Synthesis and evaluation of coumarin derivatives as potential anticancer therapies for colon cancer: In vitro antiproliferation, cell cycle arrest analyses, network pharmacology investigations, and molecular docking studies.

Drug delivery systems (DDS) offer a promising strategy to enhance the therapeutic index of chemotherapeutic agents in colon cancer by improving tumor targeting, circulation time, and controlled drug release. Despite extensive preclinical research, a quantitative synthesis evaluating the efficacy of DDS and the influence of design parameters remains lacking. We conducted a systematic review and meta-analysis of preclinical in vivo studies assessing DDS-based chemotherapy in murine models of colon cancer. A comprehensive search of PubMed, EMBASE, Scopus, Google Scholar, Cochrane CENTRAL, and ClinicalTrials.gov was performed through October 15, 2025. Outcomes included tumor growth inhibition, with subgroup analyses examining the effects of DDS platform, chemotherapeutic agent, targeting strategy, ligand type, and route of administration. Twenty-three studies comprising 25 experiments and 539 animals were included. Overall, DDS-based therapies significantly reduced tumor growth compared with controls ((WMD: - 557.7; 95% CI: - 716.8 to - 398.5; I²=88%; p < 0.001) and free-drug administration ((WMD: - 276.3; 95% CI: - 367.6 to - 185.1; I²=78%; p < 0.001). Both targeted and non-targeted DDS significantly reduced tumor growth compared with free drug treatment, while targeted DDS showed significantly greater efficacy than non-targeted systems (WMD: - 240.3; 95% CI: - 399.4 to - 81.25; I²=59%; p = 0.003). Although no statistically significant differences were observed between DDS platforms or chemotherapeutic agent subgroups, micelle-based systems and DDS formulations incorporating SN-38 or doxorubicin tended to show greater tumor growth reduction. Intravenous administration demonstrated significantly greater efficacy than intraperitoneal delivery, while hyaluronic acid- and aptamer-based targeting strategies achieved the largest tumor growth inhibition. Risk-of-bias assessment indicated moderate methodological quality, with variability in reporting of randomization, blinding, and sample size calculations. DDS-based chemotherapy consistently improves antitumor efficacy in preclinical colon cancer models, with targeting strategy, platform type, chemotherapeutic agent, and administration route influencing outcomes. These findings support the rational design of DDS platforms and underscore their translational potential. Rigorous preclinical study design and standardized reporting of efficacy and safety are essential to facilitate clinical translation.

Contemporary colorectal cancer (CRC) epidemiology reveals evolving risk factors have reconfigured CRC as a societally-modulated, quasi-age-dependent disease. Nevertheless, temporal drivers of incidence/incidence-based mortality (IBM) patterns and longitudinal trends in clinicopathological profiles, therapeutic modalities, and 5-year survival (5-YS) remain incompletely defined, necessitating methodologically rigorous studies. The Surveillance, Epidemiology, and End Results Program data (1975-2019) were analyzed using the National Cancer Institute's (NCI's) Age-Period-Cohort Analysis Tool to examine temporal drivers of US CRC epidemiology. Longitudinal trends in clinicopathological profiles, therapeutic modalities, and 5-YS were further assessed via NCI's Joinpoint Regression Program. The relative risk (RR) of incidence increased exponentially in sequentially younger birth cohort, with the annual percentage change (APC) peaking at 6.11% in 20 - 24 years, while the RR of IBM declined in successively older birth cohorts and showed no improvement in younger birth cohorts. Early-onset CRC with regional- or distant-predominant disease (notably hepatic) showed a marked shift from adjuvant to neoadjuvant therapy, including a notable increase in preoperative radiotherapy for regional rectal cancer from 19.7% (2000) to 53.8% (2019), and preoperative systemic therapy for distant colon cancer from 5.5% (2007) to 17.6% (2019). Correspondingly, stage-specific 5-YS was also superior in early-onset CRC (e.g., regional rectal cancer: 82.5% vs. 67.8%; distant colon cancer: 22.9% vs. 14.7%), with greater annual improvement (e.g., APC for regional rectal cancer: 1.60% vs. 1.46%; APC for distant colon cancer: 3.59% vs. 2.55%). However, over 50% of distant metastatic patients, especially those with late-onset disease, still received no effective treatment. While overall CRC burden decreased in the US, extreme early-onset CRC surged with poor prognosis. Despite higher regional/metastatic burden, early-onset CRC showed better survival owing to aggressive treatment and adherence. Urgent actions are needed to address the rising risk in youth and therapeutic gaps in metastatic disease.

