Chitosan nanoparticles functionalised with protocatechuic acid improve colon-targeted pazopanib delivery with multi-pathway therapeutic regulation and pharmacokinetic optimisation in colorectal cancer

Poor pharmacokinetics, insufficient tumor-selective drug accumulation, and systemic toxicity are often the main obstacles to colorectal cancer (CRC) treatment. Here, protocatechuic acid-functionalized chitosan nanoparticles (PAZ-CS-PCA-NPs) were designed to enhance the pharmacological efficacy of pazopanib via colon-targeted administration. Ionic gelation and EDC/NHS functionalization were used to create PAZ-CS-PCA-NPs, which were then assessed for hemocompatibility, pharmacokinetics, biodistribution, therapeutic efficacy, gut microbiota regulation, cognitive function, and safety in a rat model of colorectal cancer induced by dimethylhydrazine. After five hours, PAZ-CS-PCA-NPs showed less than 0.8% haemolysis and kept platelet aggregation at about 20% as opposed to more than 90% in the positive Control. With improved colonic accumulation, as verified by fluorescence imaging, subsequent to intraperitoneal delivery, the nanoformulation significantly reduced the T max from 8.0 ± 0.5 h to 0.5 ± 0.1 h and elevated the C max from 0.377 ± 0.024 to 0.553 ± 0.020 μg mL⁻ 1 . Treatment increased GPx-1 from 2.578 to 8.828 ng mL⁻ 1 , decreased LPO from 26.874 to 8.929 ng mL⁻ 1 , and lowered IL-6 from 472.6 to 36.59 ng mL⁻ 1 . Furthermore, PAZ-CS-PCA-NPs revealed no significant treatment-related organ histopathological changes during acute toxicity assessment, reduced Morris water maze escape latency from 113.6 s to 58 s, altered the abundance of selected cultivable fecal bacterial populations under the tested culture conditions, and provided a translational nanotherapeutic approach for targeted CRC therapy.

This graphic summarizes the synthesis, characterization, targeted delivery, therapeutic efficacy, and major outcomes of PAZ-CS-PCA nanoparticles for colorectal cancer treatment in rats. The nanoparticles are synthesized by combining pazonanib, chitosan, and protocatechuic acid, forming chitosan nanoparticles with a PCA-grafted surface carrying pazonanib. Characterization includes a Morris water maze test showing escape latency reduced to 58 seconds with the nanoparticles, and hemocompatibility tests indicating reduced hemolysis and platelet aggregation. Targeted delivery is demonstrated by enhanced colonic uptake in Wister rats, with treatments showing reduced colorectal tumors, restored normal colon architecture, decreased tumor sizes on CT scans, suppressed disease-related anatomical distortion on radiography, and good acute tolerability. Therapeutic efficacy data show an increase in maximum concentration from 0.377 to 0.553 micrograms per milliliter. Gut microbiota analysis involves fecal cultures on MacConkey, Lombard-Dowell, and anaerobic agar. Major outcomes include increased maximum concentration to 0.553 micrograms per milliliter, decreased time to maximum concentration to 0.5 hours, increased GPx-1 to 8.828 nanograms per milliliter, decreased LPO to 8.929 nanograms per milliliter, decreased IL-6 to 36.59 nanograms per milliliter, hemolysis remaining at 0.8 percent, and latency decreased to 58 seconds.

Abstract from PubMed Central (PMID 42964559, PMC13719970). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.