Design of folate-conjugated chitosan-pectin nanoparticles as oral colon-specific 5- fluorouracil delivery system for colon cancer treatment / Nafisah Musa
Microencapsulation of polysaccharidic nanoparticles is met with nanoscale and biological performance changes. This study designs soft agglomerates as nanoparticle vehicle to delay the drug release of nanoparticles without them undergoing physical processes that alter their geometry. The nanoparticle...
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| Format: | Thesis |
| Language: | English |
| Published: |
2021
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| Subjects: | |
| Online Access: | https://ir.uitm.edu.my/id/eprint/53636/1/53636.pdf |
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| Summary: | Microencapsulation of polysaccharidic nanoparticles is met with nanoscale and biological performance changes. This study designs soft agglomerates as nanoparticle vehicle to delay the drug release of nanoparticles without them undergoing physical processes that alter their geometry. The nanoparticles were made of high molecular weight chitosan/pectin with covalent 5-fluorouracil/folate. Nanoparticle aggregation vehicle was prepared from low molecular weight chitosan. The nanoparticles and aggregation vehicle were blended in specific weight ratios to produce soft agglomerates. Nanoparticles alone are unable to agglomerate. Adding aggregation vehicle (< 2 μm) promoted soft agglomeration with nanoparticles deposited onto its surfaces with minimal binary coalescence. The large and rough-surfaced aggregation vehicle promoted nanoparticles deposition and agglomeration. A rounder vehicle allowed assembly of nanoparticles-on-aggregation vehicle into agglomerates through interspersing smaller between larger populations. Soft agglomerates alone appeared to retard drug release in the upper gastrointestinal tract, but not able to meet the colon-specific requirement. This study probed into intracapsular-coating of soft agglomerates. In vitro drug content, drug release, in vivo pharmacokinetics including local colonic drug content, in vivo pharmacodynamics including tumour, aberrant crypt foci and clinical chemistry profiles of intracapsular-coated and uncoated soft agglomerates as well as cytotoxicity of nanoparticles were examined against the unprocessed drug. Intracapsular-coated soft agglomerates of chitosan-folate-carboxymethyl-5-FU conjugate/pectin nanoparticles with nanoparticle aggregation vehicle by means of a mix of sodium alginate and 2:1 weight ratio of calcium phosphate to calcium acetate mediated oral colon-specific drug release in vitro. The intracapsular-coated soft agglomerates were characterized to reduced drug bioavailability and enhanced drug accumulation at colon. They reduced tumor number and size (ANOVA: p < 0.05), through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike intracapsular-coated soft agglomerates of chitosan-carboxymethyl-5-FU conjugate/pectin nanoparticles with nanoparticle aggregation vehicle and unprocessed drug, the intracapsular-coated soft agglomerates of chitosan-folate-carboxymethyl-5-FU conjugate/pectin nanoparticles with nanoparticle aggregation vehicle eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. MTT assay showed that covalent conjugation of drug onto the polymeric backbone, polyelectrolyte coacervation and nanoparticulation reduced the drug cytotoxicity against the HCT 116 human colon cancer cells. Soft agglomeration and intracapsular coating of chitosan-folate/pectin coacervate nanoparticles enable orally targeting 5-fluorouracil at the cancerous colon. |
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