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Nanocarriers for the delivery of anticancer drugs and siRNA

Elsaid, Z; (2015) Nanocarriers for the delivery of anticancer drugs and siRNA. Doctoral thesis , UCL (University College London).

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Abstract

Background and Purpose: Optimal benefit in the treatment of lung cancer is impeded due to systemic side effects, sub-therapeutic drug levels at the tumour site and the development of multidrug resistance. This thesis describes three related but distinct strategies aimed at enhancing drug treatment of lung cancer. Methods: The first approach entails design of micelles using three amphiphilic derivatives of chitosan (TPGS-chitosan, retinoic acid-chitosan-PEG and lipoic acid-chitosan-PEG (LACPEG)) for the pulmonary delivery of siRNA. Polymers where characterized using FT-IR and 1H NMR. Micelles prepared from these polymers were characterised for their size, zeta potential, morphology and toxicity in A549 and PC-9 cells. Micelle complexation with siRNA was assessed using agarose gel electrophoresis and the PicoGreen assay. Gene knockdown was assessed by MTS assay and western blotting. LACPEG and LACPEG/DSPE-PEG nanocarriers were loaded with gefitinib and re-characterised for their physicochemical properties, entrapment efficiency and activity (cell death) in vitro. In vivo biodistribution of these nanocarriers was assessed in CT26 and LLC-tumour bearing BALB/c and C57BL6 mice, respectively. The third approach to drug delivery employed mixed nanocarriers of DSPE-PEG or TPGS and PLGA-PEG, for co-delivery of gefitinib and genistein. Results: Successful synthesis of amphiphilic derivatives of chitosan. Further optimisation needed for micelles prepared using the first strategy with respect to siRNA complexation, as although 100% complexation was observed using agarose gel electrophoresis and the PicoGreen assay, at an NP ratio of 1:160, this was not reflected in cell culture. LACPEG micelles, showing the smallest size, best stability and lowest toxicity, were further studied and mixed with micelles of DSPE-PEG, for improved loading of gefitinib (45% compared to 80%). These showed improved antitumour activity in vitro and whole body prolonged circulation with tumour accumulation and uptake in vivo. Similar results were obtained with gefitinib and genistein mono- and co-loaded PLGA-PEG/TPGS nanocarriers. Conclusion: LACPEG/DSPE-PEG and PLGA-PEG/TPGS nanocarriers showed promise for the delivery of anticancer drugs, demonstrating a synergistic activity from the carrier itself, as well as the co-delivery of both therapeutic molecules. Further studies are warranted for siRNA complexation.

Type: Thesis (Doctoral)
Title: Nanocarriers for the delivery of anticancer drugs and siRNA
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: http://discovery.ucl.ac.uk/id/eprint/1467125
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