Development and Evaluation of Nanoparticulate Drug Delivery Systems for Anticancer Drugs

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dc.contributor.advisor Associate Professor Sanajy Garg en
dc.contributor.advisor Professor Bruce Baguley en Ganta, Srinivas en 2008-10-10T01:06:12Z en 2008-10-10T01:06:12Z en 2008 en
dc.identifier.citation Thesis (PhD--Pharmacology)--University of Auckland, 2008. en
dc.identifier.uri en
dc.description.abstract The main aim of this study was to develop nanoparticulate drug delivery systems for chlorambucil (CHL) and asulacrine (ASL). CHL is a DNA alkylating agent. In an attempt to alter the pharmacokinetics (short half-life, rapid clearance and high volume of distribution) and improve the anticancer activity, CHL was incorporated into a lipid nanosphere (LN) formulation. The LN were composed of soybean oil as the internal oil phase, egg lecithin as the primary emulsifier, cholesterol as the phospholipid layer stabilizer, and water as the external phase. PEG-modified (long circulating) and DOTAP-modified (cationic) LN were prepared to evade the reticulo-endothelial system and enhance cellular delivery, respectively. LN prepared by ultra-sonicater and microfluidizer had an average particle size below 200 nm, with a CHL encapsulation efficiency of over 97%. Zeta potential of the LN ranged from -30.6 to +41.5 mV. The LN exhibited good physical stability over six months at 4°C and 25°C. In vitro evaluation on SKOV-3 cells showed that the cytotoxicity and the pro-apoptotic activity of CHL were significantly enhanced when given in the LN formulation compared to the CHL solution (P<0.05). An altered pharmacokinetics with increased plasma AUC and elimination half-life, and reduced clearance were observed after intravenous administration of CHL incorporated LN compared to a CHL solution (P<0.01). A marked reduction in the tissue distribution of CHL was also noted when it was given in LN. In addition, CHL incorporated in LN showed greater anticancer activity compared with the CHL solution in colon-38 tumour-bearing mice (P<0.01). These results suggest that LN could be an effective parenteral carrier for CHL delivery. ASL is an inhibitor of topoisomerase II. In an attempt to improve its efficacy by altering the pharmacokinetic profile, ASL was formulated as a nanocrystal suspension (NS). The NS was consisting of ASL nanoparticles produced by high pressure homogenization and stabilized by stabilizers. The lyophilized NS exhibited good stability over three months at 4°C and 25°C. The dissolution and solubility of ASL were enhanced in NS form compared to un-milled ASL (P<0.05). Initial peak plasma concentration and AUC were remarkably reduced in the plasma after intravenous administration of NS compared to the ASL solution (P< 0.01). This suggests reduced systemic exposure to the drug. en
dc.language.iso en en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA1841718 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. en
dc.rights.uri en
dc.title Development and Evaluation of Nanoparticulate Drug Delivery Systems for Anticancer Drugs en
dc.type Thesis en Pharmacology en The University of Auckland en Doctoral en PhD en
dc.subject.marsden Fields of Research::320000 Medical and Health Sciences::320500 Pharmacology and Pharmaceutical Sciences en
dc.rights.holder Copyright: The author en
pubs.local.anzsrc 11 - Medical and Health Sciences en Faculty of Medical & Hlth Sci en

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