This study aimed to assess the therapeutic potential of nisin,5-fluorouracil(5FU)and selenium encapsulated in folate-conjugated thiolated chitosan nanoparticles(N/5FU/Se@FTCsNPs),combined with a probiotic cocktail of ...This study aimed to assess the therapeutic potential of nisin,5-fluorouracil(5FU)and selenium encapsulated in folate-conjugated thiolated chitosan nanoparticles(N/5FU/Se@FTCsNPs),combined with a probiotic cocktail of Lactobacillus acidophilus and Bifidobacterium bifidum,against colorectal cancer(CRC).The nanoparticles(277 nm,+9.2 mV)exhibited high drug loading efficiencies(5FU:89.11%,nisin:70.68%)and pH-responsive release,with minimal drug release under gastric conditions and∼60.7%release at colonic pH,facilitating targeted delivery.The formulation remained stable for over 40 d at−20°C and 4°C,demonstrating excellent biocompatibility(<2%hemolysis)and exhibiting strong mucoadhesive and mucus-penetrating abilities.In vitro,N/5FU/Se@FTCsNPs selectively targeted CT26 colon cancer cells(IC5n:1.57μg/ml)with minimal effects on healthy cells,enhanced cellular uptake,and induced ROS-mediated apoptosis.In vivo,oral administration-especially with probiotics-significantly reduced tumor volume,improved survival rates and alleviated chemotherapy-related side effects such as diarrhea and weight loss.Biodistribution studies confirmed increased tumor targeting and decreased off-target exposure.Mechanistically,the treatment downregulated oncogenes and inflammatory markers(2-to 12.5-fold),includingβ-catenin,mTOR,COX-2 and VEGF-α,while upregulating tumor suppressors and protective genes(4 to 14.8 fold),such as PTEN,CASP9 and Mucin 2(P<0.0001).This indicates inhibition of proliferation,metastasis,inflammation,and angiogenesis,along with improved gut barrier function.Cytokine profiling and histological analysis further confirmed reduced systemic inflammation and maintained hematological safety.These findings highlight N/5FU/Se@FTCsNPs combined with probiotics as a promising,safe and effective oral therapy for CRC,leveraging microbiota modulation and targeted delivery.展开更多
基金supported by the Research Council of Tarbiat Modares University and the Iran National Science Foundation(INSF)(Grant Number:4043897).
文摘This study aimed to assess the therapeutic potential of nisin,5-fluorouracil(5FU)and selenium encapsulated in folate-conjugated thiolated chitosan nanoparticles(N/5FU/Se@FTCsNPs),combined with a probiotic cocktail of Lactobacillus acidophilus and Bifidobacterium bifidum,against colorectal cancer(CRC).The nanoparticles(277 nm,+9.2 mV)exhibited high drug loading efficiencies(5FU:89.11%,nisin:70.68%)and pH-responsive release,with minimal drug release under gastric conditions and∼60.7%release at colonic pH,facilitating targeted delivery.The formulation remained stable for over 40 d at−20°C and 4°C,demonstrating excellent biocompatibility(<2%hemolysis)and exhibiting strong mucoadhesive and mucus-penetrating abilities.In vitro,N/5FU/Se@FTCsNPs selectively targeted CT26 colon cancer cells(IC5n:1.57μg/ml)with minimal effects on healthy cells,enhanced cellular uptake,and induced ROS-mediated apoptosis.In vivo,oral administration-especially with probiotics-significantly reduced tumor volume,improved survival rates and alleviated chemotherapy-related side effects such as diarrhea and weight loss.Biodistribution studies confirmed increased tumor targeting and decreased off-target exposure.Mechanistically,the treatment downregulated oncogenes and inflammatory markers(2-to 12.5-fold),includingβ-catenin,mTOR,COX-2 and VEGF-α,while upregulating tumor suppressors and protective genes(4 to 14.8 fold),such as PTEN,CASP9 and Mucin 2(P<0.0001).This indicates inhibition of proliferation,metastasis,inflammation,and angiogenesis,along with improved gut barrier function.Cytokine profiling and histological analysis further confirmed reduced systemic inflammation and maintained hematological safety.These findings highlight N/5FU/Se@FTCsNPs combined with probiotics as a promising,safe and effective oral therapy for CRC,leveraging microbiota modulation and targeted delivery.
