The use of novel poly(allylamine) based amphiphilic polymers for drug delivery.

Hoskins, Clare

Abstract

Fourteen novel comb shaped amphiphilic polymers were successfully synthesised to determine the effect of polymer architecture on the potential of these amphiphilic polymers for hydrophobic drug delivery. Polyallylamine (PAA) was grafted with four different types of hydrophobic pendant groups (Cholesteryl (Ch), (Fmoc), (Dansyl)and (Naphth)). Some amphiphilic polymers were further reacted with methyl orange to form quaternary ammonium moieties. The polymers were characterised by elemental analysis and nuclear magnetic resonance spectroscopy (NMR). In the aqueous environment the amphiphilic polymers formed nano self assemblies with particle size from 99 to 284 nm. The critical aggregation concentration (CAC) of the self assemblies was successfully determined by surface tension measurement. The CAC ranged from the lowest value of 0.093 to the highest 1.5 mgmL-1 (Ch5 and Fmoc5 respectively). The Fmoc and Naphth grafted polymers showed the presence of two CMC values, this phenomenon was due to stacking of the planar hydrophobic ring structures resulting in excimer formation. The theory of excimer formation was confirmed by the observation of peak shifting on the emission spectra of the compounds in water over a large concentration range (0.023 “ 3 mgmL-1). The drug loading potential of the polymers was investigated using five model hydrophobic drugs, propofol, prednisolone griseofulvin, etoposide and novel anticancer agent BNIPDaoct. The Ch5 and Dansyl10 showed excellent drug solubilisation capacities. At 6 mgmL-1 the Ch5 achieved propofol solubility 70-fold greater than its aqueous solubility, prednisolone, griseofulvin and etoposide solubilitys were increased 20-fold, 30-fold and 7-fold respectively. Similarly at 6 mgmL-1 the Dansyl10 achieved a 200-fold increase on the aqueous solubility of propofol and increased the solubility of prednisolone, griseofulvin and etoposide by 100-fold and 400-fold and 12-fold respectively. The Ch5 (at 1 mgmL-1) was also used to solubilise the novel anticancer agent Bisnaphthalimidopropyl diaminooctane (BNIPDaoct) which was otherwise insoluble achieving a solubilisation of 0.3 mgmL-1. The sizes of the optimal formulations differed greatly for both modified polymers. This was possibly due to the varying architectures of both the drug and the modified polymers and their ability to expand the hydrophobic core and shield the drugs from the hostile aqueous environment. The in vitro drug release profiles, showed controlled release of the hydrophobic drugs from the core of the nano aggregates (Ch5 and Dansyl10), the time span for 100% of the drugs to be released ranged from 48- 96 h. Biological characterisation of the polymers found that most of the polymers showed negligible haemolytic activity over the concentrations tested (0.05 “ 1 mgmL-1), the IC50 values for the cytotoxicity assay ranged from 0.01740 - 0.05585 mgmL-1 on Caco-2 cells (Fmoc5 to QCh5 respectively). The quaternized polymers showed a slightly better safety profile than their unquaternized counterparts, despite exhibiting low drug solubilisation capacities. The optimal formulations of Ch5 and Dansyl10 loaded with etoposide and BNIPDaoct were tested for their cytotoxicity in vitro on Caco-2 and HEK293 cells. All formulations were capable of lowering the IC50 values when compared with the free anticancer drugs, thus increasing their therapeutic effect. The Ch5 decreased the solubility of etoposide 2.2-fold and BNIPDaoct 1.3-fold on Caco-2 cells, with Dansyl10 achieving a 14 -fold and 16“fold reduction respectively. In vivo oral administration of Ch5 and Dansyl10, griseofulvin formulations demonstrated significantly enhanced the absorption of griseofulvin absorption in rats compared with griseofulvin in water (8.89-fold and 5.20-fold increase respectively on total concentration of griseofulvin solubilised over 24 h study). A formulation of Ch5, BNIPDaoct was also shown to significantly decrease the tumour growth when treated on tumour bearing nude mice over a 4 week period. This is the first time these novel PAAs grafted with cholesteryl and dansyl have shown promising potential in hydrophobic drug delivery.

Citation

HOSKINS, C. 2010. The use of novel poly(allylamine) based amphiphilic polymers for drug delivery. Robert Gordon University, PhD thesis.

• Thesis Type: Thesis
• Deposit Date: Aug 16, 2010
• Publicly Available Date: Aug 16, 2010
• Public URL: http://hdl.handle.net/10059/511
• Award Date: Apr 30, 2010