Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700837
Title: RGD-targeted solid lipid nanoparticles containing asiatic acid for the treatment of cancer
Author: Garanti, Tanem
ISNI:       0000 0004 5989 108X
Awarding Body: University of Central Lancashire
Current Institution: University of Central Lancashire
Date of Award: 2016
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Abstract:
Selective anti-cancer treatment and targeting is needed to help minimise unwanted side-effects from conventional chemotherapy. Advanced drug delivery systems (DDSs) that have the potential for passive and active targeting have been of significant interests in the past decades, particularly with the use of nano-based drug carriers. The concept of targeting to the tumour vasculature or angiogenic blood vessels has continued to be of interests in cancer research since 1970s, as it offers promising therapeutic applications for many solid tumours. Active targeting of DDSs relies on specific interactions between the ligand (generally conjugated onto the surface of DDSs) and its receptor, which is overexpressed on target tumour tissues. In this study, arginine-glycine-aspartic acid (RGD) tripeptide was used to target the αvβ3 integrin receptor that is overexpressed by both tumour endothelial cells and various tumour tissues, potentially providing a double-killing (by targeting tumour and tumour endothelial cells) effect. Asiatic acid (AA) is an extract from a medical plant, Centella Asiatica and has demonstrated potential anti-inflammatory, as well as anti-angiogenic and anti-cancer properties. However, its poor water solubility (0.03 mg/mL) is one of the major limitations for its progression for clinical applications. To help overcome the solubility issue of AA and also to improve its therapeutic efficacy, AA was incorporated into RGD-containing solid lipid nanoparticles (SLNs) after optimisation of the SLN preparation comprised of glyceryl monostearate, glyceryl distearate and glyceryl tristearate lipids and subsequent characterisation on their physicochemical properties. The targeting ability of these AA-containing RGD-conjugated SLNs and their apoptotic / necrotic induction on cancer cells were assessed using U87 MG glioma cells and ECV-304 bladder cancer endothelial-like cells, which are known to express αvβ3 integrin. Moreover, the efficacy of both AA and AA-loaded SLNs were tested for the first time on in vitro 3D U87 MG tumour spheroids. Besides the anti-tumour efficacy, AA-containing RGD-SLNs were also investigated for their potential anti-angiogenic effect using various cellular assays of ECV-304 endothelial-like cells. Results obtained from this study showed that RGD-targeted SLN formulations improved the cellular uptake of nanoparticles compared to non-RGD containing SLNs and thus enhanced drug accumulation and cytotoxic effect seen on U87 MG and ECV-304 cells. Furthermore, AA-containing SLNs showed prevention of spheroid formation, inhibition of spheroid growth and cytotoxic effect on U87 MG spheroids, where RGD-SLNs also showed improved spheroid penetration compared to non-RGD containing SLNs. In addition, AA-loaded RGD-SLNs showed potential anti-angiogenic effect by demonstrating concentration-dependent inhibition of cell adhesion, migration and invasion, as well as disruptions in tube network of endothelial cells in in vitro angiogenesis assay. To conclude, AA-loaded RGD-targeted SLNs showed promising anti-cancer and anti-angiogenic effects in vitro, which supports its development for future clinical applications and warrants further investigation on an appropriate in vivo angiogenesis model to maximise its clinical potential.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.700837  DOI: Not available
Keywords: B210 - Pharmacology
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