Please use this identifier to cite or link to this item:
https://ptsldigital.ukm.my/jspui/handle/123456789/485650| Title: | Pluronic F127-TPGS-chitosan micelles functionalized with folic acid for the targeted co-delivery of sirna and doxorubicin |
| Authors: | Adeel Masood Butt (P59567) |
| Supervisor: | Mohd Cairul Iqbal Mohd Amin, Prof. Dr. |
| Keywords: | Doxorubicin (DOX) Cancer Tumours Multidrug resistance Dissertations, Academic -- Malaysia |
| Issue Date: | 30-Nov-2015 |
| Description: | Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance. Keeping in view of the problems, micellar system consisting of Pluronic F127 (PF127), chitosan (CS) and TPGS encapsulating DOX and complexed with siRNA was designed and conjugated with folic acid (FA) for selective targeting to tumours and reducing the multidrug resistance. The conjugation of FA with CS and PF127 was confirmed by UV, FTIR and NMR spectroscopy. Degree of substitution (DS) of FA onto PF127 and CS was 2 % and 7 % respectively. Micelles were prepared by thin film hydration method followed by CS or CS-FA coating. The critical micelles concentration (CMC) was 0.001% (w/v), hydrodynamic size of siRNA complexed PF127-TPGS-CS-FAmicelles (polyplexes) was 92 ± 11 nm and zeta potential was 7 ± 2 mV. DOX encapsulation efficiency and drug loading content were 72 ± 7 % and 1.8 ± 0.21 % respectively, whereas the siRNA loading efficiency was 98.5 ± 1 %. DOX release was enhanced at pH 5 as compared to pH 7 which could allow for the improved efficacy owing to improved release rates in acidic tumour microenvironments. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. It was observed that polyplexes enhanced cellular uptake of encapsulated DOX from 5 to 12 and 0.36 to 5 ng/μg of protein in 4T1 and 4T1-mdr cell lines, respectively. Treatment of cells with micelles or polyplexes reduced drug efflux, increased DOX-DNA binding in SKOV3 and doxorubicin resistant SKOV3-DOX human ovarian carcinoma cell lines and enhanced in vitro cytotoxicity (in MCF-7, SKOV3 and 4T1 cell lines) as compared to free DOX. Administration of DOX-loaded polyplexes resulted in enhanced tumour inhibition efficacy against 4T1 and 4T1-mdr breast tumour models in BALB/c mice. The tumour volume at the completion of treatment was reduced significantly (p<0.05) by 94 and 88% in mice with 4T1 and 4T1-mdr tumours as compared to 58 and 28% tumour inhibition in free DOX groups, respectively. The lungs in the groups treated with polyplexes showed minimal metastasis and improved median survival times. HPLC analysis of the tumour tissues showed that the highest concentration of DOX was present in groups treated with polyplexes in both drug sensitive and drug resistant tumours. Thus it could be concluded that DOX-loaded PF127-TPGS-CS-FA polyplexes have an excellent prospect as a targeted nano drug delivery system for co-delivery of DOX and siRNA due to multiple synergistic factors of selective anticancer activity, inhibition of MDR by siRNA and folate-mediated selective cellular uptake.,Doctor of Philosophy |
| Pages: | 208 |
| Call Number: | QU188.A228p 2015 9 |
| Publisher: | UKM, Kuala Lumpur |
| Appears in Collections: | Faculty of Pharmacy / Fakulti Farmasi |
Files in This Item:
| File | Description | Size | Format | |
|---|---|---|---|---|
| ukmvital_83934+Source01+Source010.PDF Restricted Access | 241.15 kB | Adobe PDF |  View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.