This study aims to develop an alternative nanoparticle-based formulation for targeted colon cancer therapy. A biocompatible thermoplastic polyurethane-oleic acid-polyethylene glycol (TPU-OLE-PEG) copolymer was synthesised. Curcumin (CUR), a natural polyphenol, was loaded into the nanoparticles, followed by folate (FO) conjugation for enable targeted delivery to HT-29 colon adenocarcinoma cells. Optimised nanoparticles exhibited a spherical, homogeneous, and monodisperse morphology with an average size of 249 ± 5.7 nm, a zeta potential (ZP) of −28.9 ± 0.8 mV, and a polydispersity index (PDI) of 0.085. The drug loading efficiency exceeded 95%, while the folate conjugation efficiency reached 98.3%. In vitro release studies indicated sustained drug delivery over 19 days. Flow cytometry analysis revealed that CUR-loaded nanoparticles reduced HT-29 cell viability to 66.35%, and FO conjugation further decreased it to 52.74%. The FO-CUR-TPU-OLE-PEG nanoparticle system exhibits strong potential as a targeted therapeutic platform for colon cancer and represents a promising alternative to currently available formulations.

ROS-amplifying HKUST-1 nanozyme for enhanced colon cancer therapy.

The therapeutic efficiency of anticancer drugs can be improved by designing stimuli-responsive drug delivery system. In the current study, dextran as a hydrophilic polymer was connected to the surface of aminated graphene via pH-sensitive bond to prepare a novel pH-sensitive drug delivery system. Then, curcumin as a chemotherapy drug was loaded onto A-GO/Dex via π-π interactions and hydrogen bonds to prepare A-GO/Dex/Cur with high loading capacity for curcumin (14.9%). The samples were analyzed by various techniques including FT-IR, TGA, TEM, XRD and DLS. A-GO/Dex/Cur revealed a pH-dependent drug release profile and possessed higher cytotoxicity and significant anticancer effects on colon cancer cells as compare to free curcumin. The results indicated the prepared pH-responsive polymer nanocomposite could be used as a promising nanocarrier for curcumin delivery in therapy of colon cancer.

High efficacy and biocompatibility: Application and biological evaluation of LA67 liposome in colon cancer therapy.

Mannose-functionalized liposomal delivery of levamisole and lipopolysaccharide enhances therapeutic responses through tumor-associated macrophage modulation in colon cancer.

Colorectal cancer (CRC) poses a serious threat to human health. CRISPR/Cas9 technology offers new therapeutic strategies for the management of this disease, but its oral application is severely hindered by the limitations of suitable delivery systems. Herein, we develop and compare two separate orally delivered, genetically and chemically modified CRISPR/Cas9 delivery platforms based on E. coli BL21 and P. pastoris X33, which upon colonization in the intestine, secreted extracellular vesicles carrying the Cas9 protein and ART1-targeting sgRNA for tumor-specific gene disruption. Arginine ADP-ribosyltransferase 1 (ART1) plays a crucial role in the biological regulation of colon cancer, which was for the first time to the best of our knowledge, employed in vivo as a target gene in this study. Furthermore, we employed polydopamine (PDA) coating and gastrointestinal synthetic epithelial lining systems to facilitate microbial viability and intestinal retention, establishing on site cell factories for sustained CRISPR secretion. In subcutaneous tumor-bearing murine models, both delivery systems demonstrated comparable antitumor efficacy with significant tumor suppression. Taken together, the genetically modified microbial platform using bacterial and yeast strategies shows great potential and broad therapeutic versatility, offering a promising CRISPR-based solution for CRC treatment.

