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Title: Evaluation of PAMAM dendrimers as delivery vehicles for platinum based anticancer drugs
Author: Kirkpatrick, Gordon
ISNI:       0000 0004 2739 8661
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2012
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Four carboxylate terminated half generation polyamdioamine (PAMAM) dendrimers (G3.5- G6.5) were conjugated with the active components of cisplatin, {Pt(NH3)2}2+, or oxaliplatin, {Pt(R,R-dach)}2+, to form dendrimer platinate complexes. The platinum content of the cisplatin containing complexes was measured using inductively coupled plasma atomic emission spectroscopy. The number of cisplatin molecules was found to increase with increasing dendrimer size, 22 – 94, however the assumed bidentate binding mode allows for a total of 32 – 256 cisplatin moieties per dendrimer. Whilst the number of cisplatin moieties increases with dendrimer size, a decrease in the binding efficiency is also observed with dendrimer size, 68 – 37% (G3.5- 6.5). This decrease is probably due to the close proximity of surface groups of larger dendrimers, i.e. more branched, increasing the difficulty in deprotonating the carboxylic acids to obtain the carboxylate required for coupling. The release of the platinum from the dendrimers, in the active form, was evaluated using 1H NMR or inductively coupled plasma mass spectroscopy (ICP-MS). An increase in the number of active cisplatin molecules released is observed with larger dendrimers, four from the G3.5 dendrimer to 59 from the G6.5 dendrimer, with the release efficiency increasing from 18 – 63%. Diffusion ordered spectroscopy NMR was also used to determine the size of the dendrimer platinate complexes. The free dendrimers increased from 2.72 to 5.93 nm, cisplatin dendrimer platinates from 1.66 to 4.01 nm and oxaliplatin dendrimer platinates from 4.03 to 14.51. The dendrimer platinates and free dendrimers were tested in vitro against the A2780 and A2780cis cancer cell lines and their activity compared to cisplatin. In all cases the dendrimer platinates showed reduced activity when compared to cisplatin whilst the free dendrimer showed no activity in vitro, IC50 > 100 mM. The in vivo activity of the G6.5 dendrimer platinate was tested in nude mice bearing A2780 xenografts and compared to cisplatin using a single dose of equivalent concentration and the G6.5 dendrimer platinate was shown to have a similar activity in vivo as cisplatin after 6 days. Similar dendrimer-platinate complexes were formed with the active component of oxaliplatin, {Pt(R,R-dach)}2+. The dendrimer-platinates were found to contain 12-63 platinum molecules per dendrimer, a reduction on the number observed for the complexes formed with the active component of cisplatin. The size of the oxaliplatin dendrimer-platinates was also determined to be greater than the cisplatin equivalent, most likely as a result of aggregation due to the hydrophobic nature of the dach ligand. The number of platinum groups released from the dendrimer is also lower than the equivalent cisplatin complexes with only 2-43 platinum moieties being released. The platinum was shown to be released from the dendrimer in an initial burst release within the first 2 hours, accounting for 85% of the releasable platinum. The {Pt(R,R-dach)}2+ dendrimer-platinates were shown to be more cytotoxic in vitro than the free {Pt(R,Rdach)} 2+ complex. In a further study a folic acid targeting group was also attached to the dendrimers to allow active targeting of cancer cells through the folate receptor. Folic acid was conjugated to 1,6-diamminohexane via an amide coupling reaction. The linker was then attached to the dendrimer through a further amide coupling reaction prior to the addition of the platinum complexes. The resulting complexes were found to contain 3-8 folate targeting groups depending on dendrimer size. The targeted cisplatin dendrimerplatinates were shown to be more cytotoxic than the non-targeted complexes however the opposite was observed for the {Pt(R,R-dach)}2+ dendrimer-platinates. The uptake of platinum by the cells increased for the folate targeted cisplatin dendrimer-platinates but decreased for the {Pt(R,R-dach)}2+ dendrimer-platinates.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available