprehensive investigations into the development and physiology of this species.