18.6. Novel biodegradable polymers for controlled and targeted pharmaceutical applications

 

Public examination of a doctoral dissertation in the field of pharmaceutical technology

Doctoral candidate: MSc (Pharm) Mika Tuppurainen

Time and venue: 18.6.2011 at 12 noon, Mediteknia Auditorium, Kuopio campus

 

Research in the area of biodegradable polymers has attracted much attention during recent decades. After first establishing their position in reconstructive surgery (e.g. as suture materials) biodegradable polymers have entered a new era in drug delivery. They have become widely used materials in the delivery of anti-cancer drugs, peptides, proteins and hormones. The major advantage of biodegradable polymers is their property to degrade into non-toxic products which are eliminated from the body without the need to physically remove them after application.

 

The objective of the present study was to develop novel biodegradable polymers for controlled and targeted pharmaceutical applications. Thus, novel 2,2-bis(2-oxazoline) linked poly(ε-caprolactone) (PCL-O) and pegylated poly(lactic acid) linked with biotin (biotin-PEG-PLA) were studied. The focus of this study was on the degradation mechanisms and a toxicity evaluation in the case of PCL-O. Biotin-PEG-PLA was prepared in the form of nanoparticles with an anticancer drug and the efficacy of avidin-biotin based cancer targeting was evaluated in vitro.

 

PCL-O polymers were synthesized by using -caprolactone precursors with different molecular weights (Mn: 1500, 3900, 7500 and 12 000 g/mol). Poly(ε-caprolactone) (PCL) and PCL-O films were incubated (22 days) in phosphate buffer solution in the presence of pancreatin (1%, pH 7.5). Surface erosion of the PCL-O films occurred, and the erosion of the PCL-O films increased in parallel with a decrease in the PCL block length. The presence of lipase inhibitors delayed the weight loss of the PCL-O films. The enzymatic degradation of the polymer produced a wide variety of water soluble oligomers which were effectively separated and identified by HPLC-ESI-MSn. According to these results, ester bonds seem to be most sensitive to enzymatic degradation and correspondingly, pancreatic lipase appears to be mainly responsible for the enzymatic erosion of the PCL-O films. In vivo degradation, erosion (weight loss) and toxicity of PCL-O discs were evaluated after their subcutaneous implantation in Wistar rats for 1, 4 and 12 weeks. The in vivo evaluation demonstrated that PCL-O polymers had been biocompatible and were safe, enzyme-sensitive biomaterials.

 

Three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology was evaluated in vitro as a way of enhancing the delivery of paclitaxel. Biotinylated nanoparticles (mean size ~110 nm) were targeted in vitro to brain tumor (glioma) cells (BT4C) by three-step avidin-biotin technology using transferrin as the targeting ligand. The three-step targeting procedure increased significantly the anti-tumoral activity of paclitaxel when compared to the commercial paclitaxel formulation Taxol® and non-targeted nanoparticles.

 

In conclusion, novel biodegradable polymers were developed for biomedical and pharmaceutical applications: PCL-O polymers show enzyme sensitive surface erosion properties and biocompatibility and biotinylated PLA-PEG nanoparticles could enhance cancer therapy.

 

The doctoral dissertation of Master of Science (Pharmacy) Mika Pulkkinen, entitled Modified poly(ε-caprolactone) and poly(lactic acid) polymers for controlled and targeted drug delivery will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Professor Minna Kellomäki of Tampere University of Technology the custos will be Professor Kristiina Järvinen of the University of Eastern Finland.

Photo available for download at http://www.uef.fi/vaitoskuvat  

Contact: Mika Pulkkinen, Farenta, Vantaa, mika.pulkkinen@farenta.fi , tel. 050 5279872

Publishing year: 2011

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