Background/Objectives: Ribosome-inactivating proteins (RIPs) are plant-derived enzymes with potent cytotoxic activity, widely studied as anticancer agents, particularly as toxic payloads in immunoconjugates. Despite numerous encouraging results reported, their clinical application has been limited by their immunogenicity. RIPs from edible plants have been proposed as potentially more suitable candidates due to their possible improved tolerability. However, this aspect still requires validation in vivo in animal models. This study investigated the cytotoxic activity, mechanisms of action and translational potential of sodin 5 (a recently characterized type 1 RIP derived from the edible plant Salsola soda L.) in human colon cancer models, comparing it to the well-known type 1 RIP saporin-S6. Methods: The effects of sodin 5 and saporin-S6 on cell viability, cell death mechanisms and epithelial barrier integrity were assessed on HT29 and Caco-2 cell lines. Sodin 5 cross-reactivity with other anti-type 1 RIP sera was evaluated by ELISA. Finally, its structural characteristics were analyzed. Results: Sodin 5 showed a cytotoxic effect comparable to that of saporin-S6 in HT29 and Caco-2 colon cancer cells, with time- and concentration-dependent reductions in viability. Both type 1 RIPs disrupted the integrity of the intestinal epithelial barrier in mono- and co-culture models and predominantly activated the apoptotic pathway, without inducing necrosis. Sodin 5 exhibited limited immunological cross-reactivity and a conserved catalytic core, supporting its potential relevance as a therapeutic payload for intestinal cancer therapy. Conclusions: Our results indicate that sodin 5 possesses promising characteristics for anticancer applications, particularly in the treatment of intestinal malignancies, where local exposure and repeated administration are often required.

RGD-modified hollow mesoporous nanoparticles loaded with cisplatin for antitumor therapy in colon cancer.

Malignant left-sided large-bowel obstruction remains a high-risk presentation that often requires urgent decompression. Self-expanding metal stents (SEMS) can convert an emergency to an elective operation and may create a window for staging, multidisciplinary planning, and (in selected patients) neoadjuvant systemic therapy. Photodynamic therapy (PDT) is a light-activated, locally delivered ablative modality that has been used historically for palliation or local control of colorectal and pelvic recurrences, but its role in contemporary management of obstructing colon cancer remains investigational. We present an anchoring case of obstructive rectosigmoid adenocarcinoma managed with endoscopic SEMS placement, interval endoluminal PDT, followed by systemic neoadjuvant therapy and curative resection with a pathologic complete response. Using this case as a framework, we review established management pathways for obstructing left-sided colon cancer (emergency surgery, diversion, and SEMS as a bridge to surgery), summarize evidence and guideline positions on SEMS and neoadjuvant therapy for resectable colon cancer, and synthesize the limited clinical literature describing PDT in colorectal malignancy. We emphasize that, given the multimodal sequence and existing evidence base, PDT should be viewed as a potential adjunct to-rather than a replacement for-SEMS, systemic therapy, or standard oncologic surgery. This case illustrates technical feasibility and conceptual integration, but does not establish efficacy; prospective study is needed to define patient selection, timing, and safety.

Colon cancer is still one of the biggest health challenges globally, and most of the available treatments are hindered by drug resistance, systemic toxicity, and suboptimal efficacy. The Poly (beta-amino esters) (PBAE)-based nanoparticles have emerged as a promising nanotechnology-driven solution to these challenges. This review begins with the synthesis and functionalization of PBAE nanoparticles by focusing on polymerization techniques, targeting strategies, and scalability for clinical applications. The physicochemical properties of these nanoparticles, such as particle size, surface morphology, zeta potential, stability, biodegradability, and drug loading efficiency, are discussed in relation to their impact on therapeutic performance. Mechanistic insights into drug encapsulation, controlled release, tumour targeting, and the potential to overcome Multidrug Resistance (MDR) are also provided. Mechanistic insights are provided, including hydrophobic interaction-based drug encapsulation for efficient drug loading, pH-responsive controlled release in acidic tumor microenvironments, receptor-mediated tumour targeting using surface-functionalized ligands, and strategies to overcome Multidrug Resistance (MDR). Thereafter, preclinical studies are assessed, which include in-vitro cytotoxicity experiments and in-vivo animal models that test for efficacy, pharmacokinetics, and biodistribution. The review will then assess the status of PBAE nanoparticles in clinical trials, focusing on safety, efficacy, and the effects on patient outcomes in colorectal cancer treatment. Finally, regulatory approval, toxicity assessments, and commercialization challenges are discussed along with recommendations for overcoming these barriers. The review concludes by highlighting advancements in nanoparticle design, emerging therapeutic strategies, and the future potential of PBAE nanoparticles to transform colorectal cancer treatment.

