Nanoparticles-in-soft microagglomerates as oral colon-specific cancer therapeutic vehicle

Polymeric nanoparticles can be conjugated with targeting ligand such as folate to elicit oral colon-specific drug delivery to treat colon cancer. Oral chemotherapy can be used as adjuvant, neo-adjuvant, or primary therapy. Nonetheless, oral cancer chemotherapeutics may experience premature drug release at the upper gastrointestinal tract due to the availability of a large specific dissolution surface area of nanoparticles leading to failure in colon cancer targeting. This study designed soft microagglomerates as carrier of nanoparticles to delay drug release. High molecular weight chitosan/pectin with covalent 5-fluorouracil/folate was processed into nanoparticles. Low molecular weight chitosan was spray-dried into nanoparticle aggregation vehicle. The soft agglomerates were produced by blending of nanoparticles and aggregation vehicle in specific weight ratios through vortex method. Adding aggregation vehicle promoted soft agglomeration with nanoparticles deposited onto its surfaces with minimal binary coalescence. Soft agglomerates prepared from 10:18 weight ratio of nanoparticles to nanoparticle aggregation vehicle using 1% chitosan solution concentration reduced the propensity of premature drug release of nanoparticles in the upper gastrointestinal region. Soft agglomerates reduced early drug release of cancer chemotherapeutics and was responsive to intracapsular sodium alginate coat to further sustain drug release. The soft microagglomerates are a viable dosage form in colon-specific drug delivery. Further study will focus on investigating intracapsular-coated soft agglomerates in vivo pharmacokinetics and pharmacodynamics behaviours with respect to local colorectal cancer.

Chitosan-capped enzyme-responsive hollow mesoporous silica nanoplatforms for colon-specific drug delivery

An enzyme-responsive colon-specific delivery system was developed based on hollow mesoporous silica spheres (HMSS) to which biodegradable chitosan (CS) was attached via cleavable azo bonds (HMSS-N=N-CS). Doxorubicin (DOX) was encapsulated in a noncrystalline state in the hollow cavity and mesopores of HMSS with the high loading amount of 35.2%. In vitro drug release proved that HMSS-N=N-CS/DOX performed enzyme-responsive drug release. The grafted CS could increase the biocompatibility and stability, and reduce the protein adsorption on HMSS. Gastrointestinal mucosa irritation and cell cytotoxicity results indicated the good biocompatibility of HMSS and HMSS-N=N-CS. Cellular uptake results indicated that the uptake of DOX was obviously increased after HMSS-N=N-CS/DOX was preincubated with a colonic enzyme mixture. HMSS-N=N-CS/DOX incubated with colon enzymes showed increased cytotoxicity, and its IC50 value was three times lower than that of HMSS-N=N-CS/DOX group without colon enzymes. The present work lays the foundation for subsequent research on mesoporous carriers for oral colon-specific drug delivery.