Sishen Wan suppresses colon cancer through dual inhibition of PI3K/AKT/mTOR and STAT3-mitophagy pathways: Network pharmacology and experimental validation.

Immunological functions of Th17 Cells in colon cancer: From pathogenic mechanisms to emerging treatments.

Targeting epithelial-mesenchymal transition and apoptosis: novel histone methyltransferase inhibitors for colon cancer suppression.

The clinical application of small interfering RNA (siRNA) therapy is limited by instability, inefficient tumor targeting, and inadequate responsiveness to the hypoxic tumor microenvironment. Therefore, this study aimed to construct a hypoxia-sensitive polymer-based nanocarrier to improve siRNA delivery efficiency and enhance antitumor effects in colorectal cancer (CRC). A hypoxia-sensitive polymer (mPEG-Azo-PEI) was synthesized and its cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The polymer was loaded with siRNA targeting the METTL3 gene to form nanoparticles, which were then optimized and characterized. Coumarin-loaded nanoparticles were also prepared to study the cellular uptake in HCT116 cells under hypoxic conditions. The Antitumor effects were evaluated via MTT and real-time polymerase chain reaction (RT-PCR) in vitro and in vivo, and a rectal cancer model was established using HCT116 cells in nude mice. Tumor size, weight, and histology (HE staining) were assessed, and RT-PCR analyzed METTL3 ex-pression. The CMC of mPEG-Azo-PEI was 0.001687 mg/mL, indicating good self-assembly stability under dilution conditions. The optimized mPEG-Azo-PEI@siRNA2 nanoparticles exhibited a mean particle size of 141.34 ± 2.31 nm, a PDI of 0.213 ± 0.011, and a zeta potential of +21.76 ± 1.76 mV. Hypoxia-triggered release reached ~95% within 24h, compared with ~10% under normoxic conditions. Coumarin uptake by HCT116 cells was enhanced under hypoxic conditions, indicating improved intracellular delivery. In vitro, the nanoparticles inhibited tumor cell proliferation, with IC50 values of 1.133 (normoxia) and 0.481 (hypoxia) nM. In vivo, mPEG-Azo-PEI@siRNA2 significantly suppressed tumor growth and improved body weight. RT-PCR confirmed the downregulation of METTL3, aligning with tumor suppression. These results demonstrated that hypoxia-sensitive mPEG-Azo-PEI@siRNA2 nanoparticles effectively delivered siRNA2 and inhibited HCT116 cell proliferation, offering a promising hypoxia-activated targeting strategy for colon cancer therapy.

Standard of care for non-metastatic colon cancer is surgery followed by stage-guided adjuvant therapy and/or structured follow-up. Upfront surgery in resectable colon cancer is irrespective of local T/N stage, whereas adjuvant systemic therapy is recommended according to pathological staging. The role of neoadjuvant chemotherapy remains unclear. Whereas perioperative systemic therapy in colon cancer seems to be safe and may lead to pathologic downstaging, evidence on improved survival and quality of life remains scarce. The PROTECTOR / FIRE‑10 trial aims to generate evidence that perioperative systemic therapy improves survival without compromising quality of life in locally advanced, mismatch-repair proficient colon cancer patients. Open-label, randomized, controlled, multicenter, phase III study with two parallel arms. Patients with locally advanced colon or upper rectal cancer staged cT3-4 and/or cN+ are randomized in a 2:1 fashion (favoring preoperative therapy) to investigate the efficacy, patient reported quality of life, and safety of preoperative therapy followed by surgery (Arm A) versus direct surgery followed by non-study specific stage-guided adjuvant therapy (Arm B). Stratification during randomization will be performed according to the following parameters: Fit for mFOLFOXIRI vs. mFOLFOX/CAPOX vs. 80%-mFOLFOX/CAPOX, ECOG 0 vs. ECOG 1-2, and left-sided primary vs. right-sided primary tumor. Only patients with confirmed mismatch-repair proficient and/or microsatellite stable tumor can be included. Preoperative treatment in Arm A is performed for a maximum of 6 biweekly cycles of FOLFOX/FOLFOXIRI or for a maximum of 4 triweekly cycles CAPOX (i.e., appr. 12 weeks). Patients in both arms should undergo quality-controlled surgery of the primary tumor, performed as complete mesocolic excision. Patients will be followed up with regard to relapse, survival and if applicable subsequent anti-cancer treatments until death or for at least 5 years after randomization, whichever date is earlier. The PROTECTOR / FIRE‑10 trial compares preoperative systemic therapy to upfront surgery (with stage-guided adjuvant therapy) in patients with locally advanced colon cancer. This study is registered with clinicaltrials.gov (NCT06899477) and EudraCT (2023-508076-11-00).

In recent years, cancer has emerged as a significant challenge for healthcare systems, posing challenges to researchers to develop new treatments. Among various cancers, colorectal cancer is a major cause of death worldwide. To develop novel compounds that strongly inhibit colon cancer cells, lonidamine-1,3,4-oxadiazole derivatives 7(a–h) were designed and synthesized. The prepared compounds were characterized by various spectral techniques, including NMR (1H and 13C), mass spectra, and HPLC. Cytotoxicity tests conducted on a colorectal cancer cell line indicated that compound (7d) demonstrated significant antiproliferative effects, achieving the lowest IC50 value of 12.91 ± 1.58 µM, thereby making it the most effective among the compounds tested. This compound induces apoptosis, as evidenced by Hoechst/PI double staining, and mitigates cell migration, demonstrating its antiproliferative and antimigratory capabilities. Molecular docking, dynamics simulations, and DFT studies helped clarify the structure–activity relationship (SAR) and mechanisms of action. ADME and toxicity predictions also supported its drug-like properties. SAR analysis identified key substituents influencing activity, guiding further optimization. Overall, compound (7d) appears to be a promising candidate for colon cancer therapy, though additional studies are necessary to assess its clinical potential. These findings could be used for designing novel cancer therapeutic or preventive LND-derived agents.

Curcumin (CUR) exhibits potent anti-cancer effects; however, its poor water solubility limits its clinical use. This study explores gelatin nanoparticles (GelNPs) as nanocarriers to improve curcumin delivery. We aimed to enhance the release and efficacy of photosensitive curcumin-loaded GelNPs (Cur-GelNPs) using infrared (IR) light-induced localized hyperthermia in a 3D co-culture cancer model. Cur-GelNPs were synthesized and characterized via DLS, FTIR, STEM, Raman, HPLC, and DSC. Cytotoxicity, migration, invasion, apoptosis, and drug resistance were assessed using MTT, Transwell, Hoechst/PI staining, and Rho123 assays, respectively. Optimal results were achieved by IR treatment at 38 °C for 30 s. Cur-GelNPs localized in the cytoplasm due to curcumin’s natural fluorescence. At 25 µg/ml, Cur-GelNPs significantly reduced the viability, invasion, and migration of colon cancer cells, while promoting apoptosis and mitochondrial damage—more effectively when combined with IR. Importantly, minimal toxicity was observed in healthy cells, suggesting selective cancer targeting. This method enables spontaneous drug-macromolecule binding, reducing time, cost, and labor. Overall, IR-activated Cur-GelNPs represent a promising approach for targeted colon cancer therapy and may offer broader contributions to nanomedicine and drug delivery